高齡少於4顆卵子是否施行PGS  活產率無差異  (6.6% vs 5.4%).

. 2020 May;37(5):1147-1154.

 doi: 10.1007/s10815-020-01765-y. Epub 2020 Apr 13.

Preimplantation genetic testing for aneuploidy in poor ovarian responders with four or fewer oocytes retrieved

Purpose: To assess whether preimplantation genetic testing for aneuploidies (PGT-A) at the blastocyst stage improves clinical outcomes compared with transfer of embryos without PGT-A in poor ovarian response (POR) patients.

Methods: Retrospective cohort study of IVF cycles from 2016 to 2019 at a single academic fertility center. IVF cycles with POR and four or fewer oocytes retrieved were stratified into PGT-A (n = 241) and non-PGT (n = 112) groups. In PGT-A cycles, trophectoderm biopsy, next-generation sequencing with 24-chromosome screening, and single euploid frozen embryo transfer were performed. In non-PGT cycles, fresh or frozen transfer of untested embryos on day 3 or 5 was performed. Main outcomes included live birth rate and miscarriage rate per retrieval.

Result(s): Patients who underwent PGT-A cycles were significantly less likely to reach embryo transfer compared with those who underwent non-PGT cycles (13.7% vs 70.6%). The live birth rate per retrieval did not differ between the PGT-A and non-PGT groups (6.6% vs 5.4%). Overall, the miscarriage rate was low. The PGT-A group demonstrated a significantly lower miscarriage rate per retrieval (0.4% vs 3.6%) as well as per pregnancy (5.9% vs 40.0%) compared with the non-PGT group. The number needed to treat to avoid one clinical miscarriage was 31 PGT-A cycles.

Conclusion(s): PGT-A did not improve live birth rate per retrieval in POR patients with four or fewer oocytes retrieved. PGT-A was associated with a lower miscarriage rate; however, a fairly large number of PGT-A cycles were needed to prevent one miscarriage.

冷凍&解凍液  混用不同廠牌  並無臨床差異

. 2018 Oct;35(10):1887-1895.

 doi: 10.1007/s10815-018-1276-4. Epub 2018 Aug 3.

Testing the efficacy and efficiency of a single "universal warming protocol" for vitrified human embryos: prospective randomized controlled trial and retrospective longitudinal cohort study

Purpose: To study the efficacy and efficiency of a "universal warming protocol" for vitrified human embryos, based on subsequent steps with 1 and 0.5 M concentration of extracellular cryoprotectant (ECCP).

Method: Two studies on patients undergoing fertility treatments via ICSI: a prospective randomized controlled trial (RCT) and a retrospective cohort study (CS).

Setting: Private assisted reproductive (AR) center. RCT: duration 01/03/2017-01/10/2017; 315 embryos at blastocyst stage obtained from 169 patients. Each patient's embryos were first randomized for vitrification with two different kits: Vitrification Kit (Kitazato, Japan) and Sage Vitrification Kit (Origio, Denmark). The embryos were randomly warmed with either Kitazato (K) or Sage (S) warming kits, specifically: group A (KK), group B (KS), group C (SK), and group D (SS).

Primary outcome measure: survival rate (number of embryos surviving per number of embryos warmed). Secondary: implantation rate (number of embryos implanted per number of embryos transferred). CS: duration 01/01/2013-31/12/2015 embryos from patients' own oocytes; 10/04/2015-31/07/2017 embryos from donors' oocytes. A total of 1055 embryos vitrified at cleavage stage obtained from 631 warming cycles: 847 of these obtained from patients' own oocytes, 208 egg-donation-derived embryos. Each patient's embryos were vitrified and warmed in various combinations of three different vitrification/warming kits: Kitazato (K), Sage (S), or made in-house in our laboratory (H). Vitrification/warming kits from different manufacturers are routinely used in our AR center, and the warming procedures are randomly performed with any available kit on a "first-in-first-out" basis, irrespective of the kit used for vitrification. Group names: KK, KS, SK, SS, SH, HK, HS, HH (embryos from patients' own oocytes); eKK, eKS, eSK, eSS (egg-donation-derived embryos).

Results: Cryo-survival rates were comparable in all study groups. RCT. Group A 99.0% (96/97), group B 98.8% (83/84), group C 98.4% (61/62), and group D 98.6% (71/72). CS. Embryos from patients' own oocytes: KK 96.4% (54/56), KS 100.0% (13/13), SK 98.8% (80/81), SS 97.2% (174/179), SH 97.6% (40/41), HK 95.2% (20/21), HS 99.5% (187/188), and HH 97.4% (261/268). Egg-donation-derived embryos: eKK 100.0% (91/91), eKS 98.4% (60/61), eSK 100.0% (26/26), and eSS 96.7 (29/30). Implantation was generally comparable in all study groups-exceptions were in CS: KS vs. SK (P = 0.049), SS (P = 0.012), HS (P = 0.010), HH (P = 0.025); and SH vs. SS (P = 0.042), HS (P = 0.035).

Conclusion: Worldwide, millions of embryos have been cryopreserved using different vitrification kits; these studies establish that it is possible to combine different kits for vitrification and warming using a universal warming protocol. This can optimize costs, simplify lab routines, and favor embryo exchange between IVF centers. 

凍胚植入FET當天P4濃度低於 5 ng/mL不易懷孕

高於5 ng/mL(>10, >20, 5-10 ng/mL)之間無差異

. 2020 May;37(5):1129-1135.

 doi: 10.1007/s10815-020-01713-w. Epub 2020 Feb 10.

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.

人工授精施行於高齡 (>43y) 懷孕率不佳 PR (1.5%) & live birth (0.3%)

. 2020 Dec;37(12):3103-3107.

 doi: 10.1007/s10815-020-01976-3. Epub 2020 Oct 26.

Is intrauterine insemination a viable treatment option for women over 43 years old? An analysis by ovarian stimulation protocol and sperm source

Purpose: The aim of this study was to determine how female age at the end of the reproductive spectrum effects success of natural cycle intrauterine insemination (IUI) or IUI in combination with ovarian stimulation.

Methods: We performed a retrospective cohort study of women 43 years of age and older at the time of IUI in a single academic fertility center between January 2011 and March 2018. Primary outcomes were both pregnancies and live births per cycle of IUI. Data are presented as percentage or mean ± SD. Fisher exact and chi-squared analyses were performed.

Results: There were 9334 IUI cycles conducted during the study period. Of these cycles, 325 IUIs (3.5%) were for women aged 43 years and over at the time of insemination (43.6 ± 0.8, range 43 to 47 years). Analysis of these 325 IUI cycles revealed 5 biochemical pregnancies (1.5%) and only 1 live birth (0.3%). The pregnancy rate did not differ between IUIs using donor sperm (N = 1/49, 2.0%) compared to IUIs with partner sperm (N = 4/276, 1.4%). The pregnancy rate did not differ between IUIs with gonadotropins (N = 2/211, 0.9%), clomiphene or letrozole (N = 2/78, 2.6%), or natural cycle (N = 1/36, 2.8%).

Conclusions: The use of intrauterine inseminations in women 43 years of age and older is an ineffective treatment strategy. This is irrespective of the use of ovarian stimulation or donor sperm. Costly gonadotropin injections did not increase the chance of pregnancy nor did oral medication when compared to natural cycle IUIs.

使用clomidmm排卵藥人工受孕失敗，若過程子宮內膜過薄(<7mm)，應於下次人工受孕改用排卵針可提高懷孕率

Gonadotrophins or clomiphene citrate in women with normogonadotropic anovulation and CC failure: does the endometrium matter? 

E M Bordewijk, N S Weiss, M J Nahuis, J Kwee, A F Lambeek, G A van Unnik, F P J Vrouenraets, B J Cohlen, T A M van de Laar-van Asseldonk, C B Lambalk ... Show more

Author Notes

Human Reproduction, Volume 35, Issue 6, June 2020, Pages 1319–1324, 

Abstract

STUDY QUESTION

Is endometrial thickness (EMT) a biomarker to select between women who should switch to gonadotropins and those who could continue clomiphene citrate (CC) after six failed ovulatory cycles?

SUMMARY ANSWER

Using a cut-off of 7 mm for EMT, we can distinguish between women who are better off switching to gonadotropins and those who could continue CC after six earlier failed ovulatory CC cycles.

WHAT IS ALREADY KNOWN

For women with normogonadotropic anovulation, CC has been a long-standing first-line treatment in conjunction with intercourse or intrauterine insemination (IUI). We recently showed that a switch to gonadotropins increases the chance of live birth by 11% in these women over continued treatment with CC after six failed ovulatory cycles, at a cost of €15 258 per additional live birth. It is unclear whether EMT can be used to identify women who can continue on CC with similar live birth rates without the extra costs of gonadotropins.

STUDY DESIGN, SIZE, DURATION

Between 8 December 2008 and 16 December 2015, 666 women with CC failure were randomly assigned to receive an additional six cycles with a change to gonadotropins (n = 331) or an additional six cycles continuing with CC (n = 335), both in conjunction with intercourse or IUI. The primary outcome was conception leading to live birth within 8 months after randomisation. EMT was measured mid-cycle before randomisation during their sixth ovulatory CC cycle. The EMT was available in 380 women, of whom 190 were allocated to gonadotropins and 190 were allocated to CC.

PARTICIPANTS/MATERIALS, SETTING, METHODS

EMT was determined in the sixth CC cycle prior to randomisation. We tested for interaction of EMT with the treatment effect using logistic regression. We performed a spline analysis to evaluate the association of EMT with chance to pregnancy leading to a live birth in the next cycles and to determine the best cut-off point. On the basis of the resulting cut-off point, we calculated the relative risk and 95% CI of live birth for gonadotropins versus CC at EMT values below and above this cut-off point. Finally, we calculated incremental cost-effectiveness ratios (ICER).

MAIN RESULTS AND THE ROLE OF CHANCE

Mid-cycle EMT in the sixth cycle interacted with treatment effect (P < 0.01). Spline analyses showed a cut-off point of 7 mm. There were 162 women (45%) who had an EMT ≤ 7 mm in the sixth ovulatory cycle and 218 women (55%) who had an EMT > 7 mm. Among the women with EMT ≤ 7 mm, gonadotropins resulted in a live birth in 44 of 79 women (56%), while CC resulted in a live birth in 28 of 83 women (34%) (RR 1.57, 95% CI 1.13–2.19). Per additional live birth with gonadotropins, the ICER was €9709 (95% CI: €5117 to €25 302). Among the women with EMT > 7 mm, gonadotropins resulted in a live birth in 53 of 111 women (48%) while CC resulted in a live birth in 52 of 107 women (49%) (RR 0.98, 95% CI 0.75–1.29).

誘導排卵過程之腦下垂體抑制劑 (GnRH antagonist, depot GnRHa , long GnRHa) )並懷孕率無明顯差異

The depot GnRH agonist protocol improves the live birth rate per fresh embryo transfer cycle, but not the cumulative live birth rate in normal responders: a randomized controlled trial and molecular mechanism study

Bei Xu, Dirk Geerts, Shiqiao Hu, Jing Yue, Zhou Li, Guijin Zhu, Lei Jin

Human Reproduction, Volume 35, Issue 6, June 2020, Pages 1306–1318,  

STUDY QUESTION

Do cumulative live birth rates (CLBRs) after one complete ART cycle differ between the three commonly used controlled ovarian stimulation (COS) protocols (GnRH antagonist, depot GnRHa (GnRH agonist) and long GnRHa) in normal responders undergoing IVF/ICSI?

SUMMARY ANSWER

There were similar CLBRs between the GnRH antagonist, depot GnRHa and long GnRHa protocols.

WHAT IS KNOWN ALREADY

There is no consensus on which COS protocol is the most optimal in women with normal ovarian response. The CLBR provides the final success rate after one complete ART cycle, including the fresh and all subsequent frozen–thawed embryo transfer (ET) cycles. We suggest that the CLBR measure would allow for better comparisons between the different treatment protocols.

STUDY DESIGN, SIZE, DURATION

A prospective controlled, randomized, open label trial was performed between May 2016 and May 2017. A total of 819 patients were allocated to the GnRH antagonist, depot GnRHa or long GnRHa protocol in a 1:1:1 ratio. The minimum follow-up time from the first IVF cycle was 2 years. To further investigate the potential effect of COS with the GnRH antagonist, depot GnRHa or long GnRHa protocol on endometrial receptivity, the expression of homeobox A10 (HOXA10), myeloid ecotropic viral integration site 1 (MEIS1) and leukemia inhibitory factor (LIF) endometrial receptivity markers was evaluated in endometrial tissue from patients treated with the different COS protocols.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Infertile women with normal ovarian response (n = 819) undergoing IVF/ICSI treatment were randomized to the GnRH antagonist, depot GnRHa or long GnRHa protocol. Both IVF and ICSI cycles were included, and the sperm samples used were either fresh or frozen partner ejaculates or frozen donor ejaculates. The primary outcome was the live birth rate (LBR) per fresh ET cycle, and the CLBR after one complete ART cycle, until the birth of a first child (after 28 weeks) or until all frozen embryos were used, whichever occurred first. Pipelle endometrial biopsies from 34 female patients were obtained on Days 7–8 after oocyte retrieval or spontaneous ovulation in natural cycles, respectively, and HOXA10, MEIS1 and LIF mRNA and protein expression levels in the human endometrium was determined by quantitative real-time PCR and western blot, respectively.

MAIN RESULTS AND THE ROLE OF CHANCE

There were no significant differences in CLBRs between the GnRH antagonist, depot GnRHa or long GnRHa protocol (71.4 versus 75.5 versus 72.2%, respectively). However, there was a significantly higher LBR per fresh ET cycle in the depot GnRHa protocol than in the long GnRHa and GnRH antagonist protocols (62.6 versus 52.1% versus 45.6%, P < 0.05). Furthermore, HOXA10, MEIS1 and LIF mRNA and protein expression in endometrium all showed significantly higher in the depot GnRHa protocol than in the long GnRHa and GnRH antagonist protocols (P < 0.05).

人工授精影響成功率主要包括: 活動精蟲總體數量 & 植入過程是否疼痛引發子宮收縮反應

其他因素包括精蟲分離方法& HCG施打時間影響並不明顯

Intrauterine insemination performance characteristics and post-processing total motile sperm count in relation to live birth for couples with unexplained infertility in a randomised, multicentre clinical trial

Karl R Hansen, Jennifer D Peck, R Matthew Coward, Robert A Wild, J C Trussell, Stephen A Krawetz, Michael P Diamond, Richard S Legro, Christos Coutifaris, Ruben Alvero ... Show more

Human Reproduction, Volume 35, Issue 6, June 2020, Pages 1296–1305,  

Abstract

STUDY QUESTION

Are intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related to live birth rate in couples with unexplained infertility?

SUMMARY ANSWER

Patient discomfort with IUI and lower inseminate TMC were associated with a reduced live birth rate, while time from hCG injection to IUI, sperm preparation method and ultrasound guidance for IUI were not associated with live birth success.

WHAT IS ALREADY KNOWN

We previously determined that some baseline characteristics of couples with unexplained infertility, including female age, duration of infertility, history of prior loss and income, were related to live birth rate across a course of ovarian stimulation and IUI treatment. However, the relationship between treatment outcomes and per-cycle characteristics, including ultrasound guidance for IUI, timing of IUI relative to hCG injection, difficult or painful IUI and inseminate TMC, are controversial, and most prior investigations have not evaluated live birth outcome.

STUDY DESIGN, SIZE, DURATION

This was a secondary analyses of 2462 cycles from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. This prospective, randomised, multicentre clinical trial determined live birth rates following IUI after ovarian stimulation with clomiphene citrate, letrozole or gonadotropins in 854 couples with unexplained infertility. It was conducted between 2011 and 2014, and couples could undergo up to four consecutive treatment cycles.

PARTICIPANTS/MATERIALS, SETTING, METHODS

AMIGOS was an NIH-sponsored Reproductive Medicine Network trial conducted at 12 clinical sites. Participants were women with unexplained infertility who were between 18 and 40 years of age. Cluster-weighted generalised estimating equations (GEE), which account for informative clustering of multiple IUI treatment cycles within the same patient, were used to determine associations between IUI performance characteristics, including inseminate TMC, and live birth rate. Efficiency curves were also generated to examine the relationship between inseminate TMC and live birth rate.

MAIN RESULTS AND THE ROLE OF CHANCE

After adjustment for treatment group and baseline factors previously associated with live birth across a course of OS-IUI treatment, patient discomfort during the IUI procedure was associated with a reduction in live birth rate (aRR 0.40 (0.16–0.96)). Time from hCG trigger injection to IUI was not significantly associated with outcome. Higher TMC was associated with greater live birth rate (TMC 15.1–20.0 million (14.8%) compared to ≤5 million (5.5%)) (aRR 2.09 (1.31–3.33)). However, live births did occur with TMC ≤ 1 million (5.1%).

 長期服用Vit D可能可減少子宮肌瘤體積

. 2020 Jan;113(1):205-216.e4.

 doi: 10.1016/j.fertnstert.2019.09.018. Epub 2019 Nov 15.

Long-term vitamin D treatment decreases human uterine leiomyoma size in a xenograft animal model

Objective: To study the effects of short- and long-term vitamin D treatment on uterine leiomyomas in vivo through cell proliferation, extracellular matrix (ECM) degradation, and apoptosis.

Design: Preclinical study of human leiomyoma treatment with vitamin D in an nonhuman animal model.

Setting: Hospital and university laboratories.

Patient(s)/animal(s): Human leiomyomas were collected from patients and implanted in ovariectomized NOD-SCID mice.

Intervention(s): Mice were treated with vitamin D (0.5 μg/kg/d or 1 μg/kg/d) or vehicle for 21 or 60 days.

Main outcome measure(s): Vitamin D effect in xenograft tissue was assessed by monitoring tumor size (18F-FDG positron-emission tomography/computerized tomography and macroscopic examination), cell proliferation (immunohistochemistry and quantitative real-time polymerase chain reaction [qRT-PCR]), ECM (Western blot), transforming growth factor (TGF) β3 (qRT-PCR), and apoptosis (Westrn blot and TUNEL).

Result(s): Short-term treatment with vitamin D did not appear to alter leiomyoma size, based on in vivo monitoring and macroscopic examination. However, long-term high-dose treatment induced a significant reduction in leiomyoma size. Cell proliferation was not decreased in the short term, whereas 1 μg/kg/d vitamin D in the long term significantly reduced proliferation compared with control. Although collagen-I and plasminogen activator inhibitor 1 were not modified by short-term treatment, they were both significantly reduced by long-term high-dose vitamin D. Similarly, long-term high-dose vitamin D significantly reduced TGF-β3 expression. Finally, apoptosis significantly increased with both short- and long-term high-dose vitamin D treatment.

Conclusion(s): Long-term vitamin D acts as an antiproliferative, antifibrotic, and proapoptotic therapy that provides a safe, nonsurgical therapeutic option for reducing uterine leiomyoma size without side-effects.