PGT
無法明顯下降胚胎染色體異常之流產
無法明顯下降習慣性流產
---PGT無法明顯提高活產率

Hum Reprod. 2019 Dec 1;34(12):2340-2348. doi: 10.1093/humrep/dez229.

Preimplantation genetic testing for aneuploidy: a comparison of live birth rates in patients with recurrent pregnancy loss due to embryonic aneuploidy or recurrent implantation failure.

Sato T1, Sugiura-Ogasawara M1, Ozawa F1, Yamamoto T2, Kato T3, Kurahashi H3, Kuroda T4, Aoyama N4, Kato K4, Kobayashi R5, Fukuda A5, Utsunomiya T6, Kuwahara A7, Saito H8, Takeshita T9, Irahara M7.

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Abstract

STUDY QUESTION:

Can preimplantation genetic testing for aneuploidy (PGT-A) improve the live birth rate and reduce the miscarriage rate in patients with recurrent pregnancy loss (RPL) caused by an abnormal embryonic karyotype and recurrent implantation failure (RIF)?

SUMMARY ANSWER:

PGT-A could not improve the live births per patient nor reduce the rate of miscarriage, in both groups.

WHAT IS KNOWN ALREADY:

PGT-A use has steadily increased worldwide. However, only a few limited studies have shown that it improves the live birth rate in selected populations in that the prognosis has been good. Such studies have excluded patients with RPL and RIF. In addition, several studies have failed to demonstrate any benefit at all. PGT-A was reported to be without advantage in patients with unexplained RPL whose embryonic karyotype had not been analysed. The efficacy of PGT-A should be examined by focusing on patients whose previous products of conception (POC) have been aneuploid, because the frequencies of abnormal and normal embryonic karyotypes have been reported as 40-50% and 5-25% in patients with RPL, respectively.

STUDY DESIGN, SIZE, DURATION:

A multi-centre, prospective pilot study was conducted from January 2017 to June 2018. A total of 171 patients were recruited for the study: an RPL group, including 41 and 38 patients treated respectively with and without PGT-A, and an RIF group, including 42 and 50 patients treated respectively with and without PGT-A. At least 10 women in each age group (35-36, 37-38, 39-40 or 41-42 years) were selected for PGT-A groups.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

All patients and controls had received IVF-ET for infertility. Patients in the RPL group had had two or more miscarriages, and at least one case of aneuploidy had been ascertained through prior POC testing. No pregnancies had occurred in the RIF group, even after at least three embryo transfers. Trophectoderm biopsy and array comparative genomic hybridisation (aCGH) were used for PGT-A. The live birth rate of PGT-A and non-PGT-A patients was compared after the development of blastocysts from up to two oocyte retrievals and a single blastocyst transfer. The miscarriage rate and the frequency of euploidy, trisomy and monosomy in the blastocysts were noted.

MAIN RESULT AND THE ROLE OF CHANCE:

There were no significant differences in the live birth rates per patient given or not given PGT-A: 26.8 versus 21.1% in the RPL group and 35.7 versus 26.0% in the RIF group, respectively. There were also no differences in the miscarriage rates per clinical pregnancies given or not given PGT-A: 14.3 versus 20.0% in the RPL group and 11.8 versus 0% in the RIF group, respectively. However, PGT-A improved the live birth rate per embryo transfer procedure in both the RPL (52.4 vs 21.6%, adjusted OR 3.89; 95% CI 1.16-13.1) and RIF groups (62.5 vs 31.7%, adjusted OR 3.75; 95% CI 1.28-10.95). Additionally, PGT-A was shown to reduce biochemical pregnancy loss per biochemical pregnancy: 12.5 and 45.0%, adjusted OR 0.14; 95% CI 0.02-0.85 in the RPL group and 10.5 and 40.9%, adjusted OR 0.17; 95% CI 0.03-0.92 in the RIF group. There was no difference in the distribution of genetic abnormalities between RPL and RIF patients, although double trisomy tended to be more frequent in RPL patients.

ICM之組成

可區分為epiblast & primitive endoderm

epiblast日後形成胚胎

 primitive endoderm日後形成胎盤

胚胎切片遠離ICM才可避免傷及epiblast

Dev Cell. 2019 Jul 22;50(2):139-154.e5. doi: 10.1016/j.devcel.2019.05.024. Epub 2019 Jun 13.

Epiblast Formation by TEAD-YAP-Dependent Expression of Pluripotency Factors and Competitive Elimination of Unspecified Cells.

Hashimoto M1, Sasaki H2.

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Abstract

The epiblast is a pluripotent cell population first formed in preimplantation embryos, and its quality is important for proper development. Here, we examined the mechanisms of epiblast formation and found that the Hippo pathway transcription factor TEAD and its coactivator YAP regulate expression of pluripotency factors. After specification of the inner cell mass, YAP accumulates in the nuclei and activates TEAD. TEAD activity is required for strong expression of pluripotency factors and is variable in the forming epiblast. Cells showing low TEAD activity are eliminated from the epiblast through cell competition. Pluripotency factor expression and MYC control cell competition downstream of TEAD activity. Cell competition eliminates unspecified cells and is required for proper organization of the epiblast. These results suggest that induction of pluripotency factors by TEAD activity and elimination of unspecified cells via cell competition ensure the production of an epiblast with naive pluripotency.

Fig. 1. Organization of a preimplantation mouse embryo (late blastocyst).
The pluripotent epiblast cells produce body of embryo. The mechanism, by which all the epiblast cells aquire high quality, has been unknown.

傳統胚胎冷凍或植入選擇Day3  Day 5
本篇指出凍胚解凍亦可選擇Day 4桑葚體冷凍解凍植入 結果比Day 3 8-16cell更佳

J Assist Reprod Genet. 2020 Feb 19. doi: 10.1007/s10815-020-01708-7. [Epub ahead of print]

Morula transfer achieves better clinical outcomes than post-thawed cleavage embryos after overnight culture in frozen embryo transfer (FET) cycles.

PURPOSE:

This study aimed to investigate the clinical outcomes of morula stage transfer derived from post-thawed cleavage embryos undergoing overnight culture in frozen embryo transfer (FET) cycles.

METHODS:

We performed a retrospective study that included 392 FET cycles with 784 thawed embryos undergoing overnight culture between January 2014 and December 2018. Embryos were divided into three groups in terms of their status: 8-16 cells without morula (group I), one morula (group II), and two morulae (group III). The clinical outcomes of these cycles were then compared between the three groups. Logistic regression analysis was performed to control for confounders.

RESULTS:

Group III was associated with a significantly higher clinical pregnancy rate (odds ratio [OR] 2.35; 95% confidence interval [CI] 1.29-4.27; P = 0.005), implantation rate (OR 3.00; CI 1.75-5.16; P < 0.001), multiple pregnancy rate (OR 4.91; CI 2.11-11.40; P < 0.001), and live birth rate (OR 1.96; CI 1.10-3.49; P = 0.022) than group I. Group II had a higher live birth rate than group I after adjustment (OR 1.70; CI 1.04-2.79; P = 0.035). There was no difference in the rate of premature delivery when compared across the three groups after adjustment.

CONCLUSION:

The transfer of morula stage embryos following the overnight culture of post-thawed cleavage embryos led to an improvement in the clinical outcomes of FET cycles. It is important to reduce the number of morula embryos transferred in order to achieve a singleton pregnancy.

 凍胚植入當天 ，P4濃度對懷孕率無明顯影響  (P4 levels < 10 ng/mL and ≥ 10 ng/mL)＿

J Assist Reprod Genet. 2020 Feb 10. doi: 10.1007/s10815-020-01713-w. [Epub ahead of print]

Do serum progesterone levels on day of embryo transfer influence pregnancy outcomes in artificial frozen-thaw cycles?

PURPOSE:

The purpose of this study is to investigate whether progesterone (P4) levels on the day of frozen-thawed embryo transfer (FET) to a hormonally prepared endometrium correlate with pregnancy outcomes.

METHODS:

This is a large retrospective cohort analysis comprising of N = 2010 FETs. In these cycles, P4 levels on the day of transfer were assessed in relation to pregnancy outcomes. A threshold of 10 ng/mL was used to simulate currently accepted levels for physiological corpus luteal function. Biochemical pregnancy, clinical pregnancy, and live birth rates were compared between those with P4 levels above and below this threshold. Analyses using transfer day P4 thresholds of 5 ng/mL and 20 ng/mL were then completed to see if these could create further prognostic power.

RESULTS:

When comparing FET outcomes in relation to P4 levels < 10 ng/mL and ≥ 10 ng/mL, we observed no differences in biochemical pregnancy rates (39.53% vs. 40.98%, p = 0.52), clinical pregnancy rates (20.82 vs. 22.78, p = 0.30), and live birth rates (14.25 vs. 16.21 p = 0.23). In patients whose P4 met the threshold of 20 ng/mL, there was similarly no statistically significant improvement in pregnancy outcomes. While there was no difference for biochemical or clinical pregnancy rates, a statistically significant improvement in live birth rates was observed for those with a transfer day P4 level ≥ 5 ng/mL.

CONCLUSIONS:

We demonstrated that P4 levels at or above 10 ng/mL on the day of FET do not confer a statistically significant improvement in pregnancy outcomes. P4 below 5 ng/mg was associated with lower live birth rates suggesting that there is a threshold below which it is difficult to salvage FET cycles.

IVF-ET黃體素使用

progesterone vaginal pessaries 400 mg bid vs. progesterone 8% vaginal gel (90 mg od) 

臨床懷孕率並無差異 (38.1 vs 40.4%)

Hum Reprod. 2020 Feb 19. pii: dez261. doi: 10.1093/humrep/dez261. [Epub ahead of print]

Efficacy, safety and tolerability of progesterone vaginal pessaries versus progesterone vaginal gel for luteal phase support after in vitro fertilisation: a randomised controlled trial.

Saunders H1, Khan C2, D'Hooghe T3,4,5, Magnúsdóttir TB6, Klingmann I7, Hrafnsdóttir S6; vaginal progesterone luteal phase support post IVF study group.

Author information

Abstract

STUDY QUESTION:

Are progesterone vaginal pessaries 400 mg twice a day (bid) non-inferior to progesterone vaginal gel (90 mg) once a day (od) in the primary endpoint of clinical pregnancy rate after 38 days of luteal phase support in women undergoing in vitro fertilisation (IVF)?

SUMMARY ANSWER:

Non-inferiority of progesterone vaginal pessaries 400 mg bid to progesterone 8% vaginal gel (90 mg od) was shown for clinical pregnancy rate after 38 days of luteal phase support.

WHAT IS KNOWN ALREADY:

To maximise successful embryo transfer after IVF, additionally administered progesterone is used for proper endometrium transformation in the luteal phase. Vaginally administered progesterone results in adequate secretory transformation of the endometrium.

STUDY DESIGN, SIZE, DURATION:

This multicentre, multinational, open, randomised, two-parallel group, non-inferiority Phase 3 clinical trial was carried out at 17 study sites in five European countries (Belgium, Bulgaria, Czech Republic, Hungary and Serbia) between October 2013 and August 2014. An interactive web response system (IWRS) was implemented for treatment allocation at the sites. Power analysis, based on the assumptions of a non-inferiority margin of -9%, a significance level of α 2.5% (one-sided), power 90%, at a reference pregnancy rate for the progesterone vaginal gel group of 30%, as well as applying a dropout rate of 10%, yielded a total number of 766 patients to be randomised.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Women aged between 18 and 40 years with a clinical indication for IVF/intracytoplasmic sperm injection (ICSI) and embryo transfer were eligible to participate. The clinical pregnancy rate was assessed by fetal heart movement measured by transvaginal ultrasound at day 38 (D38) (primary endpoint) and D70. Also assessed were biochemical pregnancy rate (assessed by serum β-hCG ≥25 IU/L), clinical implantation rates at D38, patient evaluation of vaginal bleeding and discharge (assessed by diary) and adverse event (AE) incidence, severity and relationship to study medication.

MAIN RESULTS AND THE ROLE OF CHANCE:

A total of 769 female patients were randomised to progesterone 400 mg vaginal pessaries bid (n = 385, 50.1%) or progesterone 90 mg vaginal gel od (n = 384, 49.9%). Patients receiving progesterone vaginal pessaries and progesterone vaginal gel were comparable in demographics, baseline characteristics and number of retrieved oocytes. In the full analysis set (FAS; n = 369 progesterone vaginal pessaries and n = 368 progesterone vaginal gel), clinical pregnancy rates on D38 were 38.3% for progesterone vaginal pessaries and 39.9% for progesterone vaginal gel. In the per protocol analysis set (PP; n = 357 progesterone vaginal pessaries and n = 356 progesterone vaginal gel), clinical pregnancy rates on D38 were 38.1% for progesterone vaginal pessaries and 40.4% for progesterone vaginal gel. For the differences in pregnancy rates between the progesterone vaginal pessaries group and the progesterone vaginal gel, the lower limit of the 97.5% CI was -8.6 and -9.5% for the FAS and PP datasets, respectively. The original prespecified non-inferiority margin of -9% was thus met in the FAS dataset but was marginally below this in the PP dataset. However, the pregnancy rate of the comparator was higher than the anticipated rate of 30%, and a predetermined logistic regression model including treatment group, country and age group effects without interaction terms showed non-inferiority of progesterone vaginal pessaries to progesterone vaginal gel for both the FAS and PP populations, in that the lower limits of the 95% CIs were above 0.7 for both analyses. As a result of this, the relevant authorities accepted to widen the acceptable non-inferiority margin to -10%, and as such both the FAS and PP populations succeeded in showing non-inferiority. Biochemical pregnancy and clinical implantation rates were comparable for both treatments. Both treatment groups showed similar high compliance throughout the study, and the safety profiles were also comparable between the groups. Drug-related AEs occurred with frequencies of 15.1% with progesterone vaginal pessaries and 14.4% with progesterone vaginal gel.