A reappraisal of ovarian stimulation strategies used in assisted reproductive technology.

Ovarian stimulation is a fundamental step in assisted reproductive technology (ART) with the intention of inducing ovarian follicle development prior to timed intercourse or intra-uterine insemination and facilitating the retrieval of multiple oocytes during a single in vitro fertilization (IVF) cycle. The basis of ovarian stimulation includes the administration of exogenous gonadotropins, with or without pre-treatment with oral hormonal therapy. Gonadotropin-releasing hormone agonist or antagonist is given in addition to the gonadotropins to prevent a premature rise of endogenous luteinizing hormone that would in turn lead to premature ovulation. With the advancement in technology, various stimulation protocols have been devised to cater for different patient needs. However, ovarian hyperstimulation syndrome and its serious complications may occur following ovarian stimulation. It is also evident that suboptimal ovarian stimulation strategies may have a negative impact on oogenesis, embryo quality, endometrial receptivity, and reproductive outcomes over recent years. This review describes the various forms of pre-treatment for ovarian stimulation and stimulation protocols, and aims to provide clinicians with the latest available evidence.

Biomarkers at 6 weeks' gestation in the prediction of early miscarriage in pregnancy following assisted reproductive technology.

INTRODUCTION: Miscarriage is a major concern in early pregnancy among women having conceived with assisted reproductive treatments. This study aimed to examine potential miscarriage-related biophysical and biochemical markers at 6 weeks' gestation among women with confirmed clinical pregnancy following in vitro fertilization (IVF)/embryo transfer (ET) and evaluate the performance of a model combining maternal factors, biophysical and biochemical markers at 6 weeks' gestation in the prediction of first trimester miscarriage among singleton pregnancies following IVF/ET. MATERIAL AND METHODS: A prospective cohort study was conducted in a teaching hospital between December 2017 and January 2020 including women who conceived through IVF/ET. Maternal mean arterial pressure, ultrasound markers including mean gestational sac diameter, fetal heart activity, crown rump length and mean uterine artery pulsatility index (mUTPI) and biochemical biomarkers including maternal serum soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), kisspeptin and glycodelin-A were measured at 6 weeks' gestation. Logistic regression analysis was carried out to determine significant predictors of miscarriage prior to 13 weeks' gestation and performance of screening was estimated by receiver-operating characteristics curve analysis. RESULTS: Among 169 included pregnancies, 145 (85.8%) pregnancies progressed to beyond 13 weeks' gestation and had live births whereas 24 (14.2%) pregnancies resulted in a miscarriage during the first trimester. In the miscarriage group, compared to the live birth group, maternal age, body mass index, and mean arterial pressure were significantly increased; mean gestational sac diameter, crown rump length, mUTPI, serum sFlt-1, glycodelin-A, and the rate of positive fetal heart activity were significantly decreased, while no significant differences were detected in PlGF and kisspeptin. Significant prediction for miscarriage before 13 weeks' gestation was provided by maternal age, fetal heart activity, mUTPI, and serum glycodelin-A. The combination of maternal age, ultrasound (fetal heart activity and mUTPI), and biochemical (glycodelin-A) markers achieved the highest area under the curve (AUC: 0.918, 95% CI 0.866-0.955), with estimated detection rates of 54.2% and 70.8% for miscarriage before 13 weeks' gestation, at fixed false positive rates of 5% and 10%, respectively. CONCLUSIONS: A combination of maternal age, fetal heart activity, mUTPI, and serum glycodelin-A at 6 weeks' gestation could effectively identify IVF/ET pregnancies at risk of first trimester miscarriage.

Young-onset diabetes in women with Polycystic Ovary Syndrome: A territory-wide retrospective analysis in Hong Kong.

AIM: To ascertain the risk of progression to diabetes among Chinese women with PCOS. METHODS: Women with PCOS (n = 3978) were identified from the Hong Kong Diabetes Surveillance Database based on the ICD-9 code for PCOS diagnosis and women without PCOS served as controls (n = 39780), matched 1:10 by age. RESULT(S): The mean follow-up was 6.28 ± 4.20 and 6.95 ± 4.33 years in women with PCOS and controls, respectively. The crude incidence rate of diabetes was 14.25/1000 person-years in women with PCOS compared with 3.45 in controls. The crude hazard ratio of diabetes in women with PCOS was 4.23 (95 % CI: 3.73-4.80, p < 0.001). Further stratified by age group, the risk of developing diabetes decreased with increasing age but it remained significantly higher in women with PCOS across all age groups. It also suggested that the incidence rate of diabetes in women with PCOS aged 20-29 is highly comparable to that in healthy women aged ≥ 40. More than half of the incident diabetes captured during the follow-up in women with PCOS cohort were young-onset diabetes. CONCLUSION: Women diagnosed with PCOS at a younger age have the highest relative risk of developing diabetes, suggesting frequent glycemic status screening is required to detect diabetes at an early stage.

Clinical Implementation of Expanded Carrier Screening in Pregnant Women at Early Gestational Weeks: A Chinese Cohort Study.

Demands for expanded carrier screening (ECS) are growing and ECS is becoming an important part of obstetrics practice and reproductive planning. The aim of this study is to evaluate the feasibility of a small-size ECS panel in clinical implementation and investigate Chinese couples' attitudes towards ECS. An ECS panel containing 11 recessive conditions was offered to Chinese pregnant women below 16 gestational weeks. Sequential testing of their partners was recommended for women with a positive carrier status. The reproductive decision and pregnancy outcome were surveyed for at-risk couples. A total of 1321 women performed ECS successfully and the overall carrier rate was 19.23%. The estimated at-risk couple rate was 0.83%. Sequential testing was performed in less than half of male partners. Eight at-risk couples were identified and four of them performed prenatal diagnosis. Our study demonstrated that a small-size ECS panel could yield comparable clinical value to a larger-size panel when the carrier rate of the individual condition is equal or greater than 1%. In addition, more than half of male partners whose wives were carriers declined any types of sequential testing possibly due to a lack of awareness and knowledge of genetic disorders. Genetic education is warranted for the better implementation of ECS.

Comparison of uterine artery Doppler measurements at 6 weeks of pregnancy after IVF between pregnancies that resulted in miscarriage and ongoing pregnancies.

OBJECTIVE: To compare uterine artery pulsatility index (UTPI) at 6 weeks of pregnancy following in vitro fertilization (IVF) and embryo transfer (ET) between clinical pregnancies that resulted in a miscarriage and those that were ongoing beyond 12 weeks. METHODS: A prospective observational study was conducted in an IVF unit at Prince of Wales Hospital, Hong Kong, between December 1, 2017 and December 31, 2019. UTPI was measured at 6 weeks of pregnancy among women who conceived following IVF/ET. RESULTS: Among 153 participants, 22 (14.4%) had a miscarriage whereas 131 (85.6%) had an ongoing pregnancy beyond 12 weeks. Median UTPI in pregnancies that ended in a miscarriage was significantly lower than those that progressed beyond 12 weeks (2.1, IQR 1.9-2.4 vs 2.50, IQR 2.2-2.9, respectively; P<0.001). The likelihood of the pregnancy ending in a miscarriage when the UTPI was above the 75th percentile (>2.9), between the 25th-75th percentiles (2.2-2.9), and below the 25th percentile (<2.2) was 0%, 13.2%, and 27.7%, respectively (P=0.001). CONCLUSIONS: IVF pregnancies that resulted in a miscarriage were associated with reduced resistance to uterine artery blood flow at 6 weeks of pregnancy.

Genome Sequencing Explores Complexity of Chromosomal Abnormalities in Recurrent Miscarriage.

Recurrent miscarriage (RM) affects millions of couples globally, and half of them have no demonstrated etiology. Genome sequencing (GS) is an enhanced and novel cytogenetic tool to define the contribution of chromosomal abnormalities in human diseases. In this study we evaluated its utility in RM-affected couples. We performed low-pass GS retrospectively for 1,090 RM-affected couples, all of whom had routine chromosome analysis. A customized sequencing and interpretation pipeline was developed to identify chromosomal rearrangements and deletions/duplications with confirmation by fluorescence in situ hybridization, chromosomal microarray analysis, and PCR studies. Low-pass GS yielded results in 1,077 of 1,090 couples (98.8%) and detected 127 chromosomal abnormalities in 11.7% (126/1,077) of couples; both members of one couple were identified with inversions. Of the 126 couples, 39.7% (50/126) had received former diagnostic results by karyotyping characteristic of normal human male or female karyotypes. Low-pass GS revealed additional chromosomal abnormalities in 50 (4.0%) couples, including eight with balanced translocations and 42 inversions. Follow-up studies of these couples showed a higher miscarriage/fetal-anomaly rate of 5/10 (50%) compared to 21/93 (22.6%) in couples with normal GS, resulting in a relative risk of 2.2 (95% confidence interval, 1.1 to 4.6). In these couples, this protocol significantly increased the diagnostic yield of chromosomal abnormalities per couple (11.7%) in comparison to chromosome analysis (8.0%, chi-square test p = 0.000751). In summary, low-pass GS identified underlying chromosomal aberrations in 1 in 9 RM-affected couples, enabling identification of a subgroup of couples with increased risk of subsequent miscarriage who would benefit from a personalized intervention.

Hyperandrogenism, Elevated 17-Hydroxyprogesterone and Its Urinary Metabolites in a Young Woman with Ovarian Steroid Cell Tumor, Not Otherwise Specified: Case Report and Review of the Literature.

We describe a case of a 24-year-old overweight woman who presented with hirsutism, secondary amenorrhea, clitoromegaly, and symptoms of diabetes mellitus (DM). While a diagnosis of polycystic ovary syndrome (PCOS) with its associated metabolic disturbances was initially considered, serum total testosterone, androstenedione, and 17-hydroxyprogesterone (17-OHP) measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) were significantly increased. As 17-OHP did not increase upon ACTH (Synacthen) stimulation and the urinary steroid profile (USP) was compatible with an ovarian source of 17-OHP excess rather than adrenal, non classical congenital adrenal hyperplasia (NCCAH) was unlikely and an androgen-secreting tumor was suspected. Transabdominal ultrasound revealed the presence of an enlarged right ovary with a polycystic ovary morphology and no discrete mass. Transvaginal ultrasound and [18F]- fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) enabled the localization of a right ovarian tumor. Laparoscopic right salpingo-oophorectomy was performed and a histological diagnosis of steroid cell tumor, not otherwise specified (SCT-NOS) was made. Hyperandrogenism and menstrual disturbances resolved postoperatively. A literature review revealed that 17-OHP-secreting SCT-NOS may uncommonly show positive responses to ACTH stimulation similar to 21-hydroxylase deficiency. Alternatively, USP might be useful in localizing the source of 17-OHP to the ovaries. Its diagnostic performance should be evaluated in further studies.

A prospective study of non-invasive preimplantation genetic testing for aneuploidies (NiPGT-A) using next-generation sequencing (NGS) on spent culture media (SCM).

PURPOSE: This study was to evaluate if spent culture media (SCM) of embryos could be used as a non-invasive tool to achieve aneuploidy screening. Ploidy calls, as well as concordance rates between PGT-A results from trophectoderm (TE) and SCM, were compared. Clinical outcomes of single euploid transfers were also evaluated. METHODS: The study was conducted from March 2017 to June 2018 in a university-based ART center. SCM of day 3 to the day(s) of TE biopsy of all biopsied blastocysts were collected for testing. PGT-A results of SCM were compared with the standard results of TE, with clinical relevance and outcomes examined. RESULTS: NiPGT-A using SCM gave a sensitivity of 81.6%, specificity of 48.3%, positive predictive value of 82.6%, and negative predictive value of 46.7% in ploidy calling. The concordance rates for autosomes and sex determination were 62.1% and 82.4%, respectively. There were 14 single embryo transfer cycles of euploids as determined by TE biopsy. Clinical outcomes not only confirmed 3 false positive results from SCM but also reflected the true ploidy status of the transferred embryo in one case. If ploidy calls were dichotomized without mosaic embryos, the sensitivity and NPV would increase to 91.0% and 66.7% (p = 0.60 and p = 0.25), respectively. CONCLUSIONS: Cell-free DNA found in SCM could provide ploidy information of an embryo as in PGT-A from its TE. Given its potential to reflect the comprehensive chromosomal profile of the whole embryo, more research based on clinical outcomes is required to determine if SCM could be a reliable selection tool in PGT-A.

Presence of Hepatitis B virus DNA in follicular fluid in female Hepatitis B carriers and outcome of IVF/ICSI treatment: A prospective observational study.

OBJECTIVE: To determine the relationship between the presence of detectable HBV DNA in the follicular fluid in HBV carriers with IVF/ICSI treatment outcome. STUDY DESIGN: A prospective observational study conducted in the Assisted Reproductive Unit, a tertiary referral centre affiliated with the Department of Obstetrics and Gynecology, The Chinese University of Hong Kong; and the Union Reproductive Medicine Centre at Union Hospital, Hong Kong. The primary outcome measure was pregnancy rate. Secondary outcome measures were the prevalence of detectable HBV DNA in the follicular fluid, implantation rate, clinical pregnancy rate, ongoing pregnancy rate and live birth rate. RESULTS: HBV DNA was detected in the follicular fluid of 28 (43.8%) of the 64 women, and the mean level in this group in log10 copies/mL (±SD) was 4.36 ± 1.85. Women with detectable follicular fluid HBV DNA were younger, lighter, had longer duration of infertility, higher incidence of detectable serum HBV DNA (OR 4.592, 95% C I 2.333-9.038), and significantly wider range in the number of total fertilized, viable embryos, and blastocyst rate, but no difference in cycle characteristics, stimulation and pregnancy outcomes, although the almost doubled ongoing pregnancy/live birth rate per cycle initiated (60.7% versus 38.9%) failed to reach statistical significance due to the small numbers. CONCLUSION: Our results suggested HBV infection did not appear to be detrimental to the outcome of IVF/ICSI treatment.

The Investigation and Management of Adenomyosis in Women Who Wish to Improve or Preserve Fertility.

The management of adenomyosis remains a great challenge to practicing gynaecologists. Until recently, hysterectomy has been the only definitive treatment in women who have completed child bearing. A number of nonsurgical and minimally invasive, fertility-sparing surgical treatment options have recently been developed. This review focuses on three aspects of management, namely, (1) newly introduced nonsurgical treatments; (2) management strategies of reproductive failures associated with adenomyosis; and (3) surgical approaches to the management of cystic adenomyoma.

A randomized crossover study of medroxyprogesterone acetate and Diane-35 in adolescent girls with polycystic ovarian syndrome.

OBJECTIVE: To investigate the effects of 4-month treatment of medroxyprogesterone acetate (MPA) and Diane-35 on the clinical and biochemical features of hyperandrogenism and quality of life of adolescent girls with polycystic ovarian syndrome (PCOS). DESIGN: A prospective, randomized, cross-over study. SETTING: An accredited pediatric and adolescent gynecology clinic of a university-affiliated tertiary hospital. PARTICIPANTS: 76 adolescents girls aged 14 to 19 years old with PCOS were recruited from July 2007 to July 2010. INTERVENTIONS: Girls were randomized into 2 groups. Group 1 received oral MPA for 4 months, followed by a washout period of 4 months, and then Diane-35 for another 4 months. Group 2 received the same combination but in the reverse order. MAIN OUTCOME MEASURES: Clinical and biochemical features of hyperandrogenism and quality of life were assessed. RESULTS: There was no significant difference between the 2 groups at baseline. No significant difference was found in the clinical and biochemical parameters of hyperandrogenism before and after treatment with MPA. Significant reduction of the acne score, LH/FSH ratio, and testosterone level was seen after taking Diane-35. Hirsutism was also improved but it did not reach statistical significant. When comparing post-MPA and post-Diane-35, the post-Diane-35 group had significantly improved acne score and LH/FSH ratio. No significant difference was found on quality of life between both groups after treatment. CONCLUSION: Diane-35 may be a more suitable treatment option in adolescent girls diagnosed with PCOS when compared to MPA.

Sperm cryopreservation for Chinese male cancer patients: a 17-year retrospective analysis in an assisted reproductive unit in Hong Kong.

OBJECTIVE: To review sperm cryopreservation usage rates, corresponding reproductive outcomes, and the current situation in our locality. DESIGN: Retrospective case series. SETTING: Assisted Reproductive Technology Unit of the Department of Obstetrics and Gynaecology, Prince of Wales Hospital and the Chinese University of Hong Kong. PARTICIPANTS: There were 130 Chinese male patients who underwent sperm cryopreservation before proceeding to gonadotoxic treatment from January 1995 to January 2012. MAIN OUTCOME MEASURES: Demographic data, type of cancers and treatments, semen analysis, and reproductive outcomes. RESULTS: The median patient age was 27 (range, 15-43) years. Most (85%) were single at the time of referral. Over half of the patients (51%) had testicular cancer. Five patients declined sperm cryopreservation after counselling. Among the remaining 125 men, 122 men were able to produce sperm by masturbation but 12 were found to have azoospermia, leaving a total of 110 who proceeded to semen cryopreservation. There were no significant differences in semen parameters between different cancer types. After gonadotoxic treatment, in up to 32% (n=11/34) of the patients, semen analysis yielded deterioration; four patients had azoospermia. Four patients (4%, n=4/110) came back to use their thawed semen for in-vitro fertilisation (intracytoplasmic sperm injection), which resulted in three successful singleton pregnancies. CONCLUSION: Sperm cryopreservation is a simple and effective way of preserving the fertility potential of male patients undergoing gonadotoxic treatment. This procedure is underutilised and deserves increased awareness by all possible means.

Long-term reproductive outcome after hysteroscopic proximal tubal cannulation--an outcome analysis.

BACKGROUND: The optimal therapeutic method for proximal tubal obstruction (PTO) has yet to be defined. In addition, the reported successful recanalisation rate and reproductive outcome from hysteroscopic proximal tubal cannulation have been inconsistent. AIMS: To examine the morbidity and efficacy of laparoscopic-hysteroscopic proximal tubal cannulation for treating PTO. MATERIAL AND METHODS: This was a retrospective study evaluating 70 infertile women with PTO who underwent laparoscopic-hysteroscopic proximal tubal cannulation in The Prince of Wales Hospital, a university-affiliated hospital, from January 2005 to December 2010. Demographical data and operative details were reviewed. Women were then contacted by phone and completed a structured questionnaire. Recanalisation rate, intra-operative complication, pregnancy rates and pregnancy outcomes were examined. RESULTS: Fifty women had successful proximal cannulation on at least one side of the tube, providing an overall successful recanalisation rate of 71.4% per woman and 67.0% per tube. The overall pregnancy rate after successful hysteroscopic proximal cannulation of at least one tube is 55%. The overall mean time to become pregnant from natural conception or via clomiphene induction after successful unilateral or bilateral hysteroscopic cannulation was 10.5 ± 8.9 months. The procedure is associated with minimal morbidity. No prognostic factors were significantly associated with recanalisation and pregnancy rate. CONCLUSION: Laparoscopic-hysteroscopic cannulation for proximal obstruction is a procedure with minimal morbidity and a reasonable successful recanalisation rate. It should be considered as an alternative to in vitro fertilisation.

Hysterectomy for recurrent postmenopausal bleeding revisited: missed sclerosing stromal ovarian tumour.

Sclerosing stromal tumour of the ovary is rare. Patients present with menstrual irregularities, pelvic pain, abdominal distension, and presence of a large pelvic mass during their twenties or thirties. We report a rare case of an ovarian sclerosing stromal tumour with an atypical presentation, in that it gave rise to recurrent postmenopausal bleeding.