Placental, maternal, fetal, and technical origins of false-positive cell-free DNA screening results.

The introduction of noninvasive prenatal testing has resulted in substantial reductions to previously accepted false-positive rates of prenatal screening. Despite this, the possibility of false-positive results remains a challenging consideration in clinical practice, particularly considering the increasing uptake of genome-wide noninvasive prenatal testing, and the subsequent increased proportion of high-risk results attributable to various biological events besides fetal aneuploidy. Confined placental mosaicism, whereby chromosome anomalies exclusively affect the placenta, is perhaps the most widely accepted cause of false-positive noninvasive prenatal testing. There remains, however, a substantial degree of ambiguity in the literature pertaining to the clinical ramifications of confined placental mosaicism and its potential association with placental insufficiency, and consequentially adverse pregnancy outcomes including fetal growth restriction. Other causes of false-positive noninvasive prenatal testing include vanishing twin syndrome, in which the cell-free DNA from a demised aneuploidy-affected twin triggers a high-risk result, technical failures, and maternal origins of abnormal cell-free DNA such as uterine fibroids or unrecognized mosaicisms. Most concerningly, maternal malignancies are also a documented cause of false-positive screening results. In this review, we compile what is currently known about the various causes of false-positive noninvasive prenatal testing.

The accuracy of cell-free DNA screening for fetal segmental copy number variants: A systematic review and meta-analysis.

BACKGROUND: The performance of cell-free DNA (cfDNA) screening for microscopic copy number variants (CNVs) is unclear. OBJECTIVES: This was a systematic review and meta-analysis to investigate the sensitivity, specificity and positive predictive value (PPV) of cfDNA screening for CNVs. SEARCH STRATEGY: Articles published in EMBASE, PubMed or Web of Science before November 2022 were screened for inclusion. This protocol was registered with PROSPERO (23 March 2021, CRD42021250849) prior to initiation. SELECTION CRITERIA: Articles published in English, detailing diagnostic outcomes for at least 10 high-risk CNV results with cfDNA were considered for inclusion. DATA COLLECTION AND ANALYSIS: The PPV was calculated and pooled with random-effects models for double-arcsine transformed proportions, using cases with diagnostic confirmation. Overall sensitivity, specificity and a summary receiver-operating characteristics (ROC) curve were calculated using bivariate models. The risk of bias was assessed using QUADAS-2. MAIN RESULTS: In all, 63 articles were included in the final analysis, detailing 1 591 459 cfDNA results. The pooled PPV was 37.5% (95% confidence interval [CI] 30.6-44.8), with substantial statistical heterogeneity (I2  = 93.9%). Bivariate meta-analysis estimated sensitivity and specificity to be 77.4% (95% CI 65.7-86.0) and 99.4% (95% CI 98.0-99.8), respectively, with an area under the summary ROC curve of 0.947 (95% CI 0.776-0.984). CONCLUSIONS: Approximately one-third of women who screen high-risk for CNVs with cfDNA will have an affected fetus. This value is of importance for screening counselling.

Cell-free DNA screening for rare autosomal trisomies and segmental chromosome imbalances.

OBJECTIVE: To assess the outcomes of pregnancies at high-risk for rare autosomal trisomies (RATs) and segmental imbalances (SIs) on cell-free DNA (cfDNA) screening. METHOD: A retrospective study of women who underwent cfDNA screening between September 2019 and July 2021 at three ultrasound services in Australia. Positive predictive values (PPVs) were calculated using fetal chromosomal analysis. RESULTS: Among 23,857 women screened, there were 93 high-risk results for RATs (0.39%) and 82 for SIs (0.34%). The PPVs were 3.8% (3/78, 95% CI 0.8%-10.8%) for RATs and 19.1% (13/68, 95% CI 10.6%-30.5%) for SIs. If fetuses with structural anomalies were also counted as true-positive cases, the PPV for RATS increased to 8.5% (7/82, 95% CI 3.5%-16.8%). Among 85 discordant cases with birth outcomes available (65.4%), discordant positive RATs had a significantly higher proportion of infants born below the 10th and 3rd birthweight percentiles than expected (19.6% (p = 0.022) and 9.8% (p = 0.004), respectively), which was not observed in the SI group (2.9% < 10th (p = 0.168) and 0.0% <3rd (p = 0.305)). CONCLUSION: The PPVs for SI and RAT results are low, except when a structural abnormality is also present. Discordant positive RATs are associated with growth restriction.

Blended (online and in-person) Women's Health Interprofessional Learning by Simulation (WHIPLS) for medical and midwifery students.

BACKGROUND: Blended teaching combines traditional in-person components (simulation-based training and clinical-based placement) with online resources. Due to the COVID-19 pandemic, we modified our Women's Health Interprofessional Learning through Simulation (WHIPLS) program - to develop core obstetric and gynaecological skills - into a blended teaching program. There is limited literature reporting the observations of blended teaching on learning. AIMS: To qualitatively evaluate the blended teaching program and explore how it contributes to learning. MATERIALS AND METHODS: This study was performed at Monash University in Melbourne, Australia. A total of 98 medical students and 39 midwifery students participated. Data were collected by written survey and analysed by authors using a thematic analysis framework. RESULTS: Students reported that in-person teaching remains a vital aspect of their curriculum, contributing an averaged 63.2% toward an individual's learning, compared with online. Five substantial themes demonstrate how students learnt and maximised education opportunities using a blended teaching program: 'low-pressure simulation environments', 'peer-assisted learning', 'haptic learning', 'scaffolded learning' and 'the impact of online discourse'. DISCUSSION: In-person teaching remains a cornerstone of obstetric and gynaecological clinical skills education, of which interprofessional simulation and clinical-based placement are key components. Teaching via online discourse alone, is not sufficient to completely replace and provide comparable learning outcomes, but certainly plays an important role to prime students' learning and to maximise in-person opportunities and resources. Our study reveals key pedagogies of a blended (online and in-person) learning program, providing further evidence to support its ongoing utility as a feasible and warranted approach to learning.

Ultrasound findings and detection of fetal abnormalities before 11 weeks of gestation.

OBJECTIVE: To determine the proportion of major fetal structural abnormalities that can be detected before 11 gestational weeks. METHODS: We conducted a retrospective study of individual patient files at a tertiary provider of obstetric and gynecological ultrasound in Melbourne, Australia. All women who had a pre-cell-free DNA ultrasound with a crown-rump length of less than 45 mm and had one or more ultrasounds at a later gestation were included in the analysis. The primary outcome was the incidence of a fetal structural abnormality. RESULTS: A total of 3333 cases were included in the final analysis. Overall, 316 fetuses (9.5%) had a structural abnormality detected at any point throughout gestation, of which 86 were major structural abnormalities (2.6%). Sixteen fetal abnormalities were detected before 11 weeks of gestation, including 15 major abnormalities (17.4% of the major anomalies). All major fetal abnormalities detected before 11 gestational weeks were confirmed at later ultrasound examinations or the pregnancy did not continue (in four cases due to termination of pregnancy and in one case spontaneous miscarriage before first trimester morphology ultrasound). CONCLUSION: Detection of fetal abnormalities is possible before 11 weeks of gestation. Early suspicion is more likely in cases of major structural abnormalities.

The importance of ultrasound preceding cell-free DNA screening for fetal chromosomal abnormalities.

OBJECTIVE: This study aims to determine the incidence of ultrasound findings that may change clinical management on the day of blood-sampling for cell-free DNA (cfDNA) screening. METHODS: A retrospective study was conducted at a tertiary provider of obstetric and gynecological ultrasound in Melbourne, Australia. Individual patient files were reviewed and results were collated for maternal characteristics, pre-cfDNA ultrasound reports, results and test characteristics of both cfDNA and diagnostic testing, and genetic counselling notes. The primary outcome was a potential change in patient management due to findings detected on the pre-cfDNA ultrasound. RESULTS: Of 6250 pre-cfDNA ultrasounds, 6207 were included in analysis. Of these, 598 (9.6%) pregnancies had a finding on pre-cfDNA ultrasound that had the potential to change management. The reasons for this potential change in management were detection of gestational age below 10 weeks (245, 3.9%), miscarriage (175, 2.8%), demised twin (43, 0.7%), fetal edema (115, 1.9%) and major structural abnormalities (20, 0.3%). These findings were more common in patients of advanced maternal age and in spontaneous conceptions. CONCLUSIONS: An ultrasound prior to cfDNA screening has the potential to change clinical management in almost one in 10 women. The proportion is higher in older age groups and lower in IVF-conceived pregnancies.

The Role of Fertility Preservation in Women with Endometriosis: A Systematic Review.

OBJECTIVE: To summarize the available evidence concerning fertility preservation techniques in the context of women with endometriosis. DATA SOURCES: We searched for studies published between 1984 and 2019 on endometriosis and Assisted Reproductive Technology outcomes. We searched MEDLINE and PubMed and performed a manual search of reference lists within identified studies. METHODS OF STUDY SELECTION: A total of 426 articles were identified, and 7 studies were eligible to be included for the systematic review. We included all published studies, excluding reviews, case reports, and animal studies. TABULATION, INTEGRATION, AND RESULTS: Despite a significant increase in the number of studies addressing fertility preservation over the study period, we found a relative lack of evidence addressing the use of fertility preservation techniques in women with endometriosis. The studies identified included 2 case reports, 1 histological science study, and 4 retrospective cohort studies. CONCLUSION: Women with endometriosis may benefit from fertility preservation techniques. However, there currently is a paucity of data in this population, especially when compared with other indications for fertility preservation. Although much knowledge can be translated from the oncofertility discipline, we have identified and discussed endometriosis-related changes to ovarian reserve and oocyte health that justify further well-designed research to confirm that fertility preservation outcomes are similar for women with endometriosis.

Introduction of an interprofessional gynaecology surgical skills workshop for undergraduate medical and nursing students.

BACKGROUND: Medical and nursing students may feel under-prepared to perform basic surgical and gynaecology procedural skills. There also remains scope within undergraduate programs to integrate interprofessional education, and better prepare students for interprofessional collaboration to improve patient care. AIMS: A simulation-based gynaecology surgical skills workshop program was introduced for undergraduate medical and nursing students. The aim of this study was to explore students' perceptions of a simulation-based interprofessional gynaecological skills program, using students' pre- and post-workshop confidence in taught skills reported in a post-workshop questionnaire as an outcome measure. MATERIALS AND METHODS: One hundred and sixty undergraduate medical (n = 133) and nursing (n = 27) students attended the workshop program at a tertiary university in Melbourne, Australia. A survey was completed by all students immediately after the workshop, addressing students' perceptions of surgical education, the four skill-stations (gowning/gloving, suturing, intrauterine device insertion, and urethral catheterisation), and interprofessional education. A Wilcoxon signed-rank test was performed to compare students' pre- and post-workshop confidence scores. RESULTS: Most medical and nursing students (86%) agreed their course should provide more structured surgical education. There was a statistically significant increase in post-workshop self-reported confidence scores for medical and nursing students in all four taught skills. Confidence in interprofessional behaviours also improved in both cohorts, but the improvement in nursing students did not reach statistical significance. CONCLUSIONS: Simulation-based, interprofessional, gynaecological surgery skills workshops are practical and valuable additions to undergraduate medical and nursing curricula. Further research should explore long-term retention of procedural skills and changes in interprofessional attitudes in clinical practice.

The effect of melatonin on ultrasound markers of follicular development: A double-blind placebo-controlled randomised trial.

BACKGROUND: Melatonin is a potent oxygen scavenger and is capable of altering blood flow in various vascular beds. AIMS: We aimed to determine the effect of melatonin on ovarian vascular indices during ovarian stimulation for in vitro fertilisation (IVF). MATERIALS AND METHODS: This is a pilot double-blind placebo-controlled randomised trial. Sixty-nine women (mean age 35.8 ± 4.3 years) undergoing their first cycle of IVF were randomised to receive either placebo, 2, 4 or 8 mg of melatonin, twice a day. Each participant underwent a transvaginal ultrasound at days 6-10 assessing follicular number and size. The vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI) were measured. These indices were then correlated with embryological outcomes. Informed consent was obtained from participants. This trial was registered with the Australia New Zealand Clinical Trials Registry (ACTRN12613001317785). RESULTS: The number of follicles did not differ between groups (P = 0.4). There were no differences in the VI (P = 0.4), FI (P = 0.1) or VFI (P = 0.3) in the right ovary or the FI (P = 0.3) or VFI (P = 0.3) in the left ovary between groups. When comparing placebo to any dose of melatonin, there were no differences in any measured parameter. While there was correlation between the number of follicles on ultrasound and all measured embryological outcomes, there was no correlation between ovarian vascular indices and these important clinical outcomes. CONCLUSIONS: Melatonin does not appear to change ovarian vascular indices during ovarian stimulation. In addition, such vascular indices cannot predict the number or quality of oocytes or embryos obtained in an IVF cycle. These findings require confirmation in future larger studies.

Online interprofessional simulation for undergraduate health professional students during the COVID-19 pandemic.

This report describes the Obstetric and Neonatal Simulation (ONE-Sim) workshop run in a remote learning format for medical and midwifery students in an interprofessional setting during the COVID-19 pandemic. It explores the observation of students as participants in the online learning of using Personal Protective Equipment and simulation-based learning of perinatal emergency management. This was followed by their mutual interaction and reflections. This paper aims to understand the role of synchronous remote learning through simulation and its impact on interprofessional interactions. We describe the experience of medical and midwifery students with the ONE-Sim workshop, facilitated by medical (obstetric and neonatal) and midwifery educators. Formal thematic analysis will be performed as part of the ongoing study; however, initial direct observation demonstrated that students reacted positively to the online ONE-Sim workshop and engaged well with facilitators and peers. Students mutually interacted amongst themselves, shared their previous experiences, knowledge of roles as medical and midwifery practitioners and how they see themselves in those roles in a perinatal emergency setting. The initial observations demonstrate that interprofessional education delivered in an e-learning format can be useful and meaningful, and may be utilized across a number of specialties.

Embedding assessment in a simulation skills training program for medical and midwifery students: A pre- and post-intervention evaluation.

BACKGROUND: Simulation-based programs are increasingly being used to teach obstetrics and gynaecology examinations, but it is difficult to establish student learning acquired through them. Assessment may test student learning but its role in learning itself is rarely recognised. We undertook this study to assess medical and midwifery student learning through a simulation program using a pre-test and post-test design and also to evaluate use of assessment as a method of learning. METHODS: The interprofessional simulation education program consisted of a brief pre-reading document, a lecture, a video demonstration and a hands-on workshop. Over a 24-month period, 405 medical and 104 midwifery students participated in the study and were assessed before and after the program. Numerical data were analysed using paired t-test and one-way analysis of variance. Students' perceptions of the role of assessment in learning were qualitatively analysed. RESULTS: The post-test scores were significantly higher than the pre-test (P < 0.001) with improvements in scores in both medical and midwifery groups. Students described the benefit of assessment on learning in preparation of the assessment, reinforcement of learning occurring during assessment and reflection on performance cementing previous learning as a post-assessment effect. CONCLUSION: Both medical and midwifery students demonstrated a significant improvement in their test scores and for most students the examination process itself was a positive learning experience.

Reliability of visual diagnosis of endometriosis.

OBJECTIVE: To determine whether accuracy of visual diagnosis of endometriosis at laparoscopy is determined by stage of disease. DESIGN: Prospective longitudinal cohort study (Canadian Task Force classification II-2). SETTING: Tertiary referral centers in three Australian states. PATIENTS: Of 1439 biopsy specimens, endometriosis was proved in at least one specimen in 431 patients. INTERVENTIONS: Laparoscopy with visual diagnosis and staging of endometriosis followed by histopathologic analysis and confirmation. Operations were performed by five experienced laparoscopic gynecologists. MEASUREMENTS AND MAIN RESULTS: Histopathologic confirmation of visual diagnosis of endometriosis adjusted for significant covariates. Endometriosis was accurately diagnosed in 49.7% of American Society for Reproductive Medicine (ASRM) stage I, which was significantly less accurate than for other stages of endometriosis. Deep endometriosis was more likely to be diagnosed accurately than superficial endometriosis (adjusted odds ratio, 2.51; 95% confidence interval, 1.50-4.18; p < .01). Lesion volume was also predictive, with larger lesions diagnosed more accurately than smaller lesions. In general, lesion site did not greatly influence accuracy except for superficial ovarian lesions, which were more likely to be incorrectly diagnosed visually as endometriosis (adjusted odds ratio, 0.16; 95% confidence interval, 0.06-0.41; p < .01). There was no statistically significant difference in accuracy between the gynecologic surgeons. CONCLUSION: The accuracy of visual diagnosis of endometriosis was substantially influenced by American Society of Reproductive Medicine stage, the depth and volume of the lesion, and to a lesser extent the location of the lesion.

Evaluation of online interprofessional simulation workshops for obstetric and neonatal emergencies.

Objectives: To explore student perceptions of learning and interprofessional aspects of obstetric and neonatal emergencies through online simulation-based workshops. Methods: This qualitative study was conducted at Monash University, Australia. Data were obtained from six separate online Obstetric Neonatal Emergency Simulation workshops held between May 2020 and August 2021. A total of 385 students attended and were invited to participate in the study by completing an online survey two-three weeks later. Of the attendees, 144 students completed the survey (95 medical, 45 midwifery), equating to a response rate of 37%. Survey responses were downloaded from online survey platform and separated into medical and midwifery responses. Thematic analysis of data was performed using a coding framework, resulting in development of themes and subthemes. Results: Main themes were adaptability, connectivism, preparedness for practice, experiential learning, learning through modelling and dynamics of online interaction. Students reported that online workshop was a useful alternative method to experience simulation-based learning, increase their readiness for clinical practice and foster positive interprofessional relationships. Consistent with existing literature evaluating similar in-person programs, midwifery students were most interested in interprofessional interaction (predominant theme: dynamics of online interaction), whilst medical students were more concerned with developing clinical skills (predominant themes: learning through modelling, experiential learning). Conclusions: Online learning may be a useful and convenient way of delivering interprofessional simulation-based education during the pandemic, in remote areas and as an adjunct to in-person teaching. Future studies should evaluate the impact of online learning with a mixed methods study and in comparison, to in-person programs.

The role of preoperative oral vitamin B in the cystoscopic assessment of ureteric patency.

INTRODUCTION AND HYPOTHESIS: The objective of this study is to determine whether oral vitamin B can be used as a marker of ureteric patency at cystoscopy, and thereby reduce the need for intraoperative intravenous indigo carmine. METHODS: Patients scheduled for cystoscopy, or for an operation likely to require a cystoscopy, were given three tablets of vitamin B complex orally 1-4 h prior to their operation. The time of administration, time of operation, and time of cystoscopy were recorded. The time taken for ureteric jets to be visualized was also recorded. The color of the urine was graded by the operator as being clear (negative) or bright yellow (positive), indicating ureteric patency and that no indigo carmine was required. RESULTS: Sixty-nine women in total were given vitamin B prior to their cystoscopy. One case was cancelled because of presumed but unproven aspiration. In 49 of the remaining 68 cases (72.1%), yellow urine was seen at both ureteric orifices. In 19 (27.9%) cases, yellow urine was not seen at both ureteric orifices; however, unilateral yellow, clear, or turbulent jets were seen in all but one case. The mean time from dose to cystoscopy was 162 min and the mean time for visualization of both ureteric jets was 2.2 min with no significant difference between groups. Indigo carmine was used in only two cases (2.9%). CONCLUSIONS: The results of this study show that oral vitamin B administration preoperatively has the potential to be used to reduce the requirement for intravenous indigo carmine administration. This would have advantages in reducing the cost and toxicity of intravenous indigo carmine administration. Vitamin B warrants further investigation and refinement as a marker of ureteric patency at cystoscopy.

Impact of an Interprofessional Surgical Skills Workshop on Undergraduate Medical and Nursing Student Interest in a Career in Surgery: A Thematic Analysis.

OBJECTIVE: Medical student interest in surgery is decreasing both internationally and in Australia. There is also a current shortage of perioperative nursing staff, and demand for both surgeons and perioperative nurses is only expected to rise. The aim of this qualitative thematic analysis is to explore: (1) medical and nursing student's influences on their perspectives on surgery, and (2) the impact of a novel, interprofessional, simulation-based workshop on medical and nursing student interest in surgery as a career. DESIGN: A paired, anonymous pre- and postworkshop written survey was completed by medical and nursing student participants before and immediately after the surgical skills workshop. Thematic analysis of the responses was performed by 2 researchers independently to identify themes and subthemes regarding the study aims. SETTING: The study was conducted at Monash Medical Centre, a tertiary care center in Melbourne, Australia. PARTICIPANTS: One hundred and seventy-six undergraduate medical and nursing students attended the workshop, consisting of 144 fourth-year medical students (enrolled in a 5-year course) and 32 second-year nursing student volunteers (enrolled in a 3-year course). RESULTS: Analysis of how students' prior surgical experiences impacted their perspective on surgery revealed 5 themes: inclusive mentors and role models, learning through active participation, feeling unwelcome or intimidated, demands of the surgical lifestyle, and personal factors that influenced interest in surgery as a career.Most students reported that the workshop had a beneficial effect on their perception of surgery as a career. Analysis of student responses found 3 themes that affected the impact of the workshop on their interest in surgery: simulated practice of technical skills, exposure to nontechnical aspects of surgery, and simulation fidelity. CONCLUSIONS: Interprofessional, simulated-based surgical skills workshops may improve medical and nursing students' perceptions of surgery as a career, and should be considered for inclusion in undergraduate medical and nursing curricula.

The influence of maternal ethnicity on neonatal respiratory outcome.

OBJECTIVE: Higher rates of neonatal morbidity and mortality at term combined with earlier spontaneous delivery have led to the hypothesis that babies born to South Asian born (SA-born) women may mature earlier and/or their placental function decreases earlier than babies born to Australian and New Zealand born (Aus/NZ-born) women. Whether babies born to SA-born women do better in the preterm period, however, has yet to be evaluated. In this study we investigated respiratory outcomes, indicative of functional maturity, of preterm babies born to SA-born women compared with those of Aus/NZ-born women to explore this hypothesis further. STUDY DESIGN AND SETTING: This retrospective cohort study was conducted at Monash Health. PATIENTS: Data were collected from neonatal and birth records of moderate-late preterm (32-36 weeks) infants born between 2012 and 2015 to SA-born and Aus/NZ-born women. OUTCOME MEASURES: Rates of nursery admissions and neonatal respiratory outcomes were compared. RESULTS: Babies born to Aus/NZ-born women were more likely to be admitted to a nursery (80%) compared with SA-born babies (72%, p=0.004). Babies born to SA-born mothers experienced significantly less hyaline membrane disease (7.8%), required less resuscitation at birth (28.6%) and were less likely to require ventilation (20%) than babies born to Aus/NZ-born mothers (18%, 42.2%, 34.6%; p<0.001). There was no difference in the duration of ventilation or length of stay in hospital. CONCLUSIONS: Moderate-late preterm babies born to SA-born women appear to have earlier functional maturity, as indicated by respiratory outcomes, than Aus/NZ-born babies. Our findings support the hypothesis of earlier fetal maturation in SA-born women.

Melatonin in Assisted Reproductive Technology: A Pilot Double-Blind Randomized Placebo-Controlled Clinical Trial.

Purpose: To explore in a small pilot study whether oral melatonin, administered during ovarian stimulation increases clinical pregnancy rate (CPR) after IVF and what dose might be most effective. Methods: Pilot double-blind, dose-finding, placebo-controlled randomized clinical trial in private IVF clinics in Australia between September 2014 and September 2016. One hundred and sixty women having their first cycle of IVF or ICSI were randomized to receive placebo (n = 40), melatonin 2 mg (n = 41), melatonin 4 mg (n = 39), or melatonin 8 mg (n = 40) twice per day (BD) during ovarian stimulation. The primary outcome was CPR. Secondary outcomes included serum and follicular fluid (FF) melatonin concentrations, oocyte/embryo quantity/quality, and live birth rate (LBR). Analysis was performed using the intention-to-treat principle. Results: There was no difference in CPR or LBR between any of the four groups (p = 0.5). When all the doses of melatonin were compared as a group with placebo, the CPR was 21.7% for the former and 15.0% for the latter [OR 1.57 (95% CI 0.59, 4.14), p = 0.4]. There were also no differences between the groups in total oocyte number, number of MII oocytes, number of fertilized oocytes, or the number or quality of embryos between the groups. This is despite mean FF melatonin concentration in the highest dose group (8 mg BD) being nine-fold higher compared with placebo (P < 0.001). Conclusion: No significant differences were observed in CPR or oocyte and embryo parameters despite finding a nine-fold increase in FF melatonin concentration. However, this study was not sufficiently powered to assess differences in CPR and therefore, these results should be interpreted with caution. Because this was a small RCT, a beneficial effect of melatonin on IVF pregnancy rates cannot be excluded and merits confirmation in further, larger clinical trials. ANZCTR (http://www.anzctr.org.au/ Project ID: ACTRN12613001317785).

The impact of melatonin on the sleep patterns of women undergoing IVF: a double blind RCT.

STUDY QUESTION: Does melatonin result in a dose-response effect on sleep quality and daytime sleepiness in women undergoing IVF? SUMMARY ANSWER: Melatonin, even when given at high doses twice per day, does not cause significant daytime sleepiness or change night time sleep quantity or quality. WHAT IS KNOWN ALREADY: Melatonin is being increasingly used as an adjuvant therapy for women undergoing IVF owing to its antioxidative effects. It is widely considered to be sedative but there are scant objective data on the effects of melatonin on sleep in the setting of IVF. STUDY DESIGN SIZE DURATION: The study was a double-blind placebo-controlled randomized trial of 116 women recruited between September 2014 and September 2016. PARTICIPANTS/MATERIALS SETTING METHOD: Women who were undergoing their first cycle of IVF at private IVF centers were recruited into the RCT and randomized to receive either placebo, 2 mg, 4 mg or 8 mg of melatonin, twice per day (BD) from Day 2 of their cycle until the day before oocyte retrieval. Each participant wore an accelerometer that provides an estimate of sleep and wake activity for up to 1 week of baseline and throughout treatment (up to 2 weeks). They also kept sleep diaries and completed a Karolinska sleepiness score detailing their night time sleep activity and daytime sleepiness, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 116 women were included in the intention-to-treat analysis (placebo BD (n = 32), melatonin 2 mg BD (n = 29), melatonin 4 mg BD (n = 26), melatonin 8 mg BD (n = 29)). There were no significant differences in daytime Karolinska sleepiness score between groups (P = 0.4), nor was there a significant dose-response trend (ß=0.05, 95% CI -0.22-0.31, P = 0.7). There were no differences in objective measures of sleep quantity or quality, including wake after sleep onset time, sleep onset latency, and sleep efficiency before and after treatment or between groups. There was an improvement in subjective sleep quality scores from baseline to during treatment in all groups, except 8 mg BD melatonin: placebo (percentage change -13.3%, P = 0.01), 2 mg (-14.1%, P = 0.03), 4 mg (-8.6%, P = 0.01) and 8 mg (-7.8%, P = 0.07). LIMITATIONS REASONS FOR CAUTION: As this was a subset of a larger trial, the melatonin in ART (MIART) trial, it is possible that the sample size was too small to detect statistically significant differences between the groups. WIDER IMPLICATIONS OF THE FINDINGS: While this study suggests that melatonin can be used twice per day at high doses to achieve sustained antioxidation effects, with the reassurance that this will not negatively impact daytime sleepiness or night time sleep habits, the sample size is small and may have missed a clinically significant difference. Nevertheless, our findings may have implications not only for future studies of fertility treatments (including meta-analyses), but also in other medical fields where sustained antioxidation is desired. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Monash IVF Research and Education Foundation (PY12_15). S.F. is supported by the National Health and Medical Research Council (Postgraduate Scholarship APP1074342) and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists Ella Macknight Memorial Scholarship. E.W. is supported by an National Health and Medical Research Council Program Grant (APP1113902). S.F., E.W., R.H., B.V., N.L., N.H., M.W., M.L., A.L., P.T., K.L. have nothing to declare. L.R. is a Minority shareholder in Monash IVF Group, has unrestricted grants from MSD®, Merck-Serono® and Ferring® and receives consulting fees from Ferring®. S.N.B. reports consulting fees from Johnson & Johnson Consumer Inc®, outside the submitted work. TRIAL REGISTRATION NUMBER: This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (Project ID: ACTRN12613001317785). TRIAL REGISTRATION DATE: 27/11/2013. DATE OF FIRST PATIENT'S ENROLMENT: 1/9/2014.