Mate-pair genome sequencing reveals structural variants for idiopathic male infertility.

Currently, routine genetic investigation for male infertility includes karyotyping analysis and PCR for Y chromosomal microdeletions to provide prognostic information such as sperm retrieval success rate. However, over 85% of male infertility remain idiopathic. We assessed 101 male patients with primary infertility in a retrospective cohort analysis who have previously received negative results from standard-of-care tests. Mate-pair genome sequencing (large-insert size library), an alternative long-DNA sequencing method, was performed to detect clinically significant structural variants (SVs) and copy-number neutral absence of heterozygosity (AOH). Candidate SVs were filtered against our in-house cohort of 1077 fertile men. Genes disrupted by potentially clinically significant variants were correlated with single-cell gene expression profiles of human fetal and postnatal testicular developmental lineages and adult germ cells. Follow-up studies were conducted for each patient with clinically relevant finding(s). Molecular diagnoses were made in 11.1% (7/63) of patients with non-obstructive azoospermia and 13.2% (5/38) of patients with severe oligozoospermia. Among them, 12 clinically significant SVs were identified in 12 cases, including five known syndromes, one inversion, and six SVs with direct disruption of genes by intragenic rearrangements or complex insertions. Importantly, a genetic defect related to intracytoplasmic sperm injection (ICSI) failure was identified in a patient with non-obstructive azoospermia, illustrating the additional value of an etiologic diagnosis in addition to determining sperm retrieval rate. Our study reveals a landscape of various genomic variants in 101 males with idiopathic infertility, not only advancing understanding of the underlying mechanisms of male infertility, but also impacting clinical management.

Hyoscine butylbromide in pain reduction associated with ultrasound-guided manual vacuum aspiration: a randomized placebo-controlled trial.

RESEARCH QUESTION: What is the effect of adding an anti-spasmodic drug to an existing ultrasound-guided manual vacuum aspiration (USG-MVA) protocol to alleviate immediate post-procedure abdominal cramping pain in women treated for early pregnancy loss? DESIGN: Double-blind, placebo-controlled, randomized controlled trial conducted between February 2018 and January 2020. Participants were assigned to receive a 1-ml intravenous injection containing 20-mg hyoscine butylbromide (HBB) (n=55) or saline (n =56) as a control immediately before USG-MVA. Primary outcome was reduced abdominal pain after adding a 20-mg dose of HBB to the current pain control regimen. Secondary outcomes were vaginal pain, complications and side-effects, women's pre- and post-procedure psychological state, physiological stress (saliva alpha-amylase) and procedure pain control satisfaction. Two-way mixed ANOVA was used to evaluate the main effects and interactions. RESULTS: VAS abdominal pain scores in the HBB group were 16% lower immediately after and 21% lower 2 h after surgery (not statistically significant). Two-way ANOVA indicated that time (F[1108] = 83.41, P < 0.001) was the only significant main effect for reduced abdominal pain after the procedure and vaginal pain score (F[1108] = 180.1, P < 0.0001) but not drug received. No adverse events were reported. No significant difference was found for psychological state, physiological stress and procedure pain control satisfaction between the two groups. CONCLUSIONS: Anti-spasmodic drugs can help to reduce abdominal cramping pain associated with USG-MVA; HBB produced an insignificant decrease in abdominal pain score. Further studies with longer acting or larger doses of anti-spasmodic drugs are warranted.

Ovarian reserve and recurrence 1 year post-operatively after using haemostatic sealant and bipolar diathermy for haemostasis during laparoscopic ovarian cystectomy.

RESEARCH QUESTION: Is there a difference in the ovarian reserve 1 year post-operatively in those who used a haemostatic sealant or bipolar diathermy for haemostasis during laparoscopic ovarian cystectomy for ovarian endometriomas? DESIGN: This was an extended follow-up observational study of a previous randomized controlled trial where women aged 18 to 40 years with 3-8 cm unilateral or bilateral endometriomas were randomized to receive haemostasis by a haemostatic sealant or bipolar diathermy following ovarian cystectomy. The primary outcome was the ovarian reserve as assessed by antral follicle count (AFC) 1 year post-operatively. Secondary outcomes included the recurrence rate of ovarian endometrioma, the change in anti-Müllerian hormone (AMH) and FSH concentrations, and reproductive outcomes. RESULTS: The significant increase in AFC at 3 months after initial surgery (P = 0.025) in the haemostatic sealant group compared with the diathermy group was sustained at 1 year (P = 0.024) but there was no difference in AMH or FSH concentrations between the groups throughout the follow-up period. The recurrence rate in the FloSeal group was 7.7% (n = 3/39) compared with 22.2% (n = 8/36) in the diathermy group (P = 0.060). The recurrence rate in women who had bilateral lesions was significantly higher than those with unilateral lesions (risk ratio 5.33, interquartile range 1.55-18.38). No difference in reproductive outcomes was found between the two groups. CONCLUSIONS: Applying haemostatic sealant after laparoscopic cystectomy of ovarian endometriomas produces a significantly greater improvement in AFC, which was apparent at 3-month follow-up, and was sustained at 1-year follow-up without compromising the recurrence rate.

Ovarian HBV replication following ovulation induction in female hepatitis B carriers undergoing IVF treatment: A prospective observational study.

Hepatitis B virus (HBV) can be found in ovarian tissues. This study compared HBV DNA levels in follicular fluid collected during oocyte retrieval with paired serum samples in HBV carriers after ovarian stimulation during IVF treatment for infertility. Sixty-four HBV carrier women referred to the Assisted Reproductive Units of two Hong Kong hospitals were recruited. At oocyte retrieval, the follicular fluid aspirated from the first follicle was collected for study. In 22 women, the first follicular fluid sample from both ovaries was similarly collected and studied. These women were also tested for liver function test and HBeAg. In 28 (43.8%) women, HBV DNA was detected in follicular fluid and the level correlated with serum levels (Spearman's correlation P < .001). There was concordant detection of HBV DNA in both ovaries, and the levels were significantly correlated (Spearman's correlation P = .029). In 40% of women with FF HBV DNA, the follicular fluid:serum ratio was >1.0, suggesting stimulation of HBV replication. These women also had significantly different liver function test results. Increased HBV replication exists in 40% of women with HBV DNA detected in follicular undergoing ovarian stimulation during IVF treatment.

A double-blinded, randomized placebo-controlled trial on the effect of traditional Chinese medicine formula Wuzi Yanzong pill on improving semen qualities in men with suboptimal parameters.

BACKGROUND: In Hong Kong, one of six couples is affected by subfertility problems. Male infertility contributes to half of the infertility cases. In male infertility, there is no effective treatment for patients with idiopathic infertility/poor semen parameters. Recent meta-analysis results suggest that a traditional Chinese medicine (TCM) formula - Wuzi Yanzong pill - showed a curative effect on male fertility. However, the heterogeneity of the studies could not draw a definitive conclusion on the therapeutic effect of this formula. The aim of this study is to conduct a well-designed randomized controlled trial to investigate the effect of TCM formula Wuzi Yanzong pill on improving semen qualities in men with suboptimal parameters. METHODS: This study is a double-blinded, randomized placebo-controlled trial conducted in a public hospital in Hong Kong. Participants will be randomized, using computer-generated random numbers, with a 1:1 ratio to either the Wuzi Yanzong pill formula group or the placebo group. Both groups will be administered the drugs for 12 weeks. Participants will have a total of four visits for their semen and blood assessments for a 6-month period, and we will follow up for another 6 months to record their conception outcome. The primary outcome is to compare the total motile sperm count, natural conception rate, and pregnancy outcome to those under placebo treatment. Secondary objectives are sperm functions and assisted reproductive technology outcome. DISCUSSION: To date, there are no studies using the disclosed Wuzi Yanzong formula or double-blinded, randomized trials. The Wuzi Yanzong TCM formula may provide a good clinical solution for subfertile males for which contemporary western medicine has no cure. Therefore, a well-designed randomized trial for evaluating the effect of Wuzi Yanzong TCM formula is urgently needed. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR), ChiCTR-INR-17010790 . Registered on 27 February 2017. Centre for Clinical Research and Biostatistics - Clinical Trials Registry, CUHK_CCRB00548 . Registered on 27 February 2017.

Efficacy, feasibility and patient acceptability of ultrasound-guided manual vacuum aspiration for treating early pregnancy loss.

BACKGROUND: Ultrasound-guided manual vacuum aspiration (USG-MVA) is an effective but underutilised alternative to medical or surgical evacuation of the uterus following first trimester miscarriage. AIMS: To evaluate the efficacy, feasibility and patient acceptability of USG-MVA for treating early pregnancy loss. MATERIAL AND METHODS: We invited patients with early pregnancy losses to participate in this prospective cohort study. We reviewed the medical records of the participants and their visual analogue pain score during MVA. Primary outcomes were efficacy, feasibility and patient acceptability of USG-MVA. Secondary outcomes included the success rate of culture of chorionic villi for chromosomal analysis and complications from the USG-MVA procedure. RESULTS: We included a consecutive series of 35 women who underwent the USG-MVA procedure. The efficacy of USG-MVA in achieving complete evacuation was 97.1%. The procedure was well tolerated and the mean procedure-related pain score was 6.25 out of 10 (SD 1.55). Overall, all patients were satisfied with the procedure. The successful culture rate of chromosomal analysis was 94.3%. There were no major complications. CONCLUSION: USG-MVA is an effective treatment for the management of early pregnancy loss in an out-patient setting. It is an alternative to surgical evacuation under general anaesthesia, particularly for women desiring chromosomal analysis of products of conception. Further studies are required to investigate its health-related and economic benefits in hospital service provision.

The effect of endometrial scratch on natural-cycle cryopreserved embryo transfer outcomes: a randomized controlled study.

The benefit of endometrial scratch (ES) prior to embryo transfer is controversial. Systemic analysis has confirmed its potential benefit, especially in women with repeated IVF failures, yet most studies have focused on fresh embryo transfer, and its effect on vitrified-warmed embryo transfer (FET) cycles is yet to be explored. We hereby present our prospective, double-blind, randomized controlled study on the evaluation of the implantation and pregnancy rate after ES prior to natural-cycle FET. A total of 299 patients underwent natural-cycle FET and were randomized to receive ES (n = 115) or endocervical manipulation as control (n = 114) prior to FET cycle, and a total of 196 patients had embryo transfer (93 patients in each group). Our study showed no significant difference in the implantation and pregnancy rate, as well as the clinical and ongoing pregnancy or live birth rates between the two groups. It appears that ES does not have any beneficial effect on an unselected group of women undergoing FET in natural cycles. Further studies on its effect in women with recurrent implantation failure after IVF are warranted.

A prospective randomized controlled trial of 3D versus 2D ultrasound-guided embryo transfer in women undergoing ART treatment.

STUDY QUESTION: Does three-dimensional (3D) versus two-dimensional (2D) ultrasound (US) guidance during embryo transfer (ET) increase the ongoing pregnancy rate in women undergoing ART treatment. SUMMARY ANSWER: There is no significant difference in the ongoing pregnancy rate of women undergoing 3D versus 2D US-guided ET. WHAT IS KNOWN ALREADY: Studies have suggested that 3D US may confer additional benefits compared with 2D US during ET, although this has not been tested within the context of an RCT. STUDY DESIGN, SIZE, DURATION: This was a single-blind, single centre prospective RCT performed between April 2015 and April 2016. A total of 481 recruited women were randomised into either a 3D or 2D US-guided ET group. PARTICIPANTS/MATERIALS, SETTING, METHOD: Women younger than 42 years in whom the endometrial cavity could be adequately visualised by US underwent ET in a university ART unit following a standard treatment protocol. All US examinations were performed by a single operator. In both 3D and 2D US groups, the inner catheter tip was aimed at the centre of the uterine cavity. The primary outcome measure was ongoing pregnancy rate, defined as the presence of at least one foetus with heart pulsation at 8 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in the ongoing pregnancy rate between the 3D and 2D US groups (35.4% versus 37.1%, P = 0.70; rate ratio 0.96, 95% confidence interval 0.75-1.21). There were also no significant differences in terms of positive hCG rate, biochemical pregnancy rate, implantation rate, clinical pregnancy rate, miscarriage rate, ectopic pregnancy rate and multiple pregnancy rate. LIMITATIONS, REASONS FOR CAUTION: This study recruited unselected women undergoing routine ET and was therefore not sufficiently powered to assess differences in subsets of women. WIDER IMPLICATIONS OF THE FINDINGS: Although 3D US may be a modern method for demonstrating the ET procedure, it should not be currently recommended as a strategy to improve clinical outcomes in women undergoing ART treatment. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Health and Medical Research Fund of Hong Kong. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02413697. TRIAL REGISTRATION DATE: 4 April 2015. DATE OF FIRST PATIENT'S ENROLMENT: 20 April 2015.