Australasian Recurrent Pregnancy Loss Clinical Management Guideline 2024 Part I.

Guidelines for the investigation and management of recurrent pregnancy loss (RPL) have been developed in Europe, USA and UK, but there is currently no Australasian guideline. The Australasian Certificate of Reproductive Endocrinology and Infertility Consensus Expert Panel on Trial Evidence group has prepared a two-part guideline to provide guidance on the management of RPL. In Part I chromosomal, anatomical, and endocrine factors are outlined along with relevant recommendations for clinical management, levels of evidence and grades of consensus. In Part II thrombophilia, autoimmune factors, infective, inflammatory, and endometrial causes, environmental and lifestyle factors, male factor and unexplained causes will be outlined.

Australasian recurrent pregnancy loss clinical management guideline 2024, part II.

Part II of the Australasian guideline for the investigation and management of recurrent pregnancy loss (RPL) provides evidence-based guidance on the management of RPL provided. The implications of inherited and acquired thrombophilia with respect to RPL and suggestions for clinical management are provided. Autoimmune factors, including human leukocyte antigen, cytokines, antinuclear antibodies and coeliac antibodies, and guidance for management are discussed. Infective, inflammatory and endometrial causes of RPL are discussed in detail. Environmental and lifestyle factors, male factor and unexplained causes are outlined. Levels of evidence and grades of consensus are provided for all evidence-based statements.

First uterine transplant case at the Royal Prince Alfred Hospital.

Uterine transplantation (UT) is an emerging medical treatment for women affected by absolute uterine factor infertility (AUFI). To date there have been over 90 documented cases of UT performed worldwide, with over 50 live births. UT allows women affected by AUFI the opportunity to carry and deliver a childd. The Royal Prince Alfred Hospital (RPAH) introduced a UT study in 2019; however, due to the impacts of the COVID pandemic the study was placed on hold for two years. In February 2023, RPAH performed the centre's first UT from a living unrelated donor to a 25-year-old woman with Mayer-Rokitansky-Küster-Hauser syndrome. The donor and recipient surgeries were uncomplicated and both are recovering well in the early post-operative period.

Fertility preservation in gynaecology oncology patients: Experience from an Australian tertiary oncology centre.

BACKGROUND: Management for gynaecological cancers often includes removal of the reproductive organs and/or the use of gonadotoxic therapies resulting in sub-fertility. Oncofertility and discussion of fertility preservation in these patients is critical. AIM: To determine the rate of fertility preservation discussion among a cohort of patients with a gynaecological cancer and what determinants impact likelihood of a discussion. MATERIALS AND METHODS: A seven-year quantitative retrospective study was conducted at a single oncology centre, including 15-45 year old patients with a gynaecological cancer. The primary outcome was if a fertility preservation discussion occurred during a consultation. Secondary outcomes included if a referral was made and what fertility preservation services were undertaken. Determinants that impacted the likelihood of a fertility preservation discussion were analysed. RESULTS: One hundred and twenty-one patients were analysed. There were 84 (69%) patients who had a documented fertility preservation discussion, and 46% were referred to a fertility specialist for consultation. Age was a significant determinant, with patients aged 30-39 years of age more commonly having a fertility preservation discussion. Patients with a high-grade cancer compared to patients with a lower-grade cancer (grade one or two) were only a third as likely to have a discussion surrounding their fertility (odds ratio: 0.33, 95% CI: 0.13-0.86; P = 0.02). CONCLUSION: We conclude that rates of discussion around fertility options for patients with cancer are lower than the recommended guidelines. Oncofertility is an important discipline which we believe needs to be emphasised within the gynaecology oncology community and management of patients should include a multi-disciplinary team.

Uterus transplantation and pregnancy induction: Approved protocol at the Royal Prince Alfred Hospital.

Absolute uterine factor infertility (AUFI) is defined as the absence of a uterus or the presence of a non-functional uterus. Before the first live birth from a uterus transplant in 2014, the only fertility options for women with AUFI were surrogacy and adoption. In November 2019, our team was granted approval for the first uterus transplant trial in Australia using known living donors. Our program is based on that of our overseas collaborators in Dallas, Texas; this team will also be proctoring us for our first two cases.

Fertility preservation in oncology patients: A literature review examining current fertility preservation techniques and access to oncofertility services in Australia.

BACKGROUND: In Australia, between the years 2010 and 2014, over 4500 adolescents and young adults (15-25 years old) were diagnosed with cancer. Treatment regimens are often gonadotoxic and are well known to induce ovarian and testicular failure. Oncofertility is an emerging discipline in obstetrics and gynaecology which seeks to preserve and restore the reproductive future of cancer patients. AIM: To perform a systematic literature review to assess the current fertility preservation techniques available to patients and examine access and uptake of fertility preservation in Australia. MATERIALS AND METHODS: Electronic databases, including Medline, Cochrane Review, SCOPUS and CINHAL, were searched for peer-reviewed publications and national guidelines examining oncofertility practices from 2008 to July 2018. Three hundred and seventy-five articles were initially screened, with 158 articles for full text review and an additional five clinical guidelines were identified. RESULTS: There is a paucity of Australian data on oncofertility with <50% of data included for analysis reflecting the Australian experience. The majority of primary research included retrospective papers with small cohort numbers. Key areas addressed included live birth outcomes, uptake of services and patient and physician perspectives on fertility preservation. Few articles sought to examine the positive and negative side effects of fertility preservation in oncology, social challenges of oncofertility and access to services worldwide. CONCLUSION: Oncofertility is an emerging discipline which seeks to provide safe, efficient and effective fertility preservation options for young adults and adolescents diagnosed with cancer. A multi-disciplinary approach with collaborative communication with oncologists is key to providing this service within Australia.

Steroid profiles by liquid chromatography-mass spectrometry of matched serum and single dominant ovarian follicular fluid from women undergoing IVF.

RESEARCH QUESTION: Can IVF outcomes be predicted from the steroid profile generated by liquid chromatography-mass spectrometry (LC-MS/MS) from follicular fluid collected from a single dominant follicle and serum after ovarian stimulation. DESIGN: Prospective observational cohort study in which serum and follicular fluid were collected from women and used to generate steroid profiles by LC-MS/MS. A total of 93 consecutive women enrolled for IVF treatment were recruited at the Fertility Unit, Royal Prince Alfred Women and Babies Hospital, Sydney between September 2014 and July 2015. Baseline and serum levels at oocyte retrieval, as well as follicular fluid samples from the largest single antral follicle, were collected. All samples underwent steroid analysis within a single batch to measure progesterone (P4), oestradiol (E2), oestrone (E1), dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T), dihydrotestosterone (DHT), and 3 α, 5α androstanediol (3α-diol) and 3ß, 5α androstanediol (3ß-diol). RESULTS: P4, E2, E1, A4, T, DHEA and A4 were detectable in all baseline serum levels, at oocyte retrieval and in follicular fluid samples, whereas DHT, 3α-diol and 3ß-diol were only detectable in a minority of samples. The most consistent predictor of pre-transfer (number of follicles >14mm in diameter, oocytes retrieved or fertilized, day-5 blastocysts) outcomes was baseline serum anti-Müllerian hormone. In follicular fluid, E2 was a negative predictor of the number of oocytes retrieved and the number of day-5 blastocysts but no follicular fluid steroids predicted pregnancy outcome. CONCLUSIONS: None of the nine steroids measured in follicular fluid predicted pregnancy outcome in women undergoing IVF.

Updated Australian consensus statement on management of inherited bleeding disorders in pregnancy.

INTRODUCTION: There have been significant advances in the understanding of the management of inherited bleeding disorders in pregnancy since the last Australian Haemophilia Centre Directors' Organisation (AHCDO) consensus statement was published in 2009. This updated consensus statement provides practical information for clinicians managing pregnant women who have, or carry a gene for, inherited bleeding disorders, and their potentially affected infants. It represents the consensus opinion of all AHCDO members; where evidence was lacking, recommendations have been based on clinical experience and consensus opinion. MAIN RECOMMENDATIONS: During pregnancy and delivery, women with inherited bleeding disorders may be exposed to haemostatic challenges. Women with inherited bleeding disorders, and their potentially affected infants, need specialised care during pregnancy, delivery, and postpartum, and should be managed by a multidisciplinary team that includes at a minimum an obstetrician, anaesthetist, paediatrician or neonatologist, and haematologist. Recommendations on management of pregnancy, labour, delivery, obstetric anaesthesia and postpartum care, including reducing and treating postpartum haemorrhage, are included. The management of infants known to have or be at risk of an inherited bleeding disorder is also covered. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: Key changes in this update include the addition of a summary of the expected physiological changes in coagulation factors and phenotypic severity of bleeding disorders in pregnancy; a flow chart for the recommended clinical management during pregnancy and delivery; guidance for the use of regional anaesthetic; and prophylactic treatment recommendations including concomitant tranexamic acid.

Use of the CryoPredict algorithm to predict live birth from cryopreserved embryos.

BACKGROUND: Currently, the viability of cryostored blastocysts that are subsequently re-warmed is determined via the percentage of cell survival. However, the large number of cells that forms the blastocyst can make this estimate difficult and unreliable. Studies have shown that fast re-expanding blastocysts have superior pregnancy rates. AIM: To determine whether the degree and speed of blastocoele re-expansion following cryopreservation and warming correlate with rates of live birth. MATERIALS AND METHODS: A retrospective cohort study of 757 frozen embryo transfer cycles over a 4-year period at Royal Prince Alfred Hospital, Sydney. Clinical and embryology notes were retrieved. Details regarding patient demographics, stimulation cycle from which embryos were derived, frozen embryo transfer cycles, embryology and pregnancy outcomes were recorded. RESULTS: Female (P = 0.01) and male age (P = 0.02) at the time of embryo creation were inversely associated with live birth. Fertilisation method (P = 0.03), embryo type at cryopreservation (P = 0.009), embryo grade at cryopreservation (P < 0.0001), percentage of cell survival post-thaw (P < 0.0001) and the degree of re-expansion (P = 0.003) were the IVF and embryology factors significantly associated with live birth. A predictive model (CryoPredict) was created in order to individualise the probability that the transfer of a given embryo would result in live birth. CONCLUSIONS: The degree and speed of blastocoele re-expansion postcryopreservation and subsequent warming can be used in conjunction with other parameters to predict live birth.

Persistent occiput posterior: OUTcomes following digital rotation: a pilot randomised controlled trial.

AIM: To determine the feasibility of a multicentre randomised controlled trial (RCT) to investigate whether digital rotation of the fetal head from occiput posterior (OP) position in the second stage of labour reduces the risk of operative delivery (defined as caesarean section (CS) or instrumental delivery). METHODS: We conducted the study between December 2010 and December 2011 in a tertiary referral hospital in Australia. A transabdominal ultrasound was performed early in the second stage of labour on women with cephalic, singleton pregnancies to determine the fetal position. Those women with a fetus in the OP position were randomised to either a digital rotation or a sham procedure. In all other ways, participants received their usual intrapartum care. Data regarding demographics, mode of delivery, labour, post natal period and neonatal outcomes were collected. RESULTS: One thousand and four women were consented, 834 achieved full dilatation, and 30 were randomised. An additional portable ultrasound scan and a blinded 'sham' digital rotation were acceptable to women and staff. Operative delivery rates were 13/15 in the digital rotation (four CS and nine instrumental) and 12/15 in the sham (three CS and nine instrumental) groups, respectively. CONCLUSION: A large double-blinded multicentre RCT would be feasible and acceptable to women and staff. Strategies to improve recruitment such as consenting women with an effective epidural in active labour should be considered. This would be the first RCT to answer a clinically important question which could significantly affect the operative delivery rate in Australia and internationally.

Ultrasound assessment of cervical length at 18-21 weeks' gestation in an Australian obstetric population: comparison of transabdominal and transvaginal approaches.

BACKGROUND: Using a fixed cut-off of ≤25 mm, ultrasound assessment of cervical length during the 18-23 week anomaly scan has been shown to identify approximately 50% of pregnancies that would deliver prior to 34 weeks. AIM: To determine whether a policy of reverting to transvaginal cervical assessment only if the cervix appears short (≤25 mm) on transabdominal assessment affects the efficiency of screening. METHODS: Women with a singleton pregnancy that presented for a routine anomaly scan had their cervical length assessed transabdominally, initially with the maternal bladder full (TABF) and then empty (TABE). Cervical length was then assessed transvaginally (TV). RESULTS: One hundred and ninety-eight women agreed to participate in the study. Identification of the internal and external cervical os was possible during TABF, TABE and TV sonography in 97.0, 82.8 and 100%, respectively. Compared with TV sonography, TABF overestimates cervical length (6.1 mm difference in median values; P < 0.01). There was no significant difference between TV and TABE. However, TABE assessment was not possible in one in six women. If TABF sonography was to be used as a screening tool and using ≤25 mm as the critical cut-off, the sensitivity and specificity was 15.4 and 93.2%, respectively. CONCLUSION: This study has shown that assessment of cervical length using a TA approach is only routinely possible when the bladder is full. However, measurements are significantly overestimated. Therefore, we feel that TV assessment of cervical length is the preferred method of reliable cervical assessment. As such, all women should be offered a TV assessment of cervical length at the time of the fetal anomaly ultrasound as a screening test for preterm birth.

Prolactin-Secreting Leiomyoma Causing Hyperprolactinaemia Unresponsive to Dopamine Agonist Therapy and Resolution following Myomectomy.

Prolactin-secreting leiomyomas are rare, with only eight cases reported in the literature. This case describes a 37-year-old female with hyperprolactinaemia (1846 mIU/L; 85-500 mIU/L) refractory to cabergoline causing infertility and galactorrhea. MRI pituitary was normal. The patient had a known enlarging uterine leiomyoma on serial pelvic ultrasounds (15.2 cm × 9.1 cm × 12.1 cm). The serum prolactin returned to subnormal levels two days postmyomectomy and showed recovery to normal levels in the months following surgery. Immunostaining of the leiomyoma for prolactin was negative. Despite not staining for prolactin, quick resolution of the patient's hyperprolactinaemia after myomectomy supports the diagnosis of a prolactin-secreting fibroid. A prolactin-secreting leiomyoma should be considered in patients with hyperprolactinaemia and normal pituitary MRI which is refractory to dopamine receptor agonist therapy who also have evidence of a uterine fibroid. In patients wishing to seek fertility, myomectomy should be considered to allow for normal ovulation and possibility of future fertility.

Recurrent pregnancy loss: A summary of international evidence-based guidelines and practice.

BACKGROUND: Recurrent pregnancy loss (RPL) is defined as two or more pregnancy losses. It affects <5% of couples. There are many proposed causes; however, in a significant proportion of cases, the cause is unknown. OBJECTIVE: The aim of this paper is to provide a summary of the aetiology, investigations and management of RPL, which is based on the three most recent international guidelines on RPL (European Society of Human Reproduction and Embryology, 2017; American Society for Reproductive Medicine, 2012; and the Royal College of Obstetricians and Gynaecologists, 2011). DISCUSSION: Management of RPL should occur in a specialised clinic. Appropriate investigations include karyotyping of parents and products of conception, two-dimensional/three-dimensional ultrasonography with sonohysterography, thyroid function tests, and antibodies and testing for acquired thrombophilias. Management options encompass some lifestyle modifications for smoking, alcohol, illicit drug use and caffeine consumption. Acquired thrombophilias should be treated with unfractionated heparin and low-dose aspirin.

Linking sleep disturbance to idiopathic male infertility.

Recently published data suggests that male fertility has declined over the past four decades. The reasons for the decline are unclear with up to 50% of cases of male infertility remaining unexplained (idiopathic male infertility). Whilst environmental factors and rising rates of obesity have been implicated, there is now growing evidence that sleep disturbance may be an independent causative factor. Indeed, the prevalence of sleep disturbance appears to be increasing in parallel with deterioration in population sperm quality, a commonly used surrogate marker of male fertility. Although there is some understanding of the relationship between sleep, gonadal hormone secretion and sexual function, it remains to be seen whether sleep disturbance is implicated in idiopathic male infertility. This review will detail the current evidence supporting a link between sleep disturbance and male infertility. Potential mechanistic pathways will be proposed and evidence supporting these pathways will be discussed. Further research is needed in clarifying links between sleep disturbance and idiopathic male infertility. At present the only available treatment option for men with idiopathic infertility is assisted reproductive technology. Demonstration of a causative link between sleep disturbance and idiopathic male infertility may in the future lead to additional treatment options in selected cases.

Accuracy of a Direct Progesterone Immunoassay.

BACKGROUND: Beyond the established role of serum progesterone measurement in the luteal phase of menstrual cycle to confirm recent ovulation, it is also increasingly used to detect premature luteinization during in vitro fertilization (IVF) hyperstimulation, where late follicular phase increase in serum progesterone is reportedly associated with adverse pregnancy outcomes. Virtually all serum progesterone measurements in clinical and IVF practice use direct, nonextraction immunoassays, often in multiplex, high-throughput platform assays optimized for high, postovulatory, midluteal phase serum progesterone concentrations. However, the performance of direct progesterone immunoassays for smaller increases is not established. METHODS: We studied 254 women undergoing IVF hyperstimulation with serum progesterone around the time of human chorionic gonadotropin (hCG) administration, measured in each sample by a direct progesterone immunoassay (Beckman Coulter Access) and by LC-MS. RESULTS: Immunoassay overestimated serum progesterone in almost every sample with an increasingly high variability and deviation at lower concentrations (immunoassay <5 nmol/L, equivalent to LC-MS <2 nmol/L). CONCLUSIONS: Immunoassay consistently overestimates serum progesterone levels so that low measurements (immunoassay <5 nmol/L) are too inaccurate to be used quantitatively. The utility of higher serum progesterone measurements by immunoassay and serum progesterone and other steroids measured by multiplex LC-MS profiling in predicting IVF pregnancy outcomes warrants further investigation. There is a need for caution in clinical diagnosis of premature luteinization based on increased late follicular phase serum progesterone measurements using direct progesterone immunoassay that consistently overestimates low serum progesterone concentrations.