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.

 <35歲 胚胎全凍FET可以提高懷孕率

>35歲 胚胎全凍FET沒有提高懷孕率

. 2020 Oct;37(10):2443-2451.

 doi: 10.1007/s10815-020-01934-z. Epub 2020 Sep 2.

A freeze-all strategy does not increase live birth rates in women of advanced reproductive age

Research question: Does a freeze-all strategy improve live birth rates in women of different age groups?

Design: Retrospective cohort study of 1882 first embryo transfer cycles, performed between January 2013 and December 2015. Reproductive outcomes between fresh (FRESH) or frozen (FROZEN) embryo transfers were compared in patients stratified by age: < 35, between 35 and 38, or > 38 years. Student's t test for independent samples and χ2 analyses were used as needed. A multivariable logistic regression analysis was performed adjusting for age, triggering drug, number of retrieved oocytes, number of transferred embryos, and percentage of top-quality embryos.

Main results and the role of chance: Live birth rates (LBR) were significantly higher for FROZEN in the < 35 years group (43.7% vs 24%; p < 0.001). In both the 35-38 and > 38 years groups, LBR for FROZEN vs FRESH were not statistically different (30.9% in the FROZEN group vs 29.3% in the FRESH group, p = 0.70, and 19.8% in the FROZEN group vs 12.7% in the FRESH group, p = 0.07, respectively). The multivariate analysis found a significantly positive effect of performing FROZEN on LBR in the younger group (OR 2.46, 95% CI 1.31-4.62; p = 0.005) but had no impact in women between 35 and 38 years (OR 1.01, 95% CI 0.55-1.83; p = 0.98) or older (OR 0.96, 95% CI 0.43-2.13; p = 0.92).

Conclusions: Performing a freeze-all strategy seems to result in better reproductive outcomes when compared with a fresh ET in women under 35 years, with no significant impact on older women.

Co-Q10有助於IVF懷孕率

. 2020 Oct;37(10):2377-2387.

 doi: 10.1007/s10815-020-01906-3. Epub 2020 Aug 7.

Does coenzyme Q 10 supplementation improve fertility outcomes in women undergoing assisted reproductive technology procedures? A systematic review and meta-analysis of randomized-controlled trials

Objective: Increased oxidative stress has been identified as a pathogenetic mechanism in female infertility. However, the effect of specific antioxidants, such as coenzyme Q10 (CoQ10), on the outcomes after assisted reproductive technologies (ART) has not been clarified. The aim of this study was to systematically review and meta-analyze the best available evidence regarding the effect of CoQ10 supplementation on clinical pregnancy (CPR), live birth (LBR), and miscarriage rates (MR) compared with placebo or no-treatment in women with infertility undergoing ART.

Methods: A comprehensive literature search was conducted in PubMed (MEDLINE), Cochrane, and Scopus, from inception to March 2020. Data were expressed as odds ratio (OR) with 95% confidence intervals (CI). The I2 index was employed for heterogeneity.

Results: Five randomized-controlled trials fulfilled eligibility criteria (449 infertile women; 215 in CoQ10 group and 234 in placebo/no treatment group). Oral supplementation of CoQ10 resulted in an increase of CPR when compared with placebo or no-treatment (28.8% vs. 14.1%, respectively; OR 2.44, 95% CI 1.30-4.59, p = 0.006; I2 32%). This effect remained significant when women with poor ovarian response and polycystic ovarian syndrome were analyzed separately. No difference between groups was observed regarding LBR (OR 1.67, 95% CI 0.66-4.25, p = 0.28; I2 34%) and MR (OR 0.61, 95% CI 0.13-2.81, p = 0.52; I2 0%).

Conclusions: Oral supplementation of CoQ10 may increase CPR when compared with placebo or no-treatment, in women with infertility undergoing ART procedures, without an effect on LBR or MR.

  男性高齡易合併IVF流產

Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis 

Nadia A du Fossé, Marie-Louise P van der Hoorn, Jan M M van Lith, Saskia le Cessie, Eileen E L O Lashley

Human Reproduction Update, Volume 26, Issue 5, September-October 2020, Pages 650–669, https://doi.org/10.1093/humupd/dmaa010

• Abstract 
  BACKGROUND

  Although spontaneous miscarriage is the most common complication of human pregnancy, potential contributing factors are not fully understood. Advanced maternal age has long been recognised as a major risk factor for miscarriage, being strongly related with fetal chromosomal abnormalities. The relation between paternal age and the risk of miscarriage is less evident, yet it is biologically plausible that an increasing number of genetic and epigenetic sperm abnormalities in older males may contribute to miscarriage. Previous meta-analyses showed associations between advanced paternal age and a broad spectrum of perinatal and paediatric outcomes. This is the first systematic review and meta-analysis on paternal age and spontaneous miscarriage.

  OBJECTIVE AND RATIONALE

  The aim of this systematic review and meta-analysis is to evaluate the effect of paternal age on the risk of spontaneous miscarriage.

  SEARCH METHODS

  PubMed, Embase and Cochrane databases were searched to identify relevant studies up to August 2019. The following free text and MeSH terms were used: paternal age, father’s age, male age, husband’s age, spontaneous abortion, spontaneous miscarriage, abortion, miscarriage, pregnancy loss, fetal loss and fetal death. PRISMA guidelines for systematic reviews and meta-analysis were followed. Original research articles in English language addressing the relation between paternal age and spontaneous miscarriage were included. Exclusion criteria were studies that solely focused on pregnancy outcomes following artificial reproductive technology (ART) and studies that did not adjust their effect estimates for at least maternal age. Risk of bias was qualitatively described for three domains: bias due to confounding, information bias and selection bias.

  OUTCOMES

  The search resulted in 975 original articles. Ten studies met the inclusion criteria and were included in the qualitative synthesis. Nine of these studies were included in the quantitative synthesis (meta-analysis). Advanced paternal age was found to be associated with an increased risk of miscarriage. Pooled risk estimates for miscarriage for age categories 30–34, 35–39, 40–44 and ≥45 years of age were 1.04 (95% CI 0.90, 1.21), 1.15 (0.92, 1.43), 1.23 (1.06, 1.43) and 1.43 (1.13, 1.81) respectively (reference category 25–29 years). A second meta-analysis was performed for the subgroup of studies investigating first trimester miscarriage. This showed similar pooled risk estimates for the first three age categories and a slightly higher pooled risk estimate for age category ≥45 years (1.74; 95% CI 1.26, 2.41).