Oral emergency contraception with levonorgestrel plus piroxicam: a randomised double-blind placebo-controlled trial.

BACKGROUND: Levonorgestrel, a standard drug for emergency contraception (EC), is not effective if administered post-ovulation. A cyclo-oxygenase inhibitor could contribute synergistic effects. We investigated whether a single 40 mg oral dose of piroxicam as co-treatment with levonorgestrel improved emergency contraceptive efficacy. METHODS: This was a randomised double-blind placebo-controlled trial carried out in a major community sexual and reproductive health service in Hong Kong. Women who required levonorgestrel EC within 72 h of unprotected sexual intercourse were recruited and block-randomised in a 1:1 ratio to receive a single supervised dose of levonorgestrel 1·5 mg plus either piroxicam 40 mg or placebo orally. Group assignment was concealed in opaque envelopes and masked to the women, clinicians, and investigators. At follow-up 1-2 weeks after the next expected period, the pregnancy status was noted by history or pregnancy test. The primary efficacy outcome was the proportion of pregnancies prevented out of those expected based on an established model. All women randomised to receive the study drug and who completed the follow-up were analysed. The trial was registered with ClinicalTrials.gov, NCT03614494. FINDINGS: 860 women (430 in each group) were recruited between Aug 20, 2018, and Aug 30, 2022. One (0·2%) of 418 efficacy-eligible women in the piroxicam group were pregnant, compared with seven (1·7%) of 418 in the placebo group (odds ratio 0·20 [95% CI 0·02-0·91]; p=0·036). Levonorgestrel plus piroxicam prevented 94·7% of expected pregnancies compared with 63·4% for levonorgestrel plus placebo. We noted no significant difference between the two groups in the proportion of women with advancement or delay of their next period, or in the adverse event profile. INTERPRETATION: Oral piroxicam 40 mg co-administered with levonorgestrel improved efficacy of EC in our study. Piroxicam co-administration could be considered clinically where levonorgestrel EC is the option of choice. FUNDING: None.

Endometrial stromal cells from women with repeated implantation failure display impaired invasion towards trophoblastic spheroids.

In brief: Implantation failure can occur even after the transfer of good-quality embryos. This study showed that the migration of human endometrial stromal cells towards embryonic trophoblasts is higher in women with live births in the first in vitro fertilization cycle than those with repeated implantation failure, suggesting that the chemotactic response of stroma cells is associated with successful pregnancy. Abstract: The success rate of in vitro fertilization (IVF) remains limited in some women despite transfers of good-quality embryos in repeated attempts. There is no reliable tool for assessing endometrial receptivity. This study aimed to assess the interaction between decidualized human primary endometrial stromal cells (1°-EnSC) and human embryonic stem cell-derived trophoblastic spheroids (BAP-EB) and to compare the invasion ability of decidualized 1°-EnSC towards BAP-EB between women attaining live birth in the first IVF cycle and those with repeated implantation failure (RIF). The invasion of the decidualized human endometrial cell line (T-HESC) and 1°-EnSC towards BAP-EB was studied. Real-time quantitative PCR and immunocytochemistry were employed to determine the expression of decidualization markers at mRNA and protein levels, respectively. Trophoblast-like BAP-EB-96h, instead of early trophectoderm (TE)-like BAP-EB-48h, facilitated the invasion ability of decidualized T-HESC and decidualized 1°-EnSC. Human chorionic gonadotropin at supra-physiological levels promoted the invasiveness of decidualized 1°-EnSC. The extent of BAP-EB-96h-induced invasion was significantly stronger in decidualized 1°-EnSC from women who had a live birth in the first IVF cycle when compared to those with RIF. While no difference was found in the expression of decidualization markers, PRL and IGFBP1 among two groups of women, significantly lower HLA-B was detected in the non-decidualized and decidualized 1°-EnSC from women with RIF. Collectively, the findings suggested that the invasion of decidualized 1°-EnSC towards trophoblast-like BAP-EB-96h was higher in women who had a live birth in the first IVF cycle than those with RIF.

Advanced glycation end-products and its soluble receptor are not independent predictors of incident dysglycaemia or metabolic syndrome in women with polycystic ovary syndrome: a prospective observational study.

BACKGROUND: To evaluate the association of serum advanced glycation end-products (AGEs) and its soluble receptor of AGE (sRAGE) levels with dysglycaemia and metabolic syndrome in women with polycystic ovary syndrome (PCOS). METHODS: This was an analysis of a cohort of women with PCOS who were prospectively recruited for a longitudinal observational study on their endocrine and metabolic profile between January 2010 and December 2013. The association of serum AGEs and sRAGE levels with dysglycaemia and metabolic syndrome at the second-year visit (the index visit) and the sixth-year visit (the outcome visit) were determined. Comparisons of continuous variables between groups were made using the Mann-Whitney U-test. Spearman test was used for correlation analysis. Multivariate binary logistic regression analysis was employed to identify the factors independently associated with the outcome events. RESULTS: A total of 329 women were analysed at the index visit. Significantly lower serum levels of sRAGE (both p < 0.001), but no significant difference in AGEs, were observed in those with dysglycaemia or metabolic syndrome. At the outcome visit, those with incident metabolic syndrome had a significantly lower initial serum sRAGE levels (p = 0.008). The association of serum sRAGE with dysglycaemia and metabolic syndrome at the index visit was no longer significant in multivariate logistic regression after controlling for body mass index, free androgen index and homeostatic model assessment for insulin resistance (HOMA-IR). sRAGE was also not significantly associated with incident metabolic syndrome at the outcome visit on multivariate logistic regression. CONCLUSIONS: Serum sRAGE levels are significantly lower in women with PCOS who have dysglycaemia or metabolic syndrome, and in those developing incident metabolic syndrome in four years. However, it does not have a significant independent association with these outcome measures after adjusting for body mass index, free androgen index and HOMA-IR.

Longitudinal study on sexual function and quality of life in infertile couples undergoing intrauterine insemination.

BACKGROUND: Cross-sectional studies have shown that sexual dysfunction and poor quality of life were prevalent among couples undergoing assisted reproduction at specific time points, but nothing is known about how these outcomes change over the course of their intrauterine insemination (IUI) journey. AIM: We investigated the longitudinal changes in sexual function and quality of life of infertile couples undergoing IUI. METHODS: Sixty-six infertile couples completed an anonymous questionnaire at 3 time points: after IUI counseling (T1), 1 day before IUI (T2), and 2 weeks after IUI (T3). The questionnaire consisted of demographic data, Female Sexual Function Index (FSFI) or International Index of Erectile Function-5, and Fertility Quality of Life (FertiQoL). OUTCOMES: Descriptive statistics, significance testing with the Friedman test, and post hoc analysis with the Wilcoxon signed rank test were used to compare changes in sexual function and quality of life at different time points. RESULTS: Overall, 18 (26.1%), 16 (23.2%), and 12 (17.4%) women and 29 (42.0%), 37 (53.6%), and 31 (44.9%) men were at risk for sexual dysfunction at T1, T2, and T3, respectively. There were significant differences in mean FSFI scores in arousal (3.87, 4.06, 4.10) and orgasm (4.15, 4.24, 4.39) domains at T1, T2, and T3. After post hoc analysis, only the increase in mean orgasm FSFI scores between T1 and T3 was statistically significant. Men's FertiQoL scores remained high during IUI (74.33-75.63 out of 100). Men also scored significantly higher than women on all FertiQoL domains except environment at the 3 time points. Post hoc analysis showed significant improvement in women's FertiQoL domain scores between T1 and T2: mind-body, environment, treatment, and total. Women's FertiQoL score at T2 for the treatment domain was also significantly higher than that at T3. CLINICAL IMPLICATIONS: Men should not be neglected during IUI as their erectile function got worse in the process, with half of the men being affected. Although women's quality of life showed some improvement during IUI, most of their scores were lower than men's. STRENGTHS AND LIMITATIONS: The use of psychometrically validated questionnaires and a longitudinal approach are the major strengths; a small sample size and the lack of a dyadic approach are the major limitations. CONCLUSION: During IUI, women's sexual performance and quality of life improved. The proportion of men having erectile problems was high for this age group, but men's FertiQoL scores remained good and were better than their partners' throughout IUI.

Non-Coding RNAs as Biomarkers for Embryo Quality and Pregnancy Outcomes: A Systematic Review and Meta-Analysis.

Despite advances in in vitro fertilization (IVF), there is still a lack of non-invasive and reliable biomarkers for selecting embryos with the highest developmental and implantation potential. Recently, small non-coding RNAs (sncRNAs) have been identified in biological fluids, and extracellular sncRNAs are explored as diagnostic biomarkers in the prediction of IVF outcomes. To determine the predictive role of sncRNAs in embryo quality and IVF outcomes, a systematic review and meta-analysis was performed. Articles were retrieved from PubMed, EMBASE, and Web of Science from 1990 to 31 July 2022. Eighteen studies that met the selection criteria were analyzed. In total, 22 and 47 different sncRNAs were found to be dysregulated in follicular fluid (FF) and embryo spent culture medium (SCM), respectively. MiR-663b, miR-454 and miR-320a in FF and miR-20a in SCM showed consistent dysregulation in two different studies. The meta-analysis indicated the potential predictive performance of sncRNAs as non-invasive biomarkers, with a pooled area under curve (AUC) value of 0.81 (95% CI 0.78, 0.844), a sensitivity of 0.79 (95% CI 0.72, 0.85), a specificity of 0.67 (95% CI 0.52, 0.79) and a diagnostic odds ratio (DOR) of 8 (95% CI 5, 12). Significant heterogeneity was identified among studies in sensitivity (I2 = 46.11%) and specificity (I2 = 89.73%). This study demonstrates that sncRNAs may distinguish embryos with higher developmental and implantation potentials. They can be promising non-invasive biomarkers for embryo selection in ART. However, the significant heterogeneity among studies highlights the demand for prospective multicenter studies with optimized methods and adequate sample sizes in the future.

The impact of the embryo banking on the cumulative live birth rate in women with poor ovarian response according to the Bologna criteria.

Purpose: To evaluate the impact of embryo banking on the cumulative live birth rate (CLBR) and the time to live birth (TTLB) in poor ovarian responders (POR) according to the Bologna criteria. Methods: A total of 276 infertile women undergoing IVF with POR were included in this retrospective study. They were divided into two groups with (n = 121) or without (n = 155) embryo banking at the discretion of the attending physicians. A total of 656 and 405 stimulation cycles were started in the two groups respectively during the 24 month follow-up. Results: The biochemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth rate per transfer were comparable between two groups (p > 0.05). The CLBR was significantly lower in the banking group than in the non-banking group (31.4% (38/121) and 43.2% (67/151), p < 0.05). TTLB was significantly longer in the banking group (20.5 months vs. 16.0 months, p < 0.001). In the Kaplan-Meier analysis, the cumulative incidence of live birth was significantly lower in the banking group compared with the non-banking group (Log rank test, chi-square = 21.958, p < 0.001). Conclusions: Embryo banking in women undergoing IVF with POR based on the Bologna criteria reduces CLBR and lengthens TTLB when compared with no embryo banking.

High-Throughput In Vitro Screening Identified Nemadipine as a Novel Suppressor of Embryo Implantation.

Current contraceptive methods interfere with folliculogenesis, fertilization, and embryo implantation by physical or hormonal approaches. Although hormonal contraceptive pills are effective in regulating egg formation, they are less effective in preventing embryo implantation. To explore the use of non-hormonal compounds that suppress embryo implantation, we established a high-throughput spheroid-endometrial epithelial cell co-culture assay to screen the Library of Pharmacologically Active Compounds (LOPAC) for compounds that affect trophoblastic spheroid (blastocyst surrogate) attachment onto endometrial epithelial Ishikawa cells. We identified 174 out of 1280 LOPAC that significantly suppressed BeWo spheroid attachment onto endometrial Ishikawa cells. Among the top 20 compounds, we found the one with the lowest cytotoxicity in Ishikawa cells, P11B5, which was later identified as Nemadipine-A. Nemadipine-A at 10 µM also suppressed BeWo spheroid attachment onto endometrial epithelial RL95-2 cells and primary human endometrial epithelial cells (hEECs) isolated from LH +7/8-day endometrial biopsies. Mice at 1.5 days post coitum (dpc) treated with a transcervical injection of 100 µg/kg Nemadipine-A or 500 µg/kg PRI-724 (control, Wnt-inhibitor), but not 10 µg/kg Nemadipine-A, suppressed embryo implantation compared with controls. The transcript expressions of endometrial receptivity markers, integrin αV (ITGAV) and mucin 1 (MUC1), but not ß-catenin (CTNNB1), were significantly decreased at 2.5 dpc in the uterus of treated mice compared with controls. The reduction of embryo implantation by Nemadipine-A was likely mediated through suppressing endometrial receptivity molecules ITGAV and MUC1. Nemadipine-A is a potential novel non-hormonal compound for contraception.

A pathogenic DMC1 frameshift mutation causes nonobstructive azoospermia but not primary ovarian insufficiency in humans.

Nonobstructive azoospermia (NOA) and diminished ovarian reserve (DOR) are two disorders that can lead to infertility in males and females. Genetic factors have been identified to contribute to NOA and DOR. However, the same genetic factor that can cause both NOA and DOR remains largely unknown. To explore the candidate pathogenic gene that causes both NOA and DOR, we conducted whole-exome sequencing (WES) in a non-consanguineous family with two daughters with DOR and a son with NOA. We detected one pathogenic frameshift variant (NM_007068:c.28delG, p. Glu10Asnfs*31) following a recessive inheritance mode in a meiosis gene DMC1 (DNA meiotic recombinase 1). Clinical analysis showed reduced antral follicle number in both daughters with DOR, but metaphase II oocytes could be retrieved from one of them. For the son with NOA, no spermatozoa were found after microsurgical testicular sperm extraction. A further homozygous Dmc1 knockout mice study demonstrated total failure of follicle development and spermatogenesis. These results revealed a discrepancy of DMC1 action between mice and humans. In humans, DMC1 is required for spermatogenesis but is dispensable for oogenesis, although the loss of function of this gene may lead to DOR. To our knowledge, this is the first report on the homozygous frameshift mutation as causative for both NOA and DOR and demonstrating that DMC1 is dispensable in human oogenesis.

Knowledge, perception and expectation of management of hepatitis B infection among pregnant hepatitis B carriers in Hong Kong.

Lack of awareness regarding the risk of hepatitis B virus (HBV) infection and the interventions available during pregnancy among the pregnant carriers may influence their willingness and adherence to the management. This study assessed the knowledge, perception and expectation of HBV infection among pregnant HBV carriers in Hong Kong. A prospective multicentre cross-sectional questionnaire study was carried out between August 2019 and April 2021. The general knowledge on HBV, perception and expectation, and interventions to reduce vertical transmission were questioned. Obtaining ≥70% correct answers was defined as having sufficient knowledge. 422 (82.7%) were known carriers. Only 18.4% of women had sufficient overall knowledge. The correct answer rates and percentage of sufficient knowledge were statistically lower for HBV knowledge specific to pregnancy compared with general knowledge (42.5% vs. 58.5%, p < 0.001; 8.8% vs. 30.2%, p < 0.001 respectively). Multiple logistic regression showed higher education and receiving HBV medical care within a year prior to pregnancy were associated with sufficient overall (OR 3.46; 95% CI 2.05-5.83 and OR 2.76; 95% CI 1.62-4.7, p < 0.001), and general knowledge (OR 2.86; 95% CI 1.81-4.51 and OR 2.14; 95% CI 1.33-3.44, p < 0.05). 298 (58.4%), 357 (70.0%) and 150 (29.4%) women believed they should receive care by obstetrician, hepatologist or general practitioner respectively. 46.9% did not want to initiate antiviral treatment due to the cost, perceived teratogenicity and maternal side effects. The knowledge of HBV among pregnant carriers in Hong Kong was poor despite the majority of them being aware of their carrier status prior to the pregnancy.

Immediate versus delayed frozen embryo transfer in patients following a stimulated IVF cycle: a randomised controlled trial.

STUDY QUESTION: Is there any difference in the ongoing pregnancy rate after immediate versus delayed frozen embryo transfer (FET) following a stimulated IVF cycle? SUMMARY ANSWER: Immediate FET following a stimulated IVF cycle produced significantly higher ongoing pregnancy and live birth rate than did delayed FET. WHAT IS KNOWN ALREADY: Embryo cryopreservation is an increasingly important part of IVF, but there is still no good evidence to advise when to perform FET following a stimulated IVF cycle. All published studies are retrospective, and the findings are contradictory. STUDY DESIGN, SIZE, DURATION: This was a randomised controlled non-inferiority trial of 724 infertile women carried out in two fertility centres in China between 9 August 2017 and 5 December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women having their first FET cycle after a stimulated IVF cycle were randomly assigned to either (1) the immediate group in which FET was performed in the first menstrual cycle following the stimulated IVF cycle (n = 362) or (2) the delayed group in which FET was performed in the second or later menstrual cycle following the stimulated IVF cycle (n = 362). All FET cycles were performed in hormone replacement cycles. The randomisation sequence was generated using an online randomisation program with block sizes of four. The primary outcome was the ongoing pregnancy rate, defined as a viable pregnancy beyond 12 weeks of gestation. The non-inferiority margin was -10%. Analysis was performed by both per-protocol and intention-to-treat approaches. MAIN RESULTS AND THE ROLE OF CHANCE: Women in the immediate group were slightly younger than those in the delayed group (30.0 (27.7-33.5) versus 31.0 (28.5-34.2), respectively, P = 0.006), but the proportion of women ≤35 years was comparable between the two groups (308/362, 85.1% in the immediate group versus 303/362, 83.7% in the delayed group). The ongoing pregnancy rate was 49.6% (171/345) in the immediate group and 41.5% (142/342) in the delayed group (odds ratios 0.72, 95% CI 0.53-0.98, P = 0.034). The live birth rate was 47.2% (163/345) in the immediate group and 37.7% (129/342) in the delayed group (odds ratios 0.68, 95% CI 0.50-0.92, P = 0.012). The miscarriage rate was 13.2% (26 of 197 women) in the immediate group and 24.2% (43 of 178 women) in the delayed group (odds ratios 2.10; 95% CI 1.23-3.58, P = 0.006). The multivariable logistic regression, which adjusted for potential confounding factors including maternal age, number of oocytes retrieved, embryo stage at transfer, number of transferred embryos/blastocysts, reasons for FET, ovarian stimulation protocol and trigger type, demonstrated that the ongoing pregnancy rate was still higher in the immediate group. LIMITATIONS, REASON FOR CAUTION: Despite randomisation, the two groups still differed slightly in the age of the women at IVF. The study was powered to consider the ongoing pregnancy rate, but the live birth rate may be of greater clinical interest. Conclusions relating to the observed differences between the treatment groups in terms of live birth rate should, therefore, be made with caution. WIDER IMPLICATIONS OF THE FINDINGS: Immediate FET following a stimulated IVF cycle had a significantly higher ongoing pregnancy and live birth rate than delayed FET. The findings of this study support immediate FET after a stimulated IVF cycle. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used and no competing interests were declared. TRIAL REGISTRATION NUMBER: ClinicalTials.gov identifier: NCT03201783. TRIAL REGISTRATION DATE: 28 June 2017. DATE OF FIRST PATIENT'S ENROLMENT: 9 August 2017.

Use of oral progestogen in women with threatened miscarriage in the first trimester: a randomized double-blind controlled trial.

STUDY QUESTION: Will use of oral progestogen in women with threatened miscarriage in the first trimester reduce the miscarriage rate when compared with placebo? SUMMARY ANSWER: Use of oral progestogen in women with threatened miscarriage in the first trimester did not reduce miscarriage before 20 weeks when compared with placebo. WHAT IS KNOWN ALREADY: Miscarriage is a common complication of pregnancy and occurs in 15-20% of clinically recognized pregnancies. Use of vaginal progestogens is not effective in reducing miscarriage but there is still no good evidence to support use of oral progestogen for the treatment of threatened miscarriage. STUDY DESIGN, SIZE, DURATION: This was a randomized double-blind controlled trial. A total of 406 women presenting with threatened miscarriage in the first trimester were recruited from 30 March 2016 to May 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women attending Early Pregnancy Assessment Clinics because of vaginal bleeding during the first trimester were recruited and randomly assigned to use dydrogesterone 40 mg orally, followed by 10 mg orally three times a day or placebo until 12 completed weeks of gestation or 1 week after the bleeding stopped, whichever was later. The primary outcome was the miscarriage rate before 20 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: The two groups of women had comparable age, BMI, number of previous miscarriages, gestation and ultrasound findings at presentation. The miscarriage rate before 20 weeks of gestation was similar in both groups, being 12.8% (26/203) in the progestogen group and 14.3% (29/203) in the placebo group (relative risk 0.897, 95% CI 0.548-1.467; P = 0.772). The live birth rate was 81.3% in the progestogen group versus 83.3% in the placebo group (P = 0.697). No significant differences were found between the two groups in terms of obstetric outcomes and side effects. LIMITATIONS, REASONS FOR CAUTION: The primary outcome was the miscarriage rate, rather than the live birth rate. Women were recruited from Early Pregnancy Assessment Clinics and those with heavy vaginal bleeding might be admitted into wards directly instead of attending Early Pregnancy Assessment Clinic. The severity of vaginal bleeding was subjectively graded by women themselves. The sample size was not adequate to demonstrate a smaller difference in the miscarriage rate between the progestogen and placebo groups. We did not exclude women with multiple pregnancy, which increased the risk of miscarriage although there was only one set of twin pregnancy in the placebo group. WIDER IMPLICATIONS OF THE FINDINGS: Use of oral progestogen is not recommended in women with threatened miscarriage in the first trimester. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Health and Medical Research Fund, HKSAR (reference number 12132341). All authors declared no conflict of interest. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov with an identifier NCT02128685. TRIAL REGISTRATION DATE: 1 May 2014. DATE OF FIRST PATIENT'S ENROLMENT: 30 March 2016.

A randomized double-blinded non-inferiority trial comparing fentanyl and midazolam with pethidine and diazepam for pain relief during oocyte retrieval.

RESEARCH QUESTION: Is fentanyl and midazolam non-inferior to pethidine and diazepam in pain relief during oocyte retrieval under conscious sedation? DESIGN: A randomized double-blinded non-inferiority trial of 170 infertile women undergoing oocyte retrieval under conscious sedation in an assisted reproduction centre. The women were randomized to receive intravenously either 0.1 mg fentanyl and 5 mg midazolam or 25 mg pethidine and 5 mg diazepam, plus paracervical block with 10 ml 1% lignocaine. The primary outcome was abdominal pain level during retrieval assessed by linear visual analogue scale from 0-10. Secondary outcomes included vaginal pain levels during and after retrieval and postoperative abdominal pain levels and side-effects, satisfaction level, clinical pregnancy and ongoing pregnancy rates. A pre-defined non-inferiority margin of 1 for the difference in pain levels between two groups was set. RESULTS: Vaginal and abdominal pain levels during retrieval were significantly lower in the fentanyl and midazolam group compared with the pethidine and diazepam group (per-protocol analysis, vaginal pain: 1.6 versus 4.3; mean difference: -2.7, 95% CI -3.7, -1.8; P < 0.001; abdominal pain: 2.9 versus 5.2; mean difference: -2.3, 95% CI -3.3 to -1.3; P < 0.001 for non-inferiority). No differences were observed in these pain levels after retrieval. Most women experienced no postoperative side-effects. The fentanyl and midazolam group had better sedation level, satisfaction level on pain relief and satisfaction on the overall retrieval procedure than the pethidine and diazepam group. No significant differences were found in clinical pregnancy and ongoing pregnancy rates between the two groups. CONCLUSION: The fentanyl and midazolam group had significantly lower vaginal and abdominal pain levels during oocyte retrieval than the pethidine and diazepam group.

Effect of delayed interval delivery of remaining fetus(es) in multiple pregnancies on survival: a systematic review and meta-analysis.

BACKGROUND: The management of the pregnancy after delivery of the first fetus during a second-trimester miscarriage or very early preterm birth has not been well defined. OBJECTIVE: The objective of the study was to evaluate whether delayed interval delivery of the remaining fetus(es) in twins/triplets is associated with improved survival, when compared with immediate delivery, after miscarriage or very preterm birth of the first fetus in multiple pregnancy. DATA SOURCES: PubMed, MEDLINE, and Cochrane Library were systematically searched through January 2019. STUDY ELIGIBILITY CRITERIA (STUDY DESIGN, POPULATIONS, AND INTERVENTIONS): The following eligibility criteria applied: full-text original article; included at least 5 cases of delayed interval delivery for remaining fetus(es); and reported the survival rate of the first-born and the remaining fetus(es). STUDY APPRAISAL AND SYNTHESIS METHODS: K.W.C. and W.W. searched, screened, and reviewed the articles. The quality of the studies was assessed according to the Strengthening the Reporting of Observational studies in Epidemiology checklist. If possible, data were stratified for assigned chorionicity. Effect sizes were pooled through a meta-analysis. RESULTS: A total of 2295 published article and abstracts were identified. Only 16 studies met inclusion criteria. Meta-analysis of 492 pregnancies (432 twins [88%], 56 triplets [11%], 3 quadruplets and 1 quintuplets) showed that delayed interval delivery significantly improved the perinatal survival of remaining fetus(es) compared with the first born (odds ratio, 5.22, 95% confidence interval, 2.95-9.25, I2 = 53%), before 20+0 weeks (odds ratio, 6.32, 95% confidence interval, 1.99-20.13, I2 = 0%), between 20+0 and 23+6 weeks (odds ratio, 3.31, 95% confidence interval, 1.95-5.63, I2 = 0%), and after 24+0 weeks (odds ratio, 1.92, 95% confidence interval, 1.21-3.05, I2 = 0%), in dichorionic twin pregnancy (odds ratio, 14.89, 95% confidence interval, 6.19-35.84, I2 = 0%), and unselected triplet pregnancy (odds ratio, 2.33, 95% confidence interval, 1.02-5.32, I2 = 0%. ). Among the survivors, there were no significant differences in the short-term and long-term neonatal morbidities between the first-born and the remaining fetus(es). Serious maternal morbidity was reported in 39% of pregnancy after delayed interval delivery (71 of 183). In addition, 2 cases were managed by postpartum hysterectomy and 1 reported postoperative uterovaginal fistula. There were no recorded cases of maternal mortality. CONCLUSION: Delayed interval delivery when a fetus has delivered in a multiple pregnancy is an effective management option to increase the survival rate of the remaining fetus(es). About 39% of women may experience morbidity following this management option.

A randomized triple blind controlled trial comparing the live birth rate of IVF following brief incubation versus standard incubation of gametes.

STUDY QUESTION: Does brief incubation of oocytes and spermatozoa improve the live birth rate (LBR) of IVF when compared with that of standard incubation? SUMMARY ANSWER: Brief incubation of gametes does not improve the LBR of IVF when compared with standard incubation. WHAT IS KNOWN ALREADY: Some small randomized studies showed that brief incubation was associated with a significantly higher ongoing pregnancy rate than standard incubation. STUDY DESIGN, SIZE, DURATION: This is a randomized triple blind study of 320 infertile women for their first or repeated cycles undergoing IVF between September 2015 and October 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were randomized into the brief incubation group (n = 160) or the standard incubation group (n = 160) according to a computer-generated randomization list. Oocytes were incubated with spermatozoa (0.3-1.2 million motile sperm/ml) for 3-4 h in the brief incubation group while oocytes were incubated with spermatozoa at similar concentration for 20 h in the standard incubation group. The primary outcome was the LBR (a baby born alive after 22 weeks gestation) in the fresh cycle. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in the LBR between the brief and standard incubation groups based on both intention-to-treat [33.0% (53/160) versus 36.8% (59/160), relative risk (RR) 0.898 (95% CI = 0.666-1.212), P = 0.482] and per protocol [41.4%(53/128) versus 41.0% (59/144), RR1.011 (95% CI = 0.760-1.343), P = 0.942] analyses. Clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy and implantation rates were comparable for the two groups. Similar results were found with subgroup analysis of advanced maternal age, abnormal semen analysis and repeated IVF cycles. No differences were observed in cumulative LBR between two groups. LIMITATIONS, REASONS FOR CAUTION: Various motile sperm concentrations of 0.3-1.2 million per ml were used for insemination and the reactive oxygen species level in the insemination medium was not measured. The highest level at 1.2 million per ml is still relatively low compared to prior studies, therefore we do not know whether brief incubation can improve the LBR using higher concentrations of spermatozoa. The present sample size may not be adequate to detect a smaller difference in the LBR. WIDER IMPLICATIONS OF THE FINDINGS: The present study demonstrated that a brief incubation of gametes had no significant beneficial effect on the LBR when compared with the standard incubation. The practice of brief incubation of gametes is not necessary and this can save the already tight manpower in many laboratories. STUDY FUNDING/COMPETING INTERESTS: The study was supported by the Merck-Serono China Research Fund for Fertility Experts (2015), which was not involved in study design, execution, data analysis and manuscript preparation. There are no conflicts of interest for all authors. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier NCT02534857. TRIAL REGISTRATION DATE: 28 August 2015. DATE OF FIRST PATIENT'S ENROLMENT: 8 September 2015.

Preferred problem solving and decision-making role in fertility treatment among women following an unsuccessful in vitro fertilization cycle.

BACKGROUND: While the literature on healthcare decision-making has long focused on doctor-patient interaction, fertility treatment is an exception, characterized by a triangular interplay between the doctor, the woman and her partner. This study examined treatment decision-making preferences of women undergoing in vitro fertilization (IVF) treatment, following an unsuccessful IVF cycle, especially their preferred level of doctor and spousal involvement. METHODS: A cross-sectional survey was conducted with 246 Chinese women undergoing IVF recruited from an assisted reproduction clinic of a university-affiliated hospital in Hong Kong. Data collection was conducted between January 2014 and August 2015. RESULTS: Most participants preferred sharing the decision-making tasks with their doctors (92%). In the doctor-patient relationship, passive roles were associated with higher marital satisfaction, presence of religious affiliation and secondary infertility, while autonomous roles were related to female-factor infertility. Fifty-two percent of participants anticipated sharing decision-making, while 46% preferred handing over the decision to their husbands. Preference for a passive rather than a shared role in the spousal relationship was related to a higher husband's age, greater marital satisfaction and higher anxiety. CONCLUSIONS: In brief, women tended to prefer sharing decision-making tasks with their doctor as well as actively engaging their partner in making decisions about fertility treatment. This study adds to our understanding of women's role preference and level of involvement in infertility treatment decision-making by providing quantitative evidence from women's experience. It highlights the importance of healthcare professionals in facilitating shared decision-making among couples.

Application of UPLC-MS/MS to simultaneously detect four bioactive compounds in the tumour-shrinking decoction (FM1523) for uterine fibroids treatment.

INTRODUCTION: The Chinese medicine formulation, tumour-shrinking decoction (TSD, FM1523), which consists of 15 natural medicines, is used for uterine fibroids (UFs) therapy and possesses excellent clinical therapeutic effect. OBJECTIVE: To develop a sensitive and validated analytical method for the simultaneous quantification of four crucial bioactive compounds including isorhamnetin-3-O-neohesperidoside, curcumin, peimine and tetrahydropalmatine in the principal formulation of this decoction. METHODS: An ultra-performance liquid chromatography coupled tandem mass spectrometry (UPLC-MS/MS) with an electrospray ionisation (ESI) source in multiple reaction monitoring (MRM) mode was conducted to investigate these bioactive compounds in the TSD. The chromatographic separation was performed on a C18 column when the flow rate was adjusted at 0.2 mL/min with gradient elution of acetonitrile-water with 0.1% formic acid. Accelerated solvent extraction (ASE) method with higher extraction efficiency was employed for TSD sample pre-treatment. RESULTS: The linearity, limit of detection (LOD) and limit of quantification (LOQ) were determined for this analytical method. The mean recoveries of the compounds were determined between 100.23% and 104.02% with satisfactory relative standard deviation (RSD) in the ranges of 2.65% to 3.81%. The precision was evaluated by intra-day and inter-day tests, which revealed RSD within the ranges of 1.21% to 2.14% and 1.24% to 2.32%, respectively. CONCLUSION: The bioactive compounds of TSD samples were successfully quantified via UPLC-MS/MS with MRM mode. This study could help to evaluate the pharmacokinetic study of TSD during clinical applications and present a facile strategy for quantifying bioactive compounds in traditional Chinese Medicine decoction.

Independent association of serum vitamin D with anti-Mullerian hormone levels in women with polycystic ovary syndrome.

OBJECTIVE: This study aimed at investigating the association of serum vitamin D (25(OH)D) and anti-Mullerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) as well as non-PCOS healthy ovulatory women and the possible confounding effects of adiposity and androgen. METHOD: This was a cross-sectional study conducted on serum samples collected from 451 women diagnosed with PCOS as well as 244 age-matched healthy ovulatory women in a tertiary gynaecology out-patient clinic and a family planning clinic. RESULTS: Serum 25(OH)D level was significantly higher in women recruited during summer and autumn than those recruited in winter and spring. Both serum 25(OH)D and AMH levels peaked during summer in women with PCOS. In ovulatory women, only serum 25(OH)D but not AMH level showed such seasonal variation. Serum 25(OH)D level in women with PCOS significantly correlated positively with AMH, AMH/antral follicle count (AFC) ratio, serum total testosterone, sex-hormone-binding globulin and quantitative insulin-sensitivity check index and inversely with body mass index (BMI), insulin, triglycerides and homeostatic model assessment of insulin resistance. After controlling for BMI, 25(OH)D level remained significantly correlated positively with serum AMH, AMH/AFC and total testosterone, and inversely with triglycerides. 25(OH)D level was an independent predictor of serum AMH level after controlling for age, BMI and free androgen index in women with PCOS. CONCLUSION: Serum 25(OH)D level is an independent factor significantly associated with AMH level in women with PCOS but not in ovulatory women.

Effect of exposure to second-hand smoke from husbands on biochemical hyperandrogenism, metabolic syndrome and conception rates in women with polycystic ovary syndrome undergoing ovulation induction.

STUDY QUESTION: Does second-hand smoke (SHS) exposure from husbands have adverse effects on sex hormones, metabolic profiles, clinical phenotypes and fertility outcomes in women with polycystic ovary syndrome (PCOS) undergoing ovulation induction? SUMMARY ANSWER: SHS exposure is associated with worsened biochemical hyperandrogenism, higher incidence of metabolic syndrome and reduced conception rates in women with PCOS. WHAT IS KNOWN ALREADY: Smoking in women impairs fecundity at some stages of the reproductive process including folliculogenesis, embryo transport, endometrial angiogenesis and uterine blood flow. Yet little is known about the hazard of SHS exposure in women with PCOS. STUDY DESIGN, SIZE, DURATION: This study was a secondary analysis of the Polycystic Ovary Syndrome Acupuncture and Clomiphene Trial (PCOSAct), a large randomized controlled trial conducted at 27 hospitals from 2012 to 2015 in mainland China. PARTICIPANTS/MATERIALS, SETTING, METHODS: Out of 1000 women with PCOS, SHS exposure status were available in 500 women, of whom 271 women were non-exposed and 229 exposed to cigarette smoke (170 women ≤10 cigarettes per day as low-SHS exposed and 59 women >10 cigarettes per day as high-SHS exposed). We compared circulating sex steroids, glucose and lipid metabolism, metabolic syndrome and phenotypes, fertility and obstetric outcomes between non-exposed and exposed women. MAIN RESULTS AND THE ROLE OF CHANCE: Women exposed to SHS, compared to non-exposed women, had a higher serum total testosterone (1.7 vs 1.5 nmol/L, P = 0.01), free androgen index (5.7 vs 4.0, P = 0.001) and lower sex hormone binding globulin (30.1 vs 35.6 nmol/L, P = 0.03). Metabolic syndrome, but not other phenotypes, was more frequent in exposed women as compared to non-exposed women (21.8 vs 13.3%, adjusted odds ratio (OR)=1.66; 95% CI, 1.02-2.71, P = 0.04). Ovulation rates between exposed and non-exposed groups were not significantly different (76.9 vs 82.9%, adjusted OR=0.72; 95% CI, 0.45-1.15, P = 0.17). Conception rates were significant lower in the exposed group (26.6 vs 36.9%; adjusted OR=0.61; 95% CI, 0.41-0.91; P = 0.01), while clinical pregnancy and live birth rates showed a similar trend that was not statistically significant. Gestational age, birth weight and other obstetric outcomes were not affected by SHS exposure. LIMITATIONS, REASONS FOR CAUTION: Data on SHS exposure were missing in 50% of the women. We did not assay serum nicotine or cotinine levels to quantify the SHS exposure status. WIDER IMPLICATIONS OF THE FINDINGS: These data suggest that smoking partners of infertile women with PCOS who seek treatment should be advised to quit smoking. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the National Public Welfare Projects for Chinese Medicine (201107005 and 200807002) and the National Clinical Trial Base in Chinese Medicine Special Projects (JDZX2012036 and 2015B009). There are no conflicts of interest. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov number: NCT01573858 and chictr.org.cn number: ChiCTR-TRC-12002081.

The effect of 12-month dehydroepiandrosterone supplementation on the menstrual pattern, ovarian reserve markers, and safety profile in women with premature ovarian insufficiency.

PURPOSE: To evaluate the effect of 12-month DHEA supplementation on menstrual pattern and ovarian reserve markers in women with premature ovarian insufficiency (POI) METHODS: This is a prospective observational study. Women with POI were given DHEA supplements (25 mg three times daily) for 12 months. Sonographic assessment for ovarian volume and antral follicle count (AFC) and serum measurement for anti-Mullerian hormone (AMH), follicle stimulating hormone (FSH), estradiol, testosterone, liver function, and hemoglobin level were performed at baseline and monthly for 13 months after the supplementation. Menstrual pattern, ovarian reserve markers, and side-effects were recorded. RESULTS: Between August 2011 and July 2014, 38 women with POI were recruited and 31 completed the study. The median age of women was 36 years, and the median baseline FSH and AMH concentrations were 82.2 IU/L and 0.01 ng/ml, respectively. No women had resumption of regular menstruation after DHEA supplementation. AMH, FSH, and AFC did not change significantly. No serious side effects were reported. CONCLUSIONS: Our results do not support any significant improvement in ovarian function by 12-month DHEA supplementation in women with POI.

Effect of ulipristal acetate and mifepristone at emergency contraception dose on the embryo-endometrial attachment using an in vitro human trophoblastic spheroid and endometrial cell co-culture model.

STUDY QUESTION: Do both ulipristal acetate (UPA) and mifepristone inhibit embryo-endometrial attachment at concentrations corresponding to the emergency contraception (EC) dose? SUMMARY ANSWER: Both UPA and mifepristone at concentrations corresponding to the EC dose do not have an inhibitory effect on embryo implantation, although mifepristone at a higher concentration appeared to have such an effect. WHAT IS KNOWN ALREADY: Levonorgestrel is commonly used for EC, but it only acts through inhibition of ovulation. UPA and mifepristone have higher efficacy as EC compared to levonorgestrel; while there is some suggestion that mifepristone may interfere with implantation, whether UPA has post-ovulatory action in inhibiting implantation is yet to be confirmed. STUDY DESIGN, SIZE, DURATION: An in vitro experimental study using trophoblastic spheroids made from JAr cell line as the embryo surrogate, and the Ishikawa cell line and primary human endometrial cells cultured to monolayer as the endometrial surrogate. The primary endometrial cells were collected from nine volunteer women in the mid-luteal phase with consent. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in a university gynaecology unit. The JAr and Ishikawa cell lines (or primary endometrial cells) were treated with graded concentrations of UPA (0, 0.04, 0.4 and 4 µM) or mifepristone (0, 0.1, 1 and 10 µM) for 24 h. Embryo-endometrial attachment was studied using an in vitro JAr spheroid-endometrial co-culture model. Expressions of progesterone receptor, ß-catenin and glycogen synthase kinase 3 ß (GSK-3ß) were studied with real-time RT-PCR and Western blotting, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: In the Ishikawa experiments, there was no significant difference in the JAr spheroid attachment rate after treatment with UPA at 0 (93.0%), 0.04 (93.6%), 0.4 (93.4%) and 4 (91.4%) µM concentrations (P > 0.05); the attachment rate was reduced after treatment with mifepristone only at 10 µM (79.8%, P < 0.0001) but not at 0.1 (92.1%) or 1.0 (95.2%) µM concentrations. In the primary endometrial cell experiments, again no significant difference was observed in the JAr spheroid attachment rate after treatment with UPA 4 µM (42.6%) compared to control (46.5%, P > 0.05). Both UPA and mifepristone could significantly up-regulate progesterone receptor expression. There was no significant alteration in expression of ß-catenin and GSK-3ß after treatment with UPA 4 µM or mifepristone 10 µM (P > 0.05). LIMITATIONS, REASONS FOR CAUTION: The co-culture model is only a surrogate which may not fully represent the complicated process of embryo implantation in vivo, although there is no existing perfect model for studying implantation in vitro which fully resembles the latter. WIDER IMPLICATIONS OF THE FINDINGS: The lack of inhibitory effect on embryo implantation by UPA and possibly mifepristone at concentrations corresponding to the EC dose is an important information for contraceptive counseling. STUDY FUNDING/COMPETING INTEREST(S): We had free supply of the UPA compound used in this study from Laboratoire HRA Pharma. This work was supported by a Seed Fund from the Centre of Reproduction, Development and Growth, Faculty of Medicine, The University of Hong Kong, Hong Kong.