Is home-based monitoring of ovulution to time frozen embryo transfer a cost-effective alternative for hospital-based monitoring of ovulation? Study protocol of the multicentre, non-inferiority Antarctica-2 randomised controlled trial

STUDY QUESTION: The objective of this trial is to compare the effectiveness and costs of true natural cycle (true NC-) frozen embryo transfer (FET) using urinary LH tests to modified NC-FET using repeated ultrasound monitoring and ovulation trigger to time FET in the NC. Secondary outcomes are the cancellation rates of FET (ovulation before hCG or no dominant follicle, no ovulation by LH urine test, poor embryo survival), pregnancy outcomes (miscarriage rate, clinical pregnancy rates, multiple ongoing pregnancy rates, live birth rates, costs) and neonatal outcomes (including gestational age, birthweight and sex, congenital abnormalities or diseases of babies born). WHAT IS KNOWN ALREADY: FET is at the heart of modern IVF. To allow implantation of the thawed embryo, the endometrium must be prepared either by exogenous oestrogen and progesterone supplementation (artificial cycle (AC)-FET) or by using the NC to produce endogenous oestradiol before and progesterone after ovulation to time the transfer of the thawed embryo (NC-FET). During an NC-FET, women visit the hospital repeatedly and receive an ovulation trigger to time FET (i.e. modified (m)NC-FET or hospital-based monitoring). From the woman’s point of view, a more natural approach using home-based monitoring of the ovulation with LH urine tests to allow a natural ovulation to time FET may be desired (true NC-FET or home-based monitoring). STUDY DESIGN, SIZE, DURATION: This is a multicentre, non-inferiority prospective randomised controlled trial design. Consenting women will undergo one FET cycle using either true NC-FET or mNC-FET based on randomisation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on our sample size calculation, the study group will consist of 1464 women between 18 and 45 years old who are scheduled for FET. Women with anovulatory cycles, women who need ovulation induction and women with a contra indication for pregnancy will be excluded. The primary outcome is ongoing pregnancy. Secondary outcomes are cancellation rates of FET, pregnancy outcomes (including miscarriage rate, clinical pregnancy, multiple pregnancy rate and live birth rate). Costs will be estimated by counting resource use and calculating unit prices. STUDY FUNDING/COMPETING INTEREST(S): The study received a grant from the Dutch Organisation for Health Research and Development (ZonMw 843002807; www.zonmw.nl). ZonMw has no role in the design of the study, collection, analysis, and interpretation of data or writing of the manuscript. F.B. reports personal fees from member of the external advisory board for Merck Serono, grants from Research support grant Merck Serono, outside the submitted work. A.E.P.C. reports and Unrestricted grant of Ferring B.V. to the Center for Reproductive medicine, no personal fee. Author up-to-date on Hyperthecosis. Congress meetings 2019 with Ferring B.V. and Theramex B.V. M.G. reports Department research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the submitted work. E.R.G. reports personal fees from Titus Health Care, outside the submitted work. C.B.L. reports grants from Ferring, grants from Merck, from Guerbet, outside the submitted work. The other authors have none to declare. TRIAL REGISTRATION NUMBER: Dutch Trial Register (Trial NL6414 (NTR6590), https://www.trialregister.nl/). TRIAL REGISTRATION DATE: 23 July 2017 DATE OF FIRST PATIENT’S ENROLMENT: 10 April 201

Endometrial scratching in women with one failed IVF/ICSI cycle-outcomes of a randomised controlled trial (SCRaTCH)

STUDY QUESTION: Does endometnal scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle? SUMMARY ANSWER: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%. WHAT IS KNOWN ALREADY: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes. STUDY DESIGN, SIZE, DURATION: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%). MAIN RESULTS AND THE ROLE OF CHANCE: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between - 0.7% and 9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/11 I for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI). LIMITATIONS, REASONS FOR CAUTION: This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials

Endometrial scratching in women with one failed IVF/ICSI cycle-outcomes of a randomised controlled trial (SCRaTCH)

STUDY QUESTION: Does endometrial scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle? SUMMARY ANSWER: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%. WHAT IS KNOWN ALREADY: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes. STUDY DESIGN, SIZE, DURATION: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%). MAIN RESULTS AND THE ROLE OF CHANCE: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between -0.7% and +9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratchin

Non-visualized pregnancy losses are prognostically important for unexplained recurrent miscarriage

Are non-visualized pregnancy losses (biochemical pregnancy loss and failed pregnancy of unknown location combined) in the reproductive history of women with unexplained recurrent miscarriage (RM) negatively associated with the chance of live birth in a subsequent pregnancy? Non-visualized pregnancy losses contribute negatively to the chance for live birth: each non-visualized pregnancy loss confers a relative risk (RR) for live birth of 0.90 (95% CI 0.83; 0.97), equivalent to the RR conferred by each additional clinical miscarriage. The number of clinical miscarriages prior to referral is an important determinant for live birth in women with RM, whereas the significance of non-visualized pregnancy losses is unknown. A retrospective cohort study comprising 587 women with RM seen in a tertiary RM unit 2000-2010. Data on the outcome of the first pregnancy after referral were analysed for 499 women. The study was conducted in the RM Unit at Rigshospitalet, Copenhagen, Denmark. We included all women with unexplained RM, defined as ≥3 consecutive clinical miscarriages or non-visualized pregnancy losses following spontaneous conception or homologous insemination. The category 'non-visualized pregnancy losses' combines biochemical pregnancy loss (positive hCG, no ultrasound performed) and failed PUL (pregnancy of unknown location, positive hCG, but on ultrasound, no pregnancy location established). Demographics were collected, including BMI, age at first pregnancy after referral and outcome of pregnancies prior to referral. Using our own records and records from other Danish hospitals, we verified the outcome of the first pregnancy after referral. For each non-visualized pregnancy loss and miscarriage in the women's reproductive history, the RR for live birth in the first pregnancy after referral was determined by robust Poisson regression analysis, adjusting for risk factors for negative pregnancy outcome. Non-visualized pregnancy losses constituted 37% of reported pregnancies prior to referral among women with RM. Each additional non-visualized pregnancy loss conferred an RR for live birth of 0.90 (95% CI 0.83; 0.97), which was not statistically significantly different from the corresponding RR of 0.87 (95% CI 0.80; 0.94) conferred by each clinical miscarriage. Among women with ≥2 clinical miscarriages, a reduced RR for live birth was also shown: 0.82 (95% CI 0.74; 0.92) for each clinical miscarriage and 0.89 (95% CI 0.80; 0.98) for each non-visualized pregnancy loss, respectively. Surgically treated ectopic pregnancies (EPs) were significantly more common for women with primary RM and no confirmed clinical miscarriages, compared with women with primary RM and ≥1 clinical miscarriage (22 versus 6%, difference 16% (95% CI 9.1%; 28.7%); RR for ectopic pregnancy was 4.0 (95% CI 1.92; 8.20). RM was defined as ≥3 consecutive pregnancy losses before 12 weeks' gestation, and we included only women with unexplained RM after thorough evaluation. It is uncertain whether the findings apply to other definitions of RM and among women with known causes for their miscarriages. To our knowledge, this is the first comprehensive investigation of prior non-visualized pregnancy losses and their prognostic significance for live birth in a subsequent pregnancy in women with unexplained RM. We show that a prior non-visualized pregnancy loss has a negative prognostic impact on subsequent live birth and is thus clinically significant. None. N/

Predicting adverse obstetric outcome after early pregnancy events and complications: a review

The aim was to evaluate the impact of early pregnancy events and complications as predictors of adverse obstetric outcome. We conducted a literature review on the impact of first trimester complications in previous and index pregnancies using Medline and Cochrane databases covering the period 1980-2008. Clinically relevant associations of adverse outcome in the subsequent pregnancy with an odds ratio (OR) > 2.0 after complications in a previous pregnancy are the risk of perinatal death after a single previous miscarriage, the risk of very preterm delivery (VPTD) after two or more miscarriages, the risk of placenta praevia, premature preterm rupture of membranes, VPTD and low birthweight (LBW) after recurrent miscarriage and the risk of VPTD after two or more termination of pregnancy. Clinically relevant associations of adverse obstetric outcome in the ongoing pregnancy with an OR > 2.0 after complications in the index pregnancy are the risk of LBW and very low birthweight (VLBW) after a threatened miscarriage, the risk of pregnancy-induced hypertension, pre-eclampsia, placental abruption, preterm delivery (PTD), small for gestational age and low 5-min Apgar score after detection of an intrauterine haematoma, the risk of VPTD and intrauterine growth restriction after a crown-rump length discrepancy, the risk of VPTD, LBW and VLBW after a vanishing twin phenomenon and the risk of PTD, LBW and low 5-min Apgar score in a pregnancy complicated by severe hyperemesis gravidarum. Data from our literature review indicate, by finding significant associations, that specific early pregnancy events and complications are predictors for subsequent adverse obstetric and perinatal outcome. Though, some of these associations are based on limited or small uncontrolled studies. Larger population-based controlled studies are needed to confirm these findings. Nevertheless, identification of these risks will improve obstetric care

Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease

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Vasculogenesis and Angiogenesis in the First Trimester Human Placenta: An Innovative 3D Study Using an Immersive Virtual Reality System

First trimester human villous vascularization is mainly Studied by conventional two-dimensional (213) microscopy. With this (2D) technique it is not possible to observe the spatial arrangement of the haemangioblastic cords and vessels, transition of cords into vessels and the transition of vasculogenesis to angiogenesis. The Confocal Laser Scanning Microscopy (CLSM) allows for a three-dimensional (31)) reconstruction of images of early pregnancy villous vascularization. These 3D reconstructions, however, are normally analyzed on a 2D medium, lacking depth perception. We performed a descriptive morphologic study, using an immersive Virtual Reality system to utilize the full third dimension completely. This innovative 3D technique visualizes 3D datasets as enlarged 3D holograms and provided detailed insight in the spatial arrangement of first trimester villous vascularization, the beginning of lumen formation within various junctions of haemangioblastic cords between 5 and 7 weeks gestational age and in the gradual transition of vasculogenesis to angiogenesis. This innovative immersive Virtual Reality system enables new perspectives for vascular research and will be implemented for future investigation. (C) 2009 Elsevier Ltd. All rights reserve