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.

Factors affecting the distribution of serum anti-müllerian hormone levels among infertile Asian women: a multi-nation, multi-centre, and multi-ethnicity prospective cohort study.

STUDY QUESTION: How do age, ethnicity, and other characteristics affect serum anti-mullerian hormone (AMH) levels in Asian women undergoing fertility treatment? SUMMARY ANSWER: Age, ethnicity, obesity (BMI ≥ 30 kg/m2), and polycystic ovarian syndrome (PCOS) significantly impacted serum AMH levels, with the rate of decrease accelerating as age increased; a concentration of 4.0 ng/ml was the optimal cut-off for diagnosis of PCOS. WHAT IS KNOWN ALREADY: There are significant differences in ovarian reserve among women from different races and ethnicities, and Asian women often have poorer reproductive outcomes during assisted reproductive treatment cycles. STUDY DESIGN, SIZE, DURATION: A population-based multi-nation, multi-centre, multi-ethnicity prospective cohort study of 4613 women was conducted from January 2020 to May 2021. Infertile women of 20-43 years of age were enrolled. The exclusion criteria included: age <20 or >43, non-Asian ethnicity, and missing critical data. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were Asian women of Chinese, Japanese, Korean, Thai, Vietnamese, Malay, Indian, and Indonesian ethnicities from 12 IVF centres across Asia. These women were all naïve to ovarian stimulation cycles and attended IVF centres for fertility assessment. The AMH measurement was performed using an AMH automated assay on a clinically validated platform. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 4556 infertile Asian women were included in the final analyses. The mean ± SD for serum AMH concentrations (ng/ml) across specific age groups were: overall, 3.44 ± 2.93; age <30, 4.58 ± 3.16; 30-31, 4.23 ± 3.23; 32-33, 3.90 ± 3.06; 34-35, 3.21 ± 2.65; 36-37, 2.74 ± 2.44; 38-39, 2.30 ± 1.91; 40 and above, 1.67 ± 2.00. The rate of AMH decrease was ∼0.13 ng/ml/year in patients aged 25-33 and 0.31 ng/ml/year in women aged 33-43. The highest rates of PCOS were found in Indians (18.6%), Malays (18.9%), and Vietnamese (17.7%). Age (P < 0.001), ethnicity (P < 0.001), obesity (P = 0.007), PCOS (P < 0.001), and a history of endometrioma cystectomy (P = 0.01) were significantly associated with serum AMH values. Smoking status, pretreatment with GnRH agonist (GnRHa) or the oral contraceptive pill (OCP), freezing-thawing of blood samples, and sampling on Day 2 to Day 5 of the menstrual cycle or randomly did not appear to affect serum AMH levels. An AMH concentration of 4.0 ng/ml was the optimal cut-off for PCOS diagnosis with a sensitivity of 71.7% and specificity of 75.8% (AUC = 0.81, CI 95%: 0.79-0.83; P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The incidence of PCOS was supposedly high in this cohort as some IVF clinics were tertiary referral centres for managing specific fertility issues encountered by women with PCOS. Treatment with GnRHa or OCP before AMH testing was regionally and ethnically confined, mostly in Hong Kong SAR and Japan. Moreover, this reference for serum AMH value is limited to Asian women of the ethnicities examined and may not apply to other ethnicities not included in the study. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to collate and construct age-specific reference ranges for serum AMH levels using the same bioassay on Asian women of different ethnicities. The findings of this investigation can assist clinicians to counsel and prognosticate about Asian women's ovarian reserve and reproductive potential, thus providing better strategies for personalized fertility interventions. STUDY FUNDING/COMPETING INTEREST(S): This study was technically supported by Ferring Pharmaceuticals and received no specific grant from any funding agency. All authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: NCT04203355.

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.

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.

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 controlled trial of hCG as luteal phase support in natural cycle frozen embryo transfer.

STUDY QUESTION: Does the use of hCG as luteal phase support in natural cycle frozen embryo transfer (FET) increase the ongoing pregnancy rate? STUDY ANSWER: The use of hCG in natural cycle FET did not improve the ongoing pregnancy rate. WHAT IS KNOWN ALREADY: The use of luteal phase support in stimulated cycles has been associated with higher live-birth rates and the results are similar when using hCG or progesterone. STUDY DESIGN SIZE, DURATION: This is a randomized double-blinded controlled trial of 450 women recruited between August 2013 and October 2015. PARTICIPANTS/MATERIALS SETTING METHODS: Women with regular cycles undergoing natural cycle FET were recruited. Serial serum hormonal concentrations were used to time natural ovulation and at least Day 2 cleavage embryos were replaced. Patients were randomized into either: (i) the treatment group, receiving 1500 IU hCG on the day of FET and 6 days after FET, or (ii) the control group, receiving normal saline on these 2 days. MAIN RESULTS AND THE ROLE OF CHANCE: The ongoing pregnancy rate [60/225 (26.7%) in the treatment group vs 70/225 (31.3%) in the control group, odds ratio 1.242 (95% CI 0.825-1.869)], implantation rate and miscarriage rate were comparable between the two groups. In the treatment group, there were significantly more cycles with top quality embryos transferred and a significantly higher serum oestradiol level, but a comparable serum progesterone level, 6 days after FET. However, no significant differences were observed in serum oestradiol and progesterone levels 6 days after FET between the pregnant and non-pregnant women. In the multivariate logistic regression, the number of embryos transferred was the only significant factor predictive of the ongoing pregnancy rate after natural cycle FET. LIMITATIONS REASON FOR CAUTION: This study only included FET with cleavage stage embryos and only hCG, not vaginal progesterone, was used as luteal phase support. WIDER IMPLANTATIONS OF THE FINDINGS: The findings in this study do not support the use of hCG for luteal phase support in natural cycle FET. STUDY FUNDING/COMPETING INTERESTS: No external funding was used and there were no competing interests. TRIAL REGISTRATION NUMBER: clinicaltrial.gov identifier: NCT01931384. TRIAL REGISTRATION DATE: 23/8/2013. DATE OF FIRST PATIENT'S ENROLMENT: 30/8/2013.

A randomized double blind comparison of atosiban in patients undergoing IVF treatment.

STUDY QUESTION: Does atosiban (oxytocin/vasopressin V1A receptor antagonist), given around embryo transfer improve the live birth rate of women undergoing IVF treatment? SUMMARY ANSWER: The use of atosiban around embryo transfer did not improve the live birth rate in a general population of IVF patients. WHAT IS KNOWN ALREADY: Uterine contractions in IVF cycles were significantly increased following ovarian stimulation and women with frequent uterine contractions had a lower pregnancy rates. A few observational studies suggested that the use of atosiban around embryo transfer resulted in higher pregnancy rates in women with repeated implantation failure (RIF). A non-randomized trial of IVF patients also reported higher implantation and clinical pregnancy rates after the use of atosiban. STUDY DESIGN, SIZE, DURATION: This multi-centre randomized double blind study recruited 800 general subfertile women undergoing IVF treatment between November 2011 and March 2013. Subjects were randomized into the atosiban (n = 400) and placebo (n = 400) groups according to a computer-generated randomization list. PARTICIPANTS/MATERIALS, SETTING, METHODS: Subjects were recruited and randomized in the three IVF units in Guangzhou, Hong Kong and Ho Chi Minh City. Women in the atosiban group received i.v. atosiban 30 min before embryo transfer with a bolus dose of 6.75 mg, and the infusion was continued at 18 mg/h for ∼1 h. The dose of atosiban was then reduced to 6 mg/h continued for another 2 h. Those in the placebo group received i.v. normal saline only. The primary outcome measure was the live birth rate. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in the live birth rate between the atosiban and placebo groups (39.8 versus 38.0%, P = 0.612, rate ratio 1.051, 95% confidence interval: 0.884-1.251). No significant differences were found between the two groups in the positive pregnancy test, clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy rates and implantation rate per woman. Similar results were found between the groups at different IVF centres, with a repeated cycle, presence of uterine fibroids or a serum estradiol level on the day of hCG above the median level. LIMITATIONS, REASONS FOR CAUTION: Limitations include the transfer of early cleavage embryos, no measurement of uterine contractions, no documentation of adenomyosis and incomplete tracking of congenital abnormalities in newborns. WIDER IMPLICATIONS OF THE FINDINGS: This randomized double blind study demonstrated that the use of atosiban given around embryo transfer did not improve the live birth rate in a general population of IVF patients; therefore atosiban should be given only in the context of clinical research. STUDY FUNDING/COMPETING INTERESTS: Centres in Hong Kong and Vietnam received research funding from Ferring, which was not involved in study design, execution, data analysis and manuscript preparation. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01501214.

The effect of endometrial injury on ongoing pregnancy rate in unselected subfertile women undergoing in vitro fertilization: a randomized controlled trial.

STUDY QUESTION: Does endometrial injury in the cycle preceding ovarian stimulation for in vitro fertilization (IVF) improve the ongoing pregnancy rate in unselected subfertile women? SUMMARY ANSWER: Endometrial injury induced by endometrial aspiration in the preceding cycle does not improve the ongoing pregnancy rate in unselected subfertile women undergoing IVF. WHAT IS KNOWN ALREADY: Implantation failure remains one of the major limiting factors for IVF success. Mechanical endometrial injury in the cycle preceding ovarian stimulation of IVF treatment has been shown to improve implantation and pregnancy rates in women with repeated implantation failures. There is limited data on unselected subfertile women, especially those undergoing their first IVF treatment. STUDY DESIGN, SIZE, DURATION: This randomized controlled trial recruited 300 unselected subfertile women scheduled for IVF/ICSI treatment between March 2011 and August 2013. Subjects were randomized into endometrial aspiration (EA) (n = 150) and non-EA (n = 150) groups according to a computer-generated randomization list. PARTICIPANTS/MATERIALS, SETTING, METHODS: Subjects were recruited and randomized in the assisted reproductive unit at the University of Hong Kong. In the preceding cycle, women in the EA group underwent endometrial aspiration using a Pipelle catheter in mid-luteal phase. All women were treated with a cycle of IVF/ICSI. Pregnancy outcomes were compared. MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences in baseline or cycle characteristics between the groups. There were 209 subjects (69.7%) who were undergoing their first IVF cycle and 91 (30.3%) subjects who had repeated cycles. There was no significant difference in ongoing pregnancy rates [26.7% (40/150) versus 32.0% (48/150); RR 0.833 (95% CI 0.585-1.187), P = 0.375] in the EA and non-EA groups. The implantation rates [32.8% (67/204) versus 29.7% (68/229); RR 1.080 (95% CI 0.804-1.450), P = 0.120], clinical pregnancy rates [34.0% (51/150) versus 38.0 (57/150); RR 0.895 (95% CI 0.661-1.211), P = 0.548], miscarriage rates [30.3% (17/56) versus 18.6% (11/59), RR 1.628 (95% CI 0.838-3.164), P = 0.150] and multiple pregnancy rates [31.3% (16/51) versus 19.3% (11/57), RR 1.626 (95% CI 0.833-3.172), P = 0.154] were all comparable between the EA and non-EA groups. Subgroup analysis in women having first embryo transfer (n = 209) also demonstrated no significant difference in ongoing pregnancy rates, but for women undergoing repeated cycles (n = 91), the on-going pregnancy rate was significantly lower in the EA group than in the non-EA group. LIMITATIONS, REASONS FOR CAUTION: The study aimed at assessing an unselected population of subfertile women by recruiting consecutive women attending our fertility clinic. However, since the majority of the recruited women (69.7%) were having their first IVF treatments, the results may not be generalizable to all women undergoing IVF. WIDER IMPLICATIONS OF THE FINDINGS: Previous RCTs and meta-analyses have suggested improved pregnancy rates after pretreatment endometrial injury in women with repeated implantation failure. A recent RCT also showed increased pregnancy rates in unselected subfertile women after endometrial injury, although that study was terminated early and thus underpowered. Our study showed with adequate power that no significant improvement in pregnancy rates was observed after endometrial injury in unselected women undergoing IVF treatment. STUDY FUNDING/COMPETING INTERESTS: The study was supported by the Small Project Funding 201309176012 of the Committee on Research and Conference Grants, University of Hong Kong. The authors have nothing to disclose. TRIAL REGISTRATION NUMBER: HKCTR-1646 and NCT 01977976.

Comparison of the multiples of the median of serum anti-müllerian hormone and pregnancy outcomes in patients with gestational trophoblastic disease: A case-control study.

INTRODUCTION: Chemotherapy is crucial in treating gestational trophoblastic neoplasia (GTN), but its impact on gonadotoxicity is unclear. MATERIALS AND METHODS: This case-control study included 57 GTN patients and 19 age-matched patients with molar pregnancies (MP) in 2012-2018. Multiples of the median (MoM) of the serum AMH levels were compared between the two groups, and between patients using single-agent and combination chemotherapy, at baseline, 6, 12, and 24 months after treatment. Their pregnancy outcomes were also compared. RESULTS: There was no significant difference in the MoM of serum AMH between GTN and MP groups at all time points. Single-agent chemotherapy did not adversely affect the MoM. However, those receiving combination chemotherapy had lower MoM than those receiving single-agent chemotherapy at all time points. The trend of decline from the baseline was marginally significant in patients with combination chemotherapy, but the drop was only significant at 12 months (Z = -2.69, p = 0.007) but not at 24 months (Z = -1.90; p = 0.058). Multivariable analysis revealed that combination chemotherapy did not affect the MoM. There was no significant difference in the 4-year pregnancy rate and the livebirth rate between the single-agent and combination groups who attempting pregnancy, but it took 1 year longer to achieve the first pregnancy in the combination group compared to the single-agent group (2.88 vs. 1.88 years). CONCLUSION: This study showed combination chemotherapy led to a decreasing trend of MoM of serum AMH especially at 12 months after treatment, but the drop became static at 24 months. Although pregnancy is achievable, thorough counseling is still needed in this group especially those wish to achieve pregnancy 1-2 years after treatment or with other risk factors.

Two Girls With Adrenal Insufficiency and Failing Gonads.

Congenital lipoid adrenal hyperplasia (CLAH) is a rare cause of adrenal insufficiency caused by mutations in the steroidogenic acute regulatory (StAR) gene. Patients classically present with adrenal crisis in early infancy and female external genitalia irrespective of chromosomal sex. We report 2 Chinese patients with normal female external genitalia presenting with salt wasting in the neonatal period. However, the diagnosis of CLAH was made only during pubertal years when they developed hypergonadotropic hypogonadism. One of them was subsequently found to have a 46XY karyotype and gonadectomy was performed at age 15 years. The other patient developed gonadal insufficiency and polycystic ovaries after menarche with hemorrhage into ovarian cysts requiring cystectomy. These 2 cases illustrate the importance of recognizing atypical features in neonates presenting with adrenal crisis. In managing the newborn with adrenal insufficiency and female-appearing external genitalia, the possibility of sex reversal and diagnosis of CLAH should be considered. Accurate delineation of internal pelvic organs using reliable imaging modalities or even laparoscopy, together with careful interpretation of clinical and laboratory findings, are crucial to accurate diagnosis and subsequent management.

Attachment of a trophoblastic spheroid onto endometrial epithelial cells predicts cumulative live birth in women aged 35 and older.

OBJECTIVE: To evaluate the attachment rate of a human embryonic stem cell-derived trophoblastic spheroid onto endometrial epithelial cells in predicting the cumulative live birth rate of an in vitro fertilization (IVF) cycle. DESIGN: A prospective observational study. SETTING: University hospital and research laboratory. PATIENT(S): A total of 240 infertile women from 2017-2021. INTERVENTION(S): Infertile women with regular cycles attending for IVF were recruited. An endometrial aspirate was collected from a natural cycle 1 month before IVF to determine the BAP-EB attachment rate. MAIN OUTCOME MEASURE(S): Cumulative live birth rates from a stimulated cycle and its derived frozen embryo transfer cycles within 6 months of ovarian stimulation were obtained. RESULT(S): The BAP-EB attachment rate in women who attained a cumulative live birth was similar to that in those who did not. When women were stratified by age into <35 years and ≥35 years, the BAP-EB attachment rate was significantly higher only in women aged ≥35 years having a live birth when compared with those in the same age group without a live birth. Receiver operating characteristic curve analysis of BAP-EB attachment rate in predicting cumulative live birth showed the areas under the curve of 0.559 (95% confidence interval [CI], 0.479-0.639), 0.448 (95% CI, 0.310-0.585), and 0.613 (95% CI, 0.517-0.710) for all ages, an age of <35 years, and an age of ≥35 years, respectively. CONCLUSION(S): The BAP-EB attachment rate offers only a very modest prediction of the cumulative live birth rate in women aged ≥35 years undergoing IVF. CLINICAL TRIAL REGISTRATION NUMBER: NCT02713854 (https://clinicaltrials.gov/ct2/show/NCT02713854; Date of registration, March 21, 2016; date of enrollment of the first subject, August 1, 2017).

Best Practice Contraception Care for Women with Obesity: A Review of Current Evidence.

The prevalence of obesity among females of reproductive age is increasing globally. Access to the complete range of appropriate contraceptive options is essential for upholding the reproductive rights of this population group. People with obesity can experience stigma and discrimination when seeking healthcare, and despite limited evidence for provider bias in the context of contraception, awareness for its potential at an individual provider and health systems level is essential. While use of some hormonal contraceptives may be restricted due to increased health risks in people with obesity, some methods provide noncontraceptive benefits including a reduced risk of endometrial cancer and a reduction in heavy menstrual bleeding which are more prevalent among individuals with obesity. In addition to examining systems-based approaches which facilitate the provision of inclusive contraceptive care, including long-acting reversible contraceptives which require procedural considerations, this article reviews current evidence on method-specific advantages and disadvantages for people with obesity to guide practice and policy.

The effects of not having continuous companion support during labour on pregnancy and neonatal outcomes during the COVID-19 pandemic.

OBJECTIVE: With the surge of confirmed cases of coronavirus disease 2019 (COVID-19) and its associated morbidities and mortalities, continuous companion support during labour was halted in all public hospitals in Hong Kong to prevent the spread of the virus in hospitals. The purpose of this retrospective study was to evaluate the effect of not having continuous companion support during labour on pregnancy and neonatal outcomes during the COVID-19 pandemic period in a regional hospital. STUDY DESIGN: We retrieved information on women without continuous companion support during the COVID-19 pandemic period from February 1, 2020 to May 15, 2020 and those with continuous companion support within the same period in 2019 in Queen Mary Hospital, Hong Kong. The pregnancy and neonatal outcomes were compared between the two groups. RESULTS: A total of 446 women with continuous companion support in 2019 and 340 women without continuous companion support in 2020 were included in the analysis. The rate of labour augmentation was significantly lower in women with continuous companion support than in those without continuous companion support (3.1% vs. 6.5%, respectively, p = 0.027). Babies born to women with continuous companion support were less likely to have Apgar scores <7 at 1 min than those born to women without continuous companion support (2.5% vs. 5.3%, respectively, p = 0.036). More women with continuous companion support had breastfeeding at the first hour of delivery than those without (86.3% vs. 80.6%, respectively, p = 0.030). There were no differences in other pregnancy and neonatal outcomes. The subgroup analysis with only Chinese women showed that the pregnancy and neonatal outcomes were not significantly different between the two groups. CONCLUSION: Women without continuous companion support during labour had an increased chance of labour augmentation and babies with an Apgar score <7 at 1 min, and a reduced immediate breastfeeding rate when compared with those with continuous companion support.

Sexual function and quality of life in Chinese couples undergoing assisted reproductive treatment: a prospective cohort study.

Couples undergoing assisted reproductive technologies (ART) are prone to sexual dysfunction and lower quality of life (QoL), but whether the incidence of these problems differs with the type of ART is unknown. As such, we conducted this cross-sectional survey to compare the sexual function and QoL of 75 couples undergoing intrauterine insemination (IUI), and 160 couples undergoing in vitro fertilization (IVF). They completed an anonymous questionnaire which included: (i) demographic characteristics; (ii) female sexual function index (FSFI) or (iii) international index of erectile function-5 (IIEF-5); and (iv) fertility QoL questionnaire (FertiQoL). Overall, 22.6% of wives and 39.1% of husbands were at risk for sexual dysfunction, and the risk was similar in IUI and IVF groups. Mean core/treatment/total FertiQoL scores of husbands were higher than wives: 74.98 vs. 68.24/70.02 vs. 65.87/73.52 vs. 67.54 (all p < 0.001). FertiQoL scores were similar in IUI and IVF groups except wives' treatment FertiQoL score was significantly higher in the IUI group (68.93 vs. 64.44; p = 0.009). This study confirms that risks for sexual dysfunction were similar in IUI and IVF couples. Wives undergoing IVF had significantly lower treatment FertiQoL score. In both IUI and IVF groups, husbands' QoL was better than wives' QoL.

Acceptability of different mechanisms of action of contraception in women: a questionnaire survey.

BACKGROUND: The mechanism of action of a contraceptive method is an importantg consideration in a woman's choice of contraception. For the development of new methods of contraception it is important to understand the acceptability of different contraceptive mechanisms within a population. METHODS: We recruited women attending contraceptive, termination of pregnancy or postnatal care services in Hong Kong for a questionnaire survey on their acceptability of the different ways in which contraceptive methods prevent pregnancy. Univariable and multivariable analyses were used to establish factors which may predict acceptability of the mechanism of action. RESULTS: A total of 1448 women completed the survey. The acceptability of contraceptive methods that act by preventing fertilisation ranked highest (78%), followed by those that inhibit ovulation (52%), disrupt implantation (43%) and dislodge an implanted embryo (30%). A history of termination of pregnancy was associated with greater acceptance of all posited contraceptive mechanisms. There was a very low degree of agreement between the declared acceptance of the various contraceptive mechanisms and the ever use of a method with the respective mechanism of action (Cohen's kappa coefficient range 0.017-0.162). CONCLUSIONS: In this population the acceptability of contraceptive methods that act by preventing fertilisation ranked highest, followed by those that inhibit ovulation, disrupt implantation and dislodge an implanted embryo. Women who had ever had a termination of pregnancy were more likely to accept all the posited contraceptive mechanisms.

Prospective open-label non-inferiority randomised controlled trial comparing letrozole and mifepristone pretreatment in medical management of first trimester missed miscarriage: study protocol.

INTRODUCTION: Medical treatment is a less invasive alternative to surgical management of missed miscarriage. Studies have shown that pretreatment with mifepristone can increase the complete abortion rate in management of first-trimester missed miscarriage compared with misoprostol alone. Two studies have also shown that pretreatment with letrozole could increase the efficacy compared with misoprostol alone. So far, there is no trial comparing letrozole and mifepristone pretreatment for missed miscarriage. We designed this randomised controlled trial to test the hypothesis that for first-trimester missed miscarriage, letrozole pretreatment is non-inferior to mifepristone pretreatment followed by misoprostol in terms of complete abortion rate. METHODS AND ANALYSIS: This is a prospective open-label non-inferiority randomised controlled trial conducted in a single centre. In total, 294 women diagnosed with first-trimester missed miscarriage opting for medical treatment is recruited with informed consent. They are randomly assigned to receive mifepristone or letrozole pretreatment. In the mifepristone group, each woman takes 200 mg mifepristone orally followed 24-48 hours later by 800 µg misoprostol vaginally. In the letrozole group, each woman takes 10 mg letrozole orally per day for 3 days, followed by 800 µg misoprostol vaginally on the third day of letrozole administration. Follow-up is conducted on days 15 and 42 after misoprostol administration. The primary outcome is the overall complete abortion rate. Secondary outcomes include side effects and complications during the study period. Data will be analysed with both intention-to-treat and per protocol approaches. A p<0.05 will be considered as indicating statistical significance. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Institutional Review Board of the University of Hong Kong-Shenzhen Hospital with approval number: (2020)166. Findings will be disseminated in a peer-reviewed journal and in national and/or international meetings to guide future practice. TRIAL REGISTRATION NUMBER: ChiCTR2000041480.

Effects of nonoxynol-9 (N-9) on sperm functions: systematic review and meta-analysis.

Objective: To summarize the currently available phase I and II clinical trials of the effects of nonoxynol-9 (N-9) on human sperm structure and functions. Methods: A systematic review and meta-analysis aiming to evaluate the spermicidal activity of N-9 on motility, was conducted in PubMed, EMBASE, and Cochrane databases by 10 March 2021. The counted numbers of progressive motile (PR) sperm in cervical mucus and the vanguard sperm penetration distances were analyzed. Other effects on sperm structures and physiological activities were reviewed as well. Results: In the pooled results, percentages or counted numbers of PR sperm decreased after the treatment of N-9. Vanguard sperm penetration distance was shortened in treated groups. N-9 has been confirmed to damage the structures of sperm, as well as other organelles like acrosome and mitochondria. The physiological activities such as generation of reactive oxygen species, superoxide dismutase activity, acrosin activity, and hemizona binding were all inhibited in the reviewed studies. Conclusions: N-9 has several impacts on sperm owing to its potency in reducing sperm motility and cervical mucus penetration, as well as other functional competencies. Lay summary: Nonoxynol-9 (N-9) has been used worldwide as a spermicide to kill sperm for more than 60 years but can cause side effects including vaginal irritation and can increase the rate of contraceptive failure. A detailed analysis of published literature aiming to evaluate the spermicidal activity of N-9 on sperm was carried out. In the pooled results, N-9 reduced the number of active sperm and the distance they traveled. It also caused damage to the structures of sperm and to the way the sperm acted and interacted with the egg. In conclusion, N-9 impacts on sperm in a number of ways that lead to sperm death and dysfunction.

A randomized controlled study of acupuncture for pain relief during first trimester surgical termination of pregnancy performed under local analgesia.

BACKGROUND: Acupuncture reduces pain levels in many painful conditions. This study compared pain levels during surgical termination of first trimester pregnancy by suction evacuation (SE) under local analgesia with and without the use of acupuncture. METHODS: In all, 60 nulliparous women undergoing SE before 10 weeks of gestation were randomly assigned into one of the following three groups in a 1:1:1 ratio according to a computer-generated randomization list. In the control group, women received oral diazepam 5 mg and intramuscular (i.m.) injection of pethidine 30 and 15 min, respectively, prior to SE. In the acupuncture group, women received acupuncture 10 min before SE until the end of SE while oral diazepam 5 mg and i.m. injection of normal saline were given. In the combined group, women received acupuncture in addition to the drugs in the control group. Data from 52 participants were analysed. Pain scores during and after SE, post-operative side-effects and satisfaction levels were compared. RESULTS: The three groups had similar baseline characteristics. The median pain levels during SE differed significantly between the control, acupuncture, and combined groups (80, 50 and 66 mm, respectively, p = 0.03). Pain levels during SE in the acupuncture and combined groups were significantly lower than that of the control group. However, the anxiety scores did not differ between the three groups after SE (p = 0.86). CONCLUSION: Acupuncture can provide additional benefit in terms of pain relief in women undergoing first trimester termination of pregnancy by SE under local analgesia.