排卵前子宮內膜低於7mm時   應停止繼續使用排卵藥clomiphene用於誘導排卵

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

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).

相較於傳統TE切片PGT, 使用囊胚培養液偵測胚胎染色體狀況準確率仍不理想, 高達37%無法 DNA amplification偵測染色體狀況

. 2021 Jun;115(6):1461-1470.

 doi: 10.1016/j.fertnstert.2021.01.028. Epub 2021 Mar 19.

Noninvasive preimplantation genetic testing for aneuploidy exhibits high rates of deoxyribonucleic acid amplification failure and poor correlation with results obtained using trophectoderm biopsy

Objective: To validate a commercially available noninvasive preimplantation genetic testing for aneuploidy (niPGT-A) assay by investigating the following: prevalence of deoxyribonucleic acid (DNA) amplification failure with niPGT-A; factors affecting amplification failure with niPGT-A; and frequency of discordant results between niPGT-A and traditional preimplantation genetic testing for aneuploidy.

Design: Prospective cohort study SETTING: Academic-affiliated private practice PATIENT(S): One hundred sixty-six blastocysts and their surrounding culture media from couples undergoing in vitro fertilization between July 2019 and May 2020 were analyzed.

Intervention(s): Blastocyst-stage spent culture media samples underwent niPGT-A using a commercially available kit that used whole-genome amplification with a modified multiple annealing and looping-based amplification cycle protocol followed by next-generation sequencing. Preimplantation genetic testing for aneuploidy of trophectoderm (TE) biopsies was performed using targeted next-generation sequencing.

Main outcome measure(s): The primary outcome was failure to achieve an interpretable result with niPGT-A. Factors affecting DNA amplification were also assessed. Discrepancies between niPGT-A and TE biopsy results were analyzed, and clinical outcomes were evaluated.

Result(s): Deoxyribonucleic acid amplification failures with niPGT-A were observed in 37.3% (62/166) of the samples. With TE biopsy, no embryos exhibited DNA amplification failure. Embryos with a shorter duration of exposure to the culture media and no evidence of whole-chromosome aneuploidy on the TE biopsy displayed high rates of DNA amplification failure with niPGT-A. Of 104 embryos with both niPGT-A and TE biopsy results available, whole-chromosome discordance was noted in 42 cases (40.4%). Three embryos classified as aneuploid based on the niPGT-A result progressed to successful delivery.

Conclusion(s): The rates of DNA amplification failure were high among the niPGT-A samples, virtually precluding the clinical applicability of niPGT-A in its current form.

母親PCO生產之女嬰幼年時期(3m~6y)體重較重

. 2022 Feb;39(2):461-471.

 doi: 10.1007/s10815-021-02378-9. Epub 2022 Jan 20.

Association between maternal polycystic ovary syndrome and early childhood growth: a continuous observation from 3 months to 6 years of age

Purpose: To investigate whether maternal PCOS could impact growth and development in offspring at an early age through continuous observation from age 3 months to 6 years.

Methods: This prospective study was conducted in 198 children born to mothers with PCOS and 227 children born to healthy mothers in Ningbo (Zhejiang Province, China) between October 2012 and July 2015. Measurements of offspring height, weight, head circumference, and teething were examined by trained professionals through age 6 years. Height, weight, and body mass index (BMI) were analysed using repeated measures analysis of variance between the PCOS and control groups.

Results: Offspring born to women with PCOS showed significantly higher BMI at age 12, 18, and 30 months and 5 years (P = 0.040, P = 0.000, P = 0.000, and P = 0.023, respectively). Female offspring born to women with PCOS showed significantly increased body weight at 3, 8, 12, 18, and 30 months, and 3 and 6 years (P = 0.027, P = 0.008, P = 0.010, P = 0.034, P = 0.047, P = 0.040, and P = 0.035, respectively) and significantly higher BMI at 3, 8, 12, 18, and 30 months (P = 0.009, P = 0.016, P = 0.029, P = 0.000, and P = 0.000, respectively). After adjusting for maternal, paternal, and pregnancy confounders, PCOS status presented significant associations with weight at age 3, 8, and 12 months and 3 years (P = 0.005, P = 0.004, P = 0.021, P = 0.035 respectively), and with BMI at age 3 and 8 months (P = 0.011 and P = 0.014) in female offspring.

Conclusions: Maternal PCOS is associated with an increased risk of developing obesity in female offspring.

平均LH surge & 排卵間隔是33小時

The LH surge and ovulation re-visited: a systematic review and meta-analysis and implications for true natural cycle frozen thawed embryo transfer 

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Murat Erden, Sezcan Mumusoglu, Mehtap Polat, Irem Yarali Ozbek, Sandro C Esteves, Peter Humaidan, Hakan Yarali

Human Reproduction Update, dmac012, https://doi.org/10.1093/humupd/dmac012

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08 March 2022

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Abstract

BACKGROUND

Efficient and safe embryo vitrification techniques have contributed to a marked worldwide increase in the use of elective frozen embryo transfer (FET). Pinpointing the day of ovulation, more commonly by documentation of the LH surge and less commonly by ultrasonography, is crucial for timing of FET in a true natural cycle (t-NC) to maximize the reproductive outcome.

OBJECTIVE AND RATIONALE

The definition of the onset of the LH surge should be standardized in t-NC FET cycles; however, a clear definition is lacking in the available literature. The first search question concerns the definition of the onset of the LH surge in a natural cycle. The second search question relates to the duration between the onset of the LH surge and ovulation.

SEARCH METHODS

We searched PubMed, Web of Science and Cochrane Library databases for two search questions from inception until 31 August 2021. ‘Luteinizing hormone’[MeSH] OR ‘LH’ AND ‘surge’ terms were used to identify eligible articles to answer the first question, whereas ‘Luteinizing hormone’[MeSH] OR ‘LH’ AND ‘surge’ OR ‘rise’ AND ‘ovulation’[MeSH] OR ‘follicular rupture’ OR ‘follicular collapse’ were the terms used regarding the second question. The included publications were all written in the English language, conducted in women of reproductive age with regular ovulatory cycles and in whom serial serum or urine LH measurement was performed. For the quality and risk of bias assessment of the included studies, the Strengthening the Reporting of Observational Studies in Epidemiology and modified Newcastle Ottawa Scale were used.

OUTCOMES

A total of 10 and 8 studies were included for search Questions 1 and 2, respectively. Over the years, through different studies and set-ups, testing in either serum or urine, different definitions for the onset of the LH surge have been developed without a consensus. An increase in LH level varying from 1.8- to 6-fold above the baseline LH level was used in seven studies and an increase of at least two or three standard deviations above the mean of the preceding LH measurements was used in two studies. An LH level exceeding the 30% of the amplitude (peak-baseline LH level) of the LH surge was defined as the onset day by one study. A marked inter-personal variation in the time interval between the onset of the LH surge and ovulation was seen, ranging from 22 to 56 h. When meta-analysis was performed, the mean duration in hours between the onset of the LH surge and ovulation was 33.91 (95% CI = 30.79–37.03: six studies, 187 cycles).

 Day5 囊胚 vs Day 6囊胚 染色體正常比率=49.9% vs 35.7%

染色體正常下  day5 vs day6囊胚植入懷孕率類似

. 2022 Feb;39(2):369-377.

 doi: 10.1007/s10815-022-02397-0. Epub 2022 Jan 10.

Comparison of day 5 blastocyst with day 6 blastocyst: Evidence from NGS-based PGT-A results

Purpose: Aneuploidy is one genetic factor leading to the failure of embryo implantation. This study aimed to investigate the relationship between the day of embryo blastulation and the ploidy status of embryo, to aid in selecting embryos with the most likelihood of of being euploid in a noninvasive way.

Methods: This retrospective study recruited women undergoing preimplantation genetic testing (PGT) for aneuploidy (PGT-A) with trophectoderm biopsy from January 2019 to December 2020. The ploidy status of embryos was determined by next-generation sequencing (NGS).

Results: Altogether, 2531 blastocysts from 839 PGT-A cycles were evaluated. The euploid rate of day 5 blastocysts was significantly higher than that of day 6 blastocysts, either from the same ovarian stimulation (OS) cycles (49.9% vs 35.7%, P < 0.001) or from different OS cycles (48.2% vs 27.8%, P < 0.001). This effect of increasing time to embryo blastulation significantly reducing the prevalence of euploidy was not seen in women at age 38 or older. However, after single euploid embryo transfer, the clinical outcomes of day 5 blastocysts were comparable to those of day 6 blastocysts.

Conclusions: In non-PGT cycles, our data support the selection of day 5 blastocysts for transfer over day 6 blastocysts. Further, women with poor ovarian reserve incline to obtain only day 6 blastocysts, and PGT-A is valuable for identifying the ploidy status of embryos, especially for those with advanced age. However, the stage of blastocysts will not affect the clinical outcome after transfer when they are identified as euploid.

血小板濃縮血漿RPR注射目前臨床效果(內膜增厚, 卵巢功能提升, AMH, FSH, 懷孕率)仍不明確，RPR標準施打劑量仍未統一標準

A narrative review of platelet-rich plasma (PRP) in reproductive medicine

Purpose: Platelet-rich plasma (PRP) has become a novel treatment in various aspects of medicine including orthopedics, cardiothoracic surgery, plastic surgery, dermatology, dentistry, and diabetic wound healing. PRP is now starting to become an area of interest in reproductive medicine more specifically focusing on infertility. Poor ovarian reserve, menopause, premature ovarian failure, and thin endometrium have been the main areas of research. The aim of this article is to review the existing literature on the effects of autologous PRP in reproductive medicine providing a summation of the current studies and assessing the need for additional research.

Methods: A literature search is performed using PubMed, MEDLINE, and CINAHL Plus to identify studies focusing on the use of PRP therapy in reproductive medicine. Articles were divided into 3 categories: PRP in thin lining, PRP in poor ovarian reserve, and PRP in recurrent implantation failure.

Results: In women with thin endometrium, the literature shows an increase in endometrial thickness and increase in chemical and clinical pregnancy rates following autologous PRP therapy. In women with poor ovarian reserve, autologous intraovarian PRP therapy increased anti-Mullerian hormone (AMH) levels and decreased follicle-stimulating hormone (FSH), with a trend toward increasing clinical and live birth rates. This trend was also noted in women with recurrent implantation failure.

Conclusions: Limited literature shows promise in increasing endometrial thickness, increasing AMH, and decreasing FSH levels, as well as increasing chemical and clinical pregnancy rates. The lack of standardization of PRP preparation along with the lack of large randomized controlled trials needs to be addressed in future studies. Until definitive large RCTs are available, PRP use should be considered experimental.

 Endometrial receptivity array (ERA)對於IVF-ET懷孕率無明顯提升 (33 vs 35%)

. 2018 Jul;35(7):1301-1305.

 doi: 10.1007/s10815-018-1190-9. Epub 2018 May 8.

Does the endometrial receptivity array really provide personalized embryo transfer?

Purpose: The aim of the present study was to determine the percentage of infertility patients who are diagnosed with a non-receptive endometrium according to the endometrial receptivity array (ERA) test and to examine whether adjusting the embryo transfer day according to the proposed shift in the window of implantation improves the pregnancy rate compared to non-ERA-tested patients.

Methods: A single-center retrospective cohort study, including 53 consecutive good prognosis patients (0-2 previous frozen embryo transfers) admitted to our IVF unit for a mock cycle prior to their frozen day-5 embryo (blastocyst) transfer cycle. The mock cycle included an endometrial biopsy for both the ERA test and histological assessment by the Noyes criteria (study group). The next cycle frozen embryo transfer (FET) in the study group was adjusted according to the ERA results. The control group consisted of patients who underwent FET cycles at our clinic during the same period, without performing the endometrial biopsy and ERA testing.

Results: During the study period, 503 patients (control group) underwent FET cycles without performing the ERA testing and 41 patients had FET following an ERA test. There were no between-group differences in patients' age, number of previous transfers, endometrial thickness, number of transferred embryos, and ongoing pregnancy rates (35.2 vs. 39%, respectively, p = NS). Out of the 53 patients who performed the ERA test before their first or second FET, five endometrial samples (9.4%) were found to be post-receptive, 29 (54.7%) pre-receptive, and only 19 samples (35.8%) were receptive. Women in the study group with pre- or post-receptive endometrium on ERA testing, the appropriate adjustment in timing of FET according to the ERA test resulted in a 33.3% pregnancy rate, which is comparable to the 35.2% background ongoing pregnancy rate of the control group.

Conclusions: Performing the ERA test in a mock cycle prior to a FET does not seem to improve the ongoing pregnancy rate in good prognosis patients. Further large prospective studies are needed to elucidate the role of ERA testing in both good prognosis patients and in patients with recurrent implantation failure.

Endometrial Receptivity Analysis (ERA) 對於IVF-ET成功率是否有明顯幫助仍有爭議

. 2021 Apr 14;2021(2):hoab010.

 doi: 10.1093/hropen/hoab010. eCollection 2021.

Endometrial Receptivity Analysis (ERA) test: an unproven technology

This article addresses the limitations of the endometrial receptivity array (ERA) methodology to increase implantation. Such limitations vary from the assumed inconsistency of the endometrial biopsy, the variable number of genes found to be dysregulated in endometrium samples without the embryonal-induced effect, the failure to account for the simultaneous serum progesterone level, and the expected low percentage of patients who may need this add-on procedure, to the difficulties in synchronising the endometrium with hormone replacements in successive cycles and the inherent perinatal risks associated with routine cryopreservation of embryos. Without a gold standard to compare, the claim that the window of implantation (WOI) might be off by ±12 h only requires a good argument for the advantage it provides to human procreation, knowing that embryos can linger for days before actual embedding starts and that the window is actually a few days. The intra-patient variations in the test need to be addressed. In summary, like all other add-ons, it is doubtful whether the ERA test use can significantly enhance implantation success rates.

 COVID-19疫苗對生育能力影響不大   建議接種疫苗防止病毒感染之嚴重副作用

. 2021 Dec 27;37(1):5-13.

 doi: 10.1093/humrep/deab238.

Effects of COVID-19 and mRNA vaccines on human fertility

The coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has precipitated a global health crisis of unprecedented proportions. Because of its severe impact, multiple COVID-19 vaccines are being rapidly developed, approved and manufactured. Among them, mRNA vaccines are considered as ideal candidates with special advantages to meet this challenge. However, some serious adverse events have been reported after their application, significantly increasing concerns about the safety and efficacy of the vaccines and doubts about the necessity of vaccination. Although several fertility societies have announced that COVID-19 mRNA vaccines are unlikely to affect fertility, there is no denying that the current evidence is very limited, which is one of the reasons for vaccine hesitancy in the population, especially in pregnant women. Herein, we provide an in-depth discussion on the involvement of the male and female reproductive systems during SARS-CoV-2 infection or after vaccination. On one hand, despite the low risk of infection in the male reproductive system or fetus, COVID-19 could pose an enormous threat to human reproductive health. On the other hand, our review indicates that both men and women, especially pregnant women, have no fertility problems or increased adverse pregnancy outcomes after vaccination, and, in particular, the benefits of maternal antibodies transferred through the placenta outweigh any known or potential risks. Thus, in the case of the rapid spread of COVID-19, although further research is still required, especially a larger population-based longitudinal study, it is obviously a wise option to be vaccinated instead of suffering from serious adverse symptoms of virus infection.

 ICSI 可能提高男嬰比例

. 2022 Jan;39(1):211-218.

 doi: 10.1007/s10815-021-02387-8. Epub 2022 Jan 6.

Sex ratio imbalance following blastocyst transfer is associated with ICSI but not with IVF: an analysis of 14,892 single embryo transfer cycles

Purpose: Assisted reproductive technology (ART) has an impact on secondary sex ratio (SSR), which is seemed to be elevated after blastocyst transfer (BT) but decreased following ICSI procedure. We aim to assess whether the higher SSR associated with BT could be influenced by fertilization method used.

Methods: All consecutive IVF/ICSI cycles (fresh and frozen) involving single embryo transfer (SET) resulting in a live birth between 2015 and 2019 were retrospective analyzed. Logistic regression was used to model the effect on the SSR of maternal and specific ART characteristics.

Results: Six thousand nine hundred twenty-two women were included with the crude SSR of 54.8%. The impact of BT on SSR is influenced by the fertilization method used. After adjustment for potential confounders, the SSR in the ICSI BT group was significantly higher when compared to ICSI cleavage-stage embryo SET (aOR 1.24; 95% CI 1.10-1.40, P < 0.001). However, this effect was not detected among SBT with IVF treatment (aOR 1.04; 95% CI 0.97-1.12, P = 0.260). Assessing blastocyst morphological parameters, high trophectoderm quality was significantly associated with elevated SSR (aOR 1.76, 95% CI 1.34-2.31 [A vs. C], and aOR 1.28, 95% CI 1.14-1.44 [B vs. C]). No significant difference was shown in expansion, inner cell mass, or days of blastocyst formation between male and female blastocysts.

Conclusions: The impact of BT on SSR could be influenced by the fertilization method used. The higher SSR was observed after BT with ICSI procedures but not with IVF. Interpretation of the findings is limited by the potential for selection and confounding bias.