Seminal biomarkers and their correlations to semen parameters in subfertile men.

Research question: To assess the levels of seminal biomarkers fructose, zinc and citrate and their correlations to semen parameters in infertile men. Design: 200 infertile male participants undergoing fertility assessment at Singapore General Hospital (SGH), Singapore were recruited prospectively, from June 2020 to August 2021. Their semen samples were assessed for seminal parameters, biomarker levels of fructose, citrate and zinc, leukocyte concentrations and aerobic cultures. They were also assessed for their smoking habits. Results: Sperm concentrations were negatively correlated to seminal fructose levels, r = -0.262, P < 0.001. Progressive motility were positively correlated to seminal citrate levels, r = 0.181, P = 0.014. Sperm morphology and total motile sperm count (TMSC) were positively correlated to seminal zinc and citrate levels, P < 0.05. Zinc and citrate levels were significantly reduced in teratozoospermia, asthenoteratozoospermia and oligoasthenoteratozoospermia groups compared to normozoospermia, P < 0.05. The presence of infection was associated with elevated leukocyte concentrations, lower sperm concentration (12.5 vs 55.8 million/mL, P = 0.024) and fructose levels (35.5 vs 49.2 µmol/ejaculate). Heavy smokers compared to light smokers, had lower sperm concentrations (35.3 vs 49.4 million/mL), TMSC (30.9 vs 47.5 million) and zinc levels (4.9 vs 6.7 µmol/ejaculate) and significantly lower citrate levels (52.6 vs 79.2 µmol/ejaculate, P = 0.029). Conclusions: Higher zinc and citrate levels correlated with better progressive motility, sperm morphology and TMSC. Smoking negatively impacted zinc and citrate levels, thereby affecting sperm quality. In conclusion, the inclusion of biomarkers in basic male work-up assessment would assist in identifying common deficiencies and aid in adequate replacement therapy.

Effect of fertility health awareness strategies on fertility knowledge and childbearing in young married couples (FertStart): study protocol for an effectiveness-implementation hybrid type I multicentre three-arm parallel group open-label randomised clinical trial.

INTRODUCTION: Birth rates have been declining in many advanced societies including Singapore. We designed two interventions with vastly different resource requirements, which include fertility education, personalised fertility information and a behavioural change component targeting modifiable psychological constructs to modify fertility awareness and childbearing intentions. We aim to evaluate the effect of these two interventions on knowledge, attitudes and practice around childbearing compared with a control group among young married couples in Singapore and understand the implementation factors in the setting of an effectiveness-implementation hybrid type 1 three-arm randomised trial. METHODS AND ANALYSIS: We will randomise 1200 young married couples to no intervention (control), Fertility Health Screening group (FHS) or Fertility Awareness Tools (FAT) in a 7:5:5 ratio. Couples in FHS will undergo an anti-Mullerian hormone test and semen analysis, a doctor's consultation to explain the results and standardised reproductive counselling by a trained nurse. Couples in FAT will watch a standardised video, complete an adapted fertility status awareness (FertiSTAT) tool and receive an educational brochure. The attitudes, fertility knowledge and efforts to achieve pregnancy of all couples will be assessed at baseline and 6 months post-randomisation. Birth statistics will be tracked using administrative records at 2 and 3 years. The primary outcome is the change in the woman's self-reported intended age at first birth between baseline and 6 months post-randomisation. In addition, implementation outcomes and cost-effectiveness of the two interventions will be assessed. ETHICS AND DISSEMINATION: This study has been reviewed and approved by the Centralized Institutional Review Board of SingHealth (2019/2095). Study results will be reported to the study funder and there are plans to disseminate them in scientific conferences and publications, where authorship will be determined by the International Committee of Medical Journal Editors guidelines. TRIAL REGISTRATION NUMBER: NCT04647136; ClinicalTrails.gov Identifier.

Embryo transfer day does not affect the initial maternal serum ß-hCG levels: A retrospective cohort study.

The aim of this study is to compare the serum ß-hCG values post transfer of a cleavage stage embryo versus a blastocyst stage embryo at equal time intervals post oocyte retrieval (OR) in clinically pregnant patients, and to ascertain a ß-hCG value to predict pregnancy outcomes. This is a retrospective cohort study of 560 women with clinical pregnancy who underwent an embryo transfer performed at either the cleavage stage or the blastocyst stage of embryo development between January 2003 and June 2014 at the Center for Assisted Reproduction (CARE), Singapore General Hospital. The serum ß-hCG level was measured on day 17 post OR. The ß-hCG values were not significantly different in the cleavage stage versus the blastocyst stage embryos (mean±SD: 387±486IU/L D3 vs. 352±268IU/L D5, p=0.96, median value 297 in both groups). Our study suggests that the initial maternal serum ß-hCG values were not affected by the day of transfer of the embryos since assessing the ß-hCG at equivalent points after transfer should not lead to a significant difference assuming the progress and development of the embryos occurred as expected.

Hysterosalpingo-foam sonography: patient selection and perspectives.

We present an overview of the common types of tubal patency tests, with a focus on hysterosalpingo-foam sonography (HyFoSy). Current evidence suggests that HyFoSy is an accurate alternative to X-ray hysterosalpingography (HSG) for outpatient tubal evaluation in women who are at low risk for tubal disease. It may be superior to saline hysterosalpingo-contrast sonography (HyCoSy) in excluding tubal occlusion. A hyperechogenic medium may enhance contrast visualization and enable clearer delineation of tubal anatomy. This may enhance confidence in the diagnosis of tubal patency, reduce false occlusion results, and improve the diagnostic yield of the test. It would be reasonable to deduce that HyFoSy would have similar performance characteristics as HyCoSy with other positive contrast agents. The available evidence supports the accuracy of HyFoSy compared to other forms of tubal investigation. We suggest a decision-making pathway based on the most current professional recommendations and available evidence. However, in this article, we do not provide a definitive exposition of the methods used for investigating tubal patency. Rather, we explore the contexts in which the various investigations are most and least suitable, and identify their strengths and limitations. Finally, we also discuss challenges encountered when performing tubal contrast sonography in clinical practice, including the problem of false occlusion results.

Live birth rates and safety profile using dydrogesterone for luteal phase support in assisted reproductive techniques.

INTRODUCTION: Assisted reproductive techniques (ARTs) result in a deficient luteal phase, requiring the administration of intramuscular, intravaginal or oral exogenous progesterone. Dydrogesterone, an oral retroprogesterone with good bioavailability, has been used in assisted reproductive cycles with outcomes that are comparable to those of vaginal or intramuscular progesterone. However, there are limited reviews on its use for luteal phase support in ARTs, in terms of pregnancy outcomes and associated fetal anomalies. This study aimed to review the live birth rates and associated fetal anomalies of women who were given dydrogesterone for luteal phase support in assisted reproductive cycles at a tertiary hospital in Singapore. METHODS: This retrospective descriptive study included 1,050 women who underwent in vitro fertilisation/intracytoplasmic sperm injection at the Centre for Assisted Reproduction of Singapore General Hospital between 2000 and 2011. The women were given dydrogesterone for luteal phase support. The main outcome measures were rates of pregnancy, live birth, miscarriage and fetal anomalies. RESULTS: The pregnancy and live birth rates were 34.7% and 27.7%, respectively. Among those who achieved pregnancy, 17.0% miscarried, 0.8% had ectopic pregnancies and 0.3% had molar pregnancies. Fetal anomalies were detected in 1.9% of pregnancies, all of which were terminated by choice. CONCLUSION: Since the outcomes of dydrogesterone are comparable to those of intramuscular and vaginal progesterone, it is a reasonable option to provide luteal phase support for women who are uncomfortable with injections or vaginal insertions. Randomised controlled studies are needed to determine the optimal dosage of dydrogesterone for luteal phase support in ARTs.

Multiple pregnancy is the leading contributor to cesarean sections in in vitro fertilization pregnancies: An analysis using the Robson 10-group classification system.

AIM: In vitro fertilization (IVF) pregnancy is an important contributor to rising cesarean section (CS) rates. The profile of CS in this group is not well documented. This study sought to identify leading patient categories of the Robson 10-Group Classification System (TGCS) contributing to the high IVF CS rate. METHODS: We carried out a prospective study of IVF patients who delivered in the Singapore General Hospital from January 2010 to July 2012. Parity, singleton/multiple pregnancy, previous CS, mode of labor onset and gestational age at delivery were collected based on the TGCS. All other deliveries during the study period served as control. RESULTS: There were a total of 215 IVF deliveries, of which 114 (54.4%) were CS. Group 8 (all multiple pregnancies) was the greatest contributor to the overall CS rate (43.0%). Group 2 (term nulliparous singleton cephalic pregnancies with induction of labor or planned CS) was the second largest contributor to overall CS rate (12.3%). The third and fourth leading contributors were Group 10 (preterm singleton pregnancies) and Group 5 (pregnancies with previous CS), respectively. In contrast, these two groups were top contributors to the overall CS rate for the control group. CONCLUSION: Multiple pregnancy is the principal contributor to CS in our IVF population, and reducing its incidence may reduce its CS rate. Among singleton pregnancies, planned CS and failed induction for cephalic term pregnancies and preterm singleton pregnancies were the next largest contributors, suggesting a higher prevalence of maternal request and high-risk obstetric indications requiring interventions at preterm gestations.

A comparison of hysterosalpingo-foam sonography (HyFoSy) and hysterosalpingo-contrast sonography with saline medium (HyCoSy) in the assessment of tubal patency.

OBJECTIVE: A randomized controlled selective cross-over trial was performed to compare the diagnostic yield and efficacy of ExEm foam (HyFoSy) with saline medium (HyCoSy) as a contrast agent for hysterosalping-contrast sonography in subfertile patients. STUDY DESIGN: 40 patients were randomized into HyCoSy with saline medium and HyFoSy with ExEm foam. Tubal patency were assessed according to pre-determined objective criteria that classified tubes based on degree of certainty in tubal patency. Selective cross-over testing with the other medium was performed in patients who had at least one possibly occluded or unexaminable tube on the initial test. RESULTS: 80 tubes were evaluated. On initial testing, the proportion of tubes that were classified as patent was higher with HyFoSy compared to HyCoSy (70.0% vs 40.0%, p=0.01). A higher proportion of patients in the HyCoSy group required crossover testing [80.0% (16/20) vs 45.0% (9/20), p=0.02]. On cross-over testing, 41.7% (10/24) of possibly occluded or unexaminable tubes in the HyCoSy group were re-classified as patent when examined with Ex-Em foam, compared to 8.3% (1/12) of possibly occluded or unexaminable tubes in the HyFoSy group (p=0.03). CONCLUSION: ExEm foam medium (HyFoSy) might improve the diagnostic yield and efficacy over saline medium (HyCoSy) for hysterosalpingsonography.

Use of In Vitro Fertilisation Prediction Model in an Asian Population-Experience in Singapore.

INTRODUCTION: This retrospective study was conducted to perform an external validation of the in vitro fertilisation (IVF) predict model developed by Scott Nelson et al in an Asian population. MATERIALS AND METHODS: All IVF cycles registered in the study centre from January 2005 to December 2010 were included. Observed and predicted values of at least 1 live birth per cycle were compared by discrimination, calibration. Hosmer-Lemeshow test was used to assess the goodness-of-fit of the model calibration and Brier score was used to assess overall model performance. RESULTS: Among 634 IVF cycles, rate of at least 1 live birth was 30.6%. Causes of infertility were unexplained in 35.5% cases. Fifty-seven percent of women came for their first IVF treatment. First IVF cycle showed significantly higher success in comparison to subsequent cycles. The odds ratio of successful live birth was worse in women with endometriosis. Observed outcome was found to be more than the prediction of the model. The area under the curve (AUC) in this study was found to be 0.65 that was close to that of Nelson model (0.6335) done in internal validation. Brier score (average prediction error) of model was 0.2. Chi square goodness-of-fit test indicated that there was difference between the predicted and observed value (x² =18.28, df = 8, P = 0.019). Overall statistical findings indicated that the accuracy of the prediction model fitted poorly with the study population. CONCLUSION: Ovarian reserve, treatment centre and racial effect on predictability cannot be excluded. So it is important to make a good prediction model by considering the additional factors before using the model widely.

Academy of Medicine-Ministry of Health Clinical Practice Guidelines: assessment and management of infertility at primary healthcare level.

The Academy of Medicine (AMS) and Ministry of Health (MOH) have developed the clinical practice guidelines on Assessment and Management of Infertility at Primary Healthcare Level to provide doctors and patients in Singapore with evidence-based treatment for infertility. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the AMS-MOH clinical practice guidelines on Assessment and Management of Infertility at Primary Healthcare Level, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guidelines/cpg_medical/2013/cpgmed_infertility.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Is semen polymorphonuclear leucocytes count a good predictor of male genital tract infection?

INTRODUCTION: This study aims to evaluate whether an increased polymorphonuclear leucocyte (PMN) count in semen is a good predictor of male genital tract infection, which is detected by semen culture. METHODS: A retrospective cross-sectional study examining the semen of 388 men was conducted at the in vitro fertilisation centre of a tertiary hospital. We compared the culture results of 109 men with increased semen PMN count against those of 279 men with normal semen PMN count. RESULTS: There was no significant difference in the percentage of positive cultures between men with increased PMN count in their semen and those without PMN count elevation (original sensitivity 20.8%, specificity 70.3%; p = 0.1289). The overall percentage of positive semen cultures among all 388 patients was 18.6%. CONCLUSION: Based on the positive cultures of significant organisms in the semen of our cohort, an increased semen PMN count is not a good predictor of genital tract infection in men.

Correlation between semen parameters and the Hamster Egg Penetration Test (HEPT) among fertile and subfertile men in Singapore.

The objective of this retrospective study was to distinguish between fertile and subfertile men based on their semen parameters and hamster egg penetration test (HEPT) outcome. This study involved 110 subfertile men recruited from an infertility clinic and 48 fertile men attending an antenatal clinic in Singapore. The men were required to donate a semen specimen for semen analysis and HEPT assay. The results indicated that the subfertile group had significantly lower normal sperm morphology according to the Tygerberg strict criteria, and lower progressive motility (P < .05). Semen volume, density, HEPT decondensation rate, and sperm penetration index were not significantly different between the 2 groups. Receiver operating characteristic curve analysis indicated that sperm morphology had the highest predictive power of 65.7% with a threshold value of 7%, and progressive motility had a predictive power of 61.8% with a threshold value of 50%. Using the tenth percentile of the fertile population as the cutoff, lower adjusted thresholds of 3% for sperm morphology and 28% for progressive motility were obtained, giving higher positive predictive values of 81.8% and 84.4%, respectively. This study shows that these new cutoff values can be used to screen the general population to identify subfertile men. In contrast, the HEPT proved to be an insensitive and unreliable assay in identifying subfertile males. To our knowledge the comparison of HEPT and semen parameters between subfertile and fertile men has not been previously reported in an Asian population.

The efficacy of two dosages of a continuous combined hormone replacement regimen.

OBJECTIVES: To evaluate the efficacy of a low-dose combination of estradiol (E2) and norethisterone acetate (NETA) on bone markers, lipid and bleeding profiles and menopausal symptoms. METHOD: Ninety-six healthy Chinese postmenopausal women were allocated randomly to receive 1 mg E2/0.5 mg NETA (low-dose hormone replacement therapy (HRT)) or 2 mg E2/1 mg NETA (high-dose HRT) for 6 months. RESULTS: Bone resorption markers (collagen I N-terminal telopeptides (NTX) and deoxypyridinoline (dPyr)) were significantly reduced; -66 and -32%, respectively, in high-dose HRT versus -55 and -24%, respectively, in low-dose HRT. Bone-specific alkaline phosphatase remained unchanged with either combination of hormones. Total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels were decreased significantly (-12 and -13%, respectively, in high-dose HRT vs. -7 and -8% in low-dose HRT). High density lipoprotein cholesterol (HDL-C) was decreased to a lesser extent in low-dose HRT and triglycerides (TG) levels remained unchanged. Both the low and high-dose HRT were effective in alleviating menopausal symptoms. After 6 months of treatment, 2% of women in the low-dose HRT were bleeding compared with 23% in the high-dose HRT. Breast pain occurred in 2% of women in low-dose HRT compared with 15% in high-dose HRT. The endometrium in the majority of the women remained normal. CONCLUSION: Menopausal symptoms were reduced effectively in postmenopausal women on either low-dose or high-dose HRT. TC, LDL-C levels and bone resorption markers were reduced in a dose-dependent manner. Low-dose HRT provided a better bleeding profile and the incidence of breast pain was low.