Dataset Information

Vaginal progesterone as luteal phase support in natural cycle frozen-thawed embryo transfer (ProFET): protocol for a multicentre, open-label, randomised controlled trial.

ABSTRACT:

Introduction

Vaginal progesterone supplementation is frequently given to patients receiving frozen embryo transfer (FET) in the natural cycle aiming to increase the chance of pregnancy and live birth. To date, only a few studies have investigated if progesterone supplementation is beneficial in these cycles and the level of evidence for progesterone supplementation is very low.

Methods and analysis

The ProFET trial is a multicentre, open-label, randomised controlled trial powered for this investigation, including 1800 women with regular menstrual cycles (24-35 days), aged 18-43 years planned for natural cycle-FET receiving a single blastocyst for transfer. Participants are randomised (1:1:1) to either luteal phase progesterone for 3 weeks, luteal phase progesterone for 7 weeks or no luteal phase progesterone. The participating study centres consist of 12 in vitro fertilisation-clinics in Sweden and 1 in Iceland. The primary outcome is to investigate if luteal phase support (LPS) by vaginal progesterone increases the chance of a live birth per randomised patient in a natural FET cycle compared with no LPS.

Ethics and dissemination

The trial was approved by the Swedish Ethical Review Authority (ID 2020-06774, 2021-02822 and 2022-01502-02) and the Swedish Medical Products Agency (ID nr 5.1-2020-102613). All participants are required to provide written informed consent. The outcome of this study will be disseminated to the public through broadcasts, newspapers and presentations at scientific congresses as well as publications in international scientific journals.

Trial registration number

NCT04725864.

SUBMITTER: Stadelmann C

PROVIDER: S-EPMC9272105 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHuman chorionic gonadotropin (hCG) as one of the first signals secreted by the embryo to the mother may have a direct effect on the endometrium at implantation. The current study was aim to compare the clinical outcomes after frozen-thawed embryo transfer (FET) treated with artificial cycles (AC) between women who were administered intramuscular injection of human chorionic gonadotropin (hCG) as luteal phase support and the routine group.MethodsA randomized controlled trial of 245 women was conducted at the Assisted Reproduction Center, Northwest Women's and Children's Hospital, Xi'an, China from January 2019 to January 2020. Women <40 years of age undergoing their first FET treated with AC were included. Patients were randomly allocated into either: (1) the hCG treatment group, who received intramuscular injection of hCG since the third day of progesterone administration, at a dose of 2000 IU once every two days, for a total of four times, (2) the control group, receiving routine protocol without placebo on these four days. Clinical outcomes of the two groups were analyzed.ResultsThe primary outcome ongoing pregnancy rate in the hCG treatment group versus the control group was 73/124 (58.87%) versus 75/121 (61.98%), respectively (odds ratio [OR], 95% confidence interval [CI]:0.88, 0.53-1.47, P = 0.619). Secondary clinical outcomes including biochemical pregnancy, clinical pregnancy, early pregnancy loss, multiple pregnancy, live birth and preterm birth were also comparable between the two groups through the univariate analysis and multivariable regression analysis (P > 0.05).ConclusionIn women undergoing AC-FET, there was no significant difference in the clinical outcomes between the hCG treatment group and the control group. Clinicians should be cautious about adding IM-hCG as luteal phase support to improve the clinical outcome after AC-FET.Clinical trial registrationhttp://www.chictr.org.cn/showprojen.aspx?proj=32511, identifier ChiCTR1800020342.

Project description:UnlabelledTo compare Crinone vaginal progesterone gel with intramuscularly injected progesterone for luteal phase support in progesterone-supplemented frozen-thawed embryo transfer (FET) cycles, a randomized prospective study of patients qualified for FET was conducted between September 2010 and January 2013 at a hospital in Shanghai, China. From the day of transformation into secretory phase endometrium (day 0), Crinone vaginal gel (90 mg/d) was administered to patients in the Gel Group, while progesterone (40 mg/d) was injected intramuscularly in patients in the Inj Group (n = 750 per group). All patients received oral dydrogesterone (20 mg/d) and estradiol valerate (4–8 mg/d). Day 3 embryos with the highest pre-frozen scores were transferred to patients in the two groups and the clinical outcomes compared. This study comprised 1,500 cycles (750 in each group). Twenty-nine cycles in the Gel Group and 24 in the Inj Group were withdrawn. There were no significant differences between groups in age, endometrial thickness, endometrial preparation time or number of embryos transferred. No significant differences were observed between the Gel Group and Inj Group in the rates of live birth (32.6% vs. 31.7%, P = 0.71), clinical pregnancy (40.1% vs. 40.6%, P = 0.831), implantation (25.8% vs. 25.3%, P = 0.772), abortion (16.3% vs. 18.3%, P = 0.514) or ectopic pregnancy (2.8% vs. 4.4%, P = 0.288). Multivariate logistic regression analysis revealed that the odds ratios (95% confidence intervals) for the rates of live birth, clinical pregnancy, abortion and ectopic pregnancy (Gel Group relative to Inj Group) were 1.036 (0.829–1.295), 0.971 (0.785–1.200), 0.919 (0.595–1.420) and 0.649 (0.261–1.614), respectively. Our study revealed that using Crinone vaginal gel in FET cycles achieved similar pregnancy outcomes to intramuscular progesterone, indicating that vaginal gel is a viable alternative to intramuscular injection.Trial registrationChinese Clinical Trial Registry ChiCTR-TRC-14004565.

Project description:Study questionDoes supplementation with vaginal tablets of progesterone after frozen-thawed embryo transfer in natural cycles improve the live birth rate?Summary answerSupplementation with vaginal tablets of progesterone after frozen-thawed embryo transfer in natural cycles significantly improves the number of live births.What is known alreadyProgesterone supplementation during luteal phase and early pregnancy may improve the number of live births after frozen-thawed embryo transfer. However, due to the limited number of previous studies, being mainly retrospective, evidence is still limited.Study design, size, durationThis is a prospective randomized controlled trial, performed at two university clinics. In total, 500 subjects were randomized with a 1:1 allocation into two groups, during the period February 2013 to March 2018. Randomization was performed after a frozen embryo transfer in a natural cycle by use of opaque sealed envelopes. The primary outcome was live birth rate; secondary outcomes were pregnancy, biochemical pregnancy, clinical pregnancy and miscarriage rate, and if there was a possible association between the serum progesterone concentration on the day of embryo transfer and live birth rate.Participants/materials, setting, methodsWomen, receiving embryo transfer in natural cycles participated in the study. The embryos were frozen on Day 2, 3, 5 or 6. In total, 672 women having regular menstrual cycles were invited to participate in the study; of those, 500 agreed to participate and 488 were finally included in the study. Half of the study subjects received progesterone supplementation with progesterone vaginal tablets, 100 mg twice daily, starting from the day of embryo transfer. The other half of the subjects were not given any treatment. Blood samples for serum progesterone measurements were collected from all subjects on the day of embryo transfer.Main results and the role of chanceThere were no differences in background characteristics between the study groups. In the progesterone supplemented group, 83 of 243 patients (34.2%) had a live birth, compared to 59 of 245 patients (24.1%) in the control group (odds ratio 1.635, 95% CI 1.102-2.428, P = 0.017*). The number of pregnancies was 104 of 243 (42.8%) and 83 of 245 (33.9%), respectively (odds ratio 1.465, 95% CI 1.012-2.108, P = 0.049*) and the number of clinical pregnancies was 91 of 243 (37.4%) and 70 of 245 (28.6%), respectively (odds ratio 1.497, 95% CI 1.024-2.188, P = 0.043*). There were no significant differences in biochemical pregnancy rate or miscarriage rate. There was no correlation between outcome and serum progesterone concentration.Limitations, reasons for cautionThe study was not blinded because placebo tablets were not available. Supplementation started on embryo transfer day, regardless of the age of the embryos, which resulted in a shorter supplementation time for Day 5/6 embryos compared to Day 2/3 embryos.Wider implications of the findingsSupplementation with progesterone in natural cycles improved the number of live births after frozen-thawed embryo transfer and should therefore be considered for introduction in clinical routine.Study funding/competing interest(s)The study was funded by Uppsala University, the Uppsala-Family Planning Foundation, and Ferring Pharmaceuticals AB, Malmö, Sweden. The authors have no personal conflicting interests to declare.Trial registration numberNL4152.Trial registration date5 December 2013.Date of first patient’s enrolment18 February 2013.

Project description:Background: Nowadays, the choice of frozen embryo transfer (FET) regimens is mainly guided by personal convenience. Clinicians prefer the predictability and reliability of artificial cycle (AC) FET and have extended its usage to general in vitro fertilization population. More recent primary studies are beginning to challenge the comparability of AC-FET and suggest reduced clinical pregnancy rate and live birth rate (LBR) compared with those in modified natural cycle (mNC) FET (ovulation triggered by human chorionic gonadotrophin) and stimulated cycle (SC) FET. Objective: To assess the pregnancy outcomes within matched mNC-FET, SC-FET, and AC-FET cycles by using propensity score matching (PSM) in a larger cohort. Methods: A total of 16,946 women who underwent their first autologous FET cycle between July 2014 and July 2017 were evaluated. PSM, using the nearest neighbor matching, were established to adjust the baseline features within the three protocols in proportion of 1:1 (mNC-FET vs. SC-FET, mNC-FET vs. AC-FET, SC-FET vs. AC-FET). Furthermore, there were 3,567, 2,917, and 3,964 cycles compared between matched mNC-FET and SC-FET, mNC-FET and AC-FET, and SC-FET and AC-FET after the PSM, respectively. Results: LBR was significant lower in the AC-FET group than that in the mNC-FET (40.0 vs. 43.3%) and SC-FET groups (40.9 vs. 46.5%). The adjusted odds ratios (95% CIs) were 1.11 (1.00, 1.24) for mNC/AC (P = 0.044) and 0.84 (0.76, 0.92) for AC/SC (P < 0.001), which indicated that the AC-FET group was associated with lowest LBR. The LBR was comparable between matched mNC-FET and SC-FET after adjusting for endometrial thickness. Moreover, a lower clinical pregnancy rate and a higher risk of early pregnancy loss were discovered in AC-FET cycles compared with those in SC-FET. Conclusion: In view of our data, AC used for scheduling FET was associated with lower LBR compared with SC and modified natural cycle. This interpretation requires future verification from well-designed prospective multicenter randomized clinical trials, although the comparisons in our study were conducted in the homogenous population after the PSM.