取卵前P4上升(>2 ng/ml)並不會影響胚胎之著床率

Late follicular phase progesterone elevation during ovarian stimulation is not associated with decreased implantation of chromosomally screened embryos in thaw cycles

Human Reproduction, Volume 35, Issue 8, August 2020, Pages 1889–1899, https://doi.org/10.1093/humrep/deaa123

Abstract

STUDY QUESTION

What is the impact of a late follicular phase progesterone elevation (LFPE) during controlled ovarian hyperstimulation (COH) on embryonic competence and reproductive potential in thaw cycles of preimplantation genetic testing for aneuploidy (PGT-A) screened embryos?

SUMMARY ANSWER

Our study findings suggest that LFPE, utilizing a progesterone cutoff value of 2.0 ng/ml, is neither associated with impaired embryonic development, increased rate of embryonic aneuploidy, nor compromised implantation and pregnancy outcomes following a euploid frozen embryo transfer (FET) cycle.

WHAT IS KNOWN ALREADY

Premature progesterone elevation during COH has been associated with lower pregnancy rates due to altered endometrial receptivity in fresh IVF cycles. Also, increased levels of progesterone (P) have been suggested to be a marker for ovarian dysfunction, with some evidence to show an association between LFPE and suboptimal embryonic development. However, the effect of LFPE on embryonic competence is still controversial.

STUDY DESIGN, SIZE, DURATION

Retrospective cohort analysis in a single, academic ART center from September 2016 to March 2020. In total, 5244 COH cycles for IVF/PGT-A were analyzed, of those 5141 were included in the analysis. A total of 23 991 blastocysts underwent trophectoderm biopsy and PGT analysis. Additionally, the clinical IVF outcomes of 5806 single euploid FET cycles were evaluated.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Cohorts were separated in two groups: Group 1: oocytes retrieved from cycles with normal P levels during ovulation trigger (P ≤ 2.0 ng/ml); Group 2: oocytes retrieved after cycles in which LFPE was noted (P > 2.0 ng/ml). Extended culture and PGT-A was performed. Secondly, IVF outcomes after a single euploid FET were evaluated for each cohort.

MAIN RESULTS AND THE ROLE OF CHANCE

Four thousand nine hundred and twenty-five cycles in Group 1 were compared with 216 cycles on Group 2. Oocyte maturity rates, fertilization rates and blastulation rates were comparable among groups. A 65.3% (n = 22 654) rate of utilizable blastocysts was found in patients with normal P levels and were comparable to the 62.4% (n = 1337) observed in those with LFPE (P = 0.19). The euploidy rates were 52.8% (n = 11 964) and 53.4% (n = 714), respectively, albeit this difference was not statistically significant (P = 0.81). Our multivariate analysis was fitted with a generalized estimating equation (GEE) and no association was found with LFPE and an increased odds of embryo aneuploidy (adjusted odds ratio 1.04 95% CI 0.86–1.27, P = 0.62). A sub-analysis of subsequent 5806 euploid FET cycles (normal P: n = 5617 cycles and elevated P: n = 189 cycles) showed no differences among groups in patient’s BMI, Anti-Müllerian hormone (AMH), endometrial thickness at FET and number of prior IVF cycles. However, a significant difference was found in patient’s age and oocyte age. The number of good quality embryos transferred, implantation rate, clinical pregnancy rate, ongoing pregnancy rate, multiple pregnancy rate and clinical pregnancy loss rates were comparable among groups. Of the registered live births (normal P group: n = 2198; elevated P group: n = 52), there were no significant differences in gestational age weeks (39.0 ± 1.89 versus 39.24 ± 1.53, P = 0.25) and birth weight (3317 ± 571.9 versus 3 266 ± 455.8 g, P = 0.26) at delivery, respectively.

 注射黃體素可能比口服或塞劑黃體素有更高懷孕著床率

Fertil Steril. 2019 Sep;112(3):491-502.e3. doi: 10.1016/j.fertnstert.2019.04.021. Epub 2019 Jun 11.

Evaluation of progestogen supplementation for luteal phase support in fresh in vitro fertilization cycles

Amal Mohammed 1, Kathryn J Woad 2, George E Mann 3, Jim Craigon 3, Nick Raine-Fenning 4, Robert S Robinson 5

Objective: To evaluate the effectiveness of progestogen supplementation in improving clinical pregnancy rates in women undergoing fresh IVF cycles and to compare different routes, start times, durations, and estrogen coadministration regimen.

Patient(s): Women undergoing fresh IVF cycles who did and did not receive progestogen supplementation.

Intervention(s): Summary odds ratios (ORs) were calculated by binomial logistic regression.

Main outcome measure(s): Clinical pregnancy rates.

Result(s): Eighty-two articles (26,726 women) were included. Clinical pregnancy rates were increased by IM (OR = 4.57), vaginal (OR = 3.34), SC (OR = 3.36), or oral (OR = 2.57) progestogen supplementation versus no treatment. The greatest benefit was observed when progestogens were supplemented IM versus vaginally (OR = 1.37). The optimal time to commence administration was between oocyte retrieval and ET (OR = 1.31), with oocyte retrieval +1 day being most beneficial. Coadministration of estrogen had no benefit (OR = 1.33), whether progestogens were coadministered vaginally or IM. Clinical pregnancy rates were equivalent when progestogen supplementation was ceased after ≤3 weeks or continued for up to 12 weeks (OR = 1.06).

Conclusion(s): This broad-ranging meta-analysis highlights the need to reevaluate current clinical practice. The use of progestogens in fresh IVF cycles is substantially beneficial to clinical pregnancy. Critically, the use of IM progestogens should not be dismissed, as it yielded the greatest clinical pregnancy rates. Pregnancy success was impacted by initiation of therapy, with 1 day after oocyte retrieval being optimal. There is little evidence to support coadministration of estrogen or prolonging progestogen treatment beyond 3 weeks.

 IVM懷孕之寶寶追蹤與一般IVF寶寶無明顯差異

Fertil Steril. 2019 Oct;112(4):691-699. doi: 10.1016/j.fertnstert.2019.05.034. Epub 2019 Jul 29.

Obstetrical, neonatal, and long-term outcomes of children conceived from in vitro matured oocytes

Eun Jeong Yu 1, Tae Ki Yoon 1, Woo Sik Lee 2, Eun A Park 1, Jin Young Heo 1, Ye Kyu Ko 1, Jayeon Kim 3

Abstract

Objective: To investigate the obstetrical, neonatal, and long-term outcomes of in vitro maturation (IVM) compared with conventional in vitro fertilization (IVF) in women with polycystic ovarian syndrome (PCOS).

Patient(s): One hundred eighty-four patients undergoing IVM were compared with 366 patients undergoing conventional IVF. All had PCOS and were matched for patient age, gestational age at birth, and the number of fetuses.

Main outcome measure(s): Obstetrics, neonatal outcomes, and childhood medical problems and development.

Result(s): Women's mean age at oocytes retrieval was 32.6 ± 2.9 years. Children's mean age was 7.5 ± 2.3 years. There were no differences in the frequency of obstetrical and neonatal outcomes between the two groups. No difference was found in birth weights between the two groups. The incidence of congenital anomalies was similar between the groups (4.3% in IVM group vs. 4.1% in IVF group). No significant difference was observed between the two groups in the frequency and duration of hospitalization during childhood. Growth developmental status of both groups was within normal range.

Conclusion(s): In a matched setting between IVM and IVF babies born from women with PCOS, no significant increased risk associated with IVM was been identified after a mean follow-up of 7.5 years.

植入前使用黃體素後造成子宮內膜變薄反應者   胚胎著床率較高

Fertil Steril. 2019 Sep;112(3):503-509.e1. doi: 10.1016/j.fertnstert.2019.05.001. Epub 2019 Jun 24.

Endometrial compaction (decreased thickness) in response to progesterone results in optimal pregnancy outcome in frozen-thawed embryo transfers

Jigal Haas 1, Ramsey Smith 2, Eran Zilberberg 2, Dan Nayot 2, James Meriano 2, Eran Barzilay 3, Robert F Casper 4

Objective: To evaluate whether the change in endometrial thickness between the end of the estrogen phase and the day of embryo transfer has an impact on the pregnancy rate in frozen-thawed embryo transfer (FET) cycles.

Patient(s): Ultrasound images in 274 FET cycles were reviewed. All patients underwent endometrial preparation with the use of hormonal therapy.

Interventions(s): Ultrasound measurements of endometrial thickness at the end of the estrogen phase and the day of embryo transfer.

Main outcome measure(s): The change in endometrial thickness and ongoing pregnancy rate.

Result(s): We calculated the ongoing pregnancy rate in patients whose endometrial thickness decreased (compacted) after starting progesterone by 5%, 10%, 15%, or 20% compared with patients with no change or increased endometrial thickness. The ongoing pregnancy rate was significantly increased at all levels of compaction compared with no compaction. The ongoing pregnancy rate showed a significant increase with each decreasing quartile of change in thickness (increased percentage of compaction) in the progesterone phase compared with the estrogen phase.

Conclusion(s): There is a highly significant inverse correlation between the ongoing pregnancy rate and the change of endometrial thickness between the end of estrogen administration and the day of embryo transfer. 

囊胚 TE cell內 mitochondrial DNA copy number 與囊胚著床率無關

ARTICLE| VOLUME 41, ISSUE 2, P183-190, AUGUST 01, 2020

Mitochondrial DNA content is not predictive of reproductive competence in euploid blastocysts

Published:May 14, 2020DOI:https://doi.org/10.1016/j.rbmo.2020.04.011

Research question

Does mitochondrial DNA (mtDNA) copy number predict the reproductive potential of euploid human blastocysts?

Design

To investigate whether the amount of mtDNA in trophectoderm biopsies correlates with IVF outcome, euploid human blastocysts ( n = 615) used in single embryo transfer were analysed. Furthermore, to determine whether mtDNA content is predictive of reproductive outcome within a given cohort, paired sibling embryos ( n = 78) transferred in two consecutive cycles carried out in the same patient (in which one cycle failed to result in implantation and the other cycle resulted in sustained implantation) were studied. Targeted amplification followed by quantitative real-time polymerase chain reaction for two mitochondrial loci (16S and MajArc) relative to a multicopy nuclear genome locus (AluYb8) were carried out to determine relative mtDNA copy number.

Results

Sustained implantation was not associated with relative mtDNA copy number ( P = 0.78), and there was no threshold value above or below which ongoing implantation was more or less likely. No correlation was observed between maternal age and relative mtDNA copy number ( P = 0.39). In addition, no association was found between relative mtDNA levels of sibling embryos and ensuing implantation and delivery rates in women who underwent a successful single embryo transfer before or after a failed transfer using embryos derived from the same cohort of oocytes ( P = 0.70).

Conclusions

In trophectoderm samples, mitochondrial DNA copy number analysis was not found to be predictive of euploid human embryo reproductive competence. These data do not support the use of mitochondrial DNA copy number in clinical decision making when selecting which embryo to transfer.

使用GnRHa 破卵  2天後只使用一次1500iu HCG  可取代傳統傳統植入後黃體素補充

Comparison of clinical outcomes after two different oocytes triggering protocols and associated luteal phase support: GnRH agonist triggering followed by 1500 IU of hCG 48 hours post oocyte retrieval, and hCG triggering followed by vaginal progesterone

Shahar Kol

Linoy Segal

Published:July 30, 2020DOI:https://doi.org/10.1016/j.rbmo.2020.07.024

GnRH agonist trigger after GnRH antagonist-based ovarian stimulation protocol for IVF is gaining popularity, because it prevents ovarian hyper-stimulation syndrome, and allows for near physiological LH and FSH surges. Small dose of hCG (1500 IU) on the day of oocyte retrieval, followed by daily progesterone administration, is currently the preferred way to secure adequate luteal support following GnRH agonist trigger. In the current study, we questioned the possibility that a bolus of 1500 IU hCG, given two days after oocyte retrieval, may be sufficient to sustain adequate luteal support without additional progesterone treatment.

Design

This is a non-interventional retrospective cohort study. From April 2017 to August 2018, we included data of 154 consecutive patients who were treated with GnRH agonist trigger followed by day two hCG (1500 IU) support only (study group). Data were compared with 155 consecutive patients who were treated with hCG (6500 IU) trigger followed by conventional progesterone luteal support (control group).

Results

Pregnancy, miscarriage and live birth rates were comparable between the study and control groups. In those patients who became pregnant, mean estradiol level 14 days post oocyte retrieval was 4,719 pmol/l and 2,672 pmol/l in the study and control group, respectively (P<.001), reflecting robust luteal activity in the study group.

Conclusions

We conclude that a bolus of 1500 IU hCG, administered two days after retrieval, can provide excellent luteal support, without the need for further progesterone supplementation.

子宮腺肌症對於IVF有不良影響

施行超長療程結果優於長療程

The impact of adenomyosis on IVF in infertile women with normal ovarian reserve following long or ultra-long GnRH-agonist treatment.

Open AccessPublished:August 01, 2020DOI:https://doi.org/10.1016/j.rbmo.2020.07.027

Does adenomyosis impact IVF independent of decreased ovarian reserve, and what are the characteristics and IVF outcome of ultra-long GnRH-agonist protocol in adenomyosis༟

Design

We carried out an observational cohort study with three groups of patients who were treated with IVF. Group A:362 patients with adenomyosis using the ultra-long GnRH-agonist protocol. Group B:127 patients with adenomyosis using the long GnRH-agonist protocol. Group C: 3,471 patients with tubal infertility using the long GnRH-agonist protocol. All patients were the first IVF treatment cycle and presented with normal ovarian reserve.

Results

(1) Compared with groups B and C, the number of oocytes retrieved in group A decreased, and the Gn(gonadotrophin) dosage and Gn duration in group A were higher, (p<0.05). (2) In long GnRH-agonist treatment, the clinical pregnancy rate(OR 0.492, 95%CI 0.327-0.742, P<0.001),implantation rate(OR 0.527, 95%CI 0.350-0.794, P=0.002) and live birth rate(OR 0.442, 95%CI 0.291-0.673, P<0.001) decreased and abortion rate(OR 3.078, 95%CI 1.593–5.948, P<0.001) increased in adenomyosis patients compared with tubal infertility. (3) For adenomyosis patients, clinical pregnancy rate(OR 1.925, 95%CI 1.137–3.250, P=0.015),implantation rate(OR 1.694, 95%CI 1.006-2.854, P=0.047) and live birth rate(OR 1.704, 95%CI 1.012–2.859, P=0.044) increased in the ultra-long GnRH-agonist treatment compared with long GnRH-agonist treatments

Conclusion

Adenomyosis could have a negative impact on IVF outcomes independent of ovarian reserve following long GnRH-agonist protocol. Adenomyosis patients experiencing ultralong GnRH-agonist protocol could have a better pregnancy outcome than those undergoing long GnRH-agonist protocol.

精子DNA fragmentation 與胚胎發育及著床率無明顯相關

Sperm DNA fragmentation on the day of fertilization is not associated with embryologic or clinical outcomes after IVF/ICSI

. 2020 Jan;37(1):71-76.

 doi: 10.1007/s10815-019-01632-5. Epub 2019 Nov 21.

Purpose: To evaluate if sperm DNA fragmentation (SDF) in the sample used for intracytoplasmic sperm injection (ICSI) impacts outcomes after euploid blastocyst transfer.

Methods: Prospective cohort study of couples undergoing IVF with preimplantation genetic testing for aneuploidy from December 2014-June 2017. Sperm collected on the day of ICSI was analyzed for SDF using the sperm chromatin structure assay (SCSA®). Semen analysis parameters, embryologic outcomes, and clinical outcomes after euploid blastocyst transfer were compared between groups with DNA fragmentation index (DFI) ≤ 15% and DFI > 15% using Mann-Whitney U, t tests, and generalized linear mixed effects models.

Results: Two hundred thirty-four patients were included. One hundred seventy-nine men had DFI ≤ 15% (low DFI group) and 55 men had DFI > 15% group (high DFI group). Total motile sperm and sperm concentration were significantly lower in the group with DFI > 15% vs. DFI ≤ 15%. There was no difference in fertilization (86.3 vs. 84.2%, adjusted OR (95% CI) 0.86 (0.63-1.18)), blastulation (49.5 vs. 48.8%, adjusted OR 1.02 (0.75-1.36)), or euploidy (55.7 vs. 52.1%, adjusted OR 0.96 (0.7-1.31)) between the low and high DFI groups, respectively. Clinical outcomes were similar between low and high DFI groups, including implantation rate (68.8 vs. 79.8%), ongoing pregnancy rate (65.9 vs. 72.6%), and miscarriage rate (4.2 vs. 8.8%), respectively.

Conclusion: Sperm DNA fragmentation on the day of ICSI is not associated with embryologic or clinical outcomes after euploid blastocyst transfer. Increasing levels of SDF are associated with low sperm concentration and total motile sperm count.