Early Pregnancy Development and Obstetric Outcome

__Abstract__ The following research objectives were defined: 1. To determine an unambiguous Dutch terminology to describe events in early pregnancy (Chapter 1.2) 2. To explore whether determining the due date by the last period is influenced by preference for certain dates, and whether this is associated with adverse obstetric and neonatal outcome (Chapter 2.1). To evaluate the effect of nonvisualized early pregnancy losses (biochemical pregnancy losses and failed pregnancies of unknown location) on the chance of live birth in the subsequent pregnancy (Chapter 2.2). To investigate whether events and complications in early pregnancy are associated with adverse obstetric and neonatal outcome (Chapter 2.3). 3. To investigate whether the use of a 3 dimensional Virtual Reality (VR) system to create enhanced 3 dimensional rendering images of 3 dimensional dataset created by a confocal laser scanning microscopy of early chorionic villous vascularization is consistent and useful to perform morphometric measurements and to describe the spatial arrangement of the cords and vessels in relation to the vasculosyncytial membrane (Chapter 3.1). To determine the effect of smoking on the chorionic villous vascularization in first trimester of pregnancy using a 3 dimensional VR system (Chapter 3.2). 4. To study whether idiopathic second trimester fetal loss (Chapter 4.1), preeclampsia and intrauterine growth restriction (Chapter 4.2) are associated with an underdeveloped chorionic villous vascularization

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

Compromised chorionic villous vascularization in idiopathic second trimester fetal loss

Background For normal fetal growth and development a well-developed chorionic villous vascularization is essential. Aim The aim of this study is to investigate whether idiopathic second trimester fetal loss is associated with an underdeveloped chorionic villous vascularization. Methods 38 placentas after late miscarriage, classified as idiopathic fetal loss (IFL, n = 16) or as fetal loss due to intrauterine infection (IUI, n = 22) were collected. After CD34 immunohistochemical staining the villous stromal area, number of villous vessels, vascular area and vascular area density (central, peripheral and total) were measured in randomly selected immature intermediate villi. Results The mean gestational age was 19 + 4 weeks for the IFL group and 20 + 6 weeks for the IUI group. After controlling for gestational age, we found no differences in fetal weight, placental weight, villous stromal area, number of vessels and central vascular features. The mean peripheral vascular area and peripheral vascular area density were, after adjusting for gestational age, reduced in the IFL group. Conclusion Idiopathic second trimester fetal loss is associated with a reduced peripheral chorionic villous vascularization. We hypothesize that in these cases, placentation is already disturbed in first trimester of pregnancy, leading to a reduced materno–fetal interface in second trimester, thus to early postplacental fetal hypoxia and fetal death

Economic evaluation of endometrial scratching before the second IVF/ICSI treatment:a cost-effectiveness analysis of a randomized controlled trial (SCRaTCH trial)

STUDY QUESTION: Is a single endometrial scratch prior to the second fresh IVF/ICSI treatment cost-effective compared to no scratch, when evaluated over a 12-month follow-up period? SUMMARY ANSWER: The incremental cost-effectiveness ratio (ICER) for an endometrial scratch was €6524 per additional live birth, but due to uncertainty regarding the increase in live birth rate this has to be interpreted with caution. WHAT IS KNOWN ALREADY: Endometrial scratching is thought to improve the chances of success in couples with previously failed embryo implantation in IVF/ICSI treatment. It has been widely implemented in daily practice, despite the lack of conclusive evidence of its effectiveness and without investigating whether scratching allows for a cost-effective method to reduce the number of IVF/ICSI cycles needed to achieve a live birth. STUDY DESIGN, SIZE, DURATION: This economic evaluation is based on a multicentre randomized controlled trial carried out in the Netherlands (SCRaTCH trial) that compared a single scratch prior to the second IVF/ICSI treatment with no scratch in couples with a failed full first IVF/ICSI cycle. Follow-up was 12 months after randomization.Economic evaluation was performed from a healthcare and societal perspective by taking both direct medical costs and lost productivity costs into account. It was performed for the primary outcome of biochemical pregnancy leading to live birth after 12 months of follow-up as well as the secondary outcome of live birth after the second fresh IVF/ICSI treatment (i.e. the first after randomization). To allow for worldwide interpretation of the data, cost level scenario analysis and sensitivity analysis was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: From January 2016 until July 2018, 933 women with a failed first IVF/ICSI cycle were included in the trial. Data on treatment and pregnancy were recorded up until 12 months after randomization, and the resulting live birth outcomes (even if after 12 months) were also recorded.Total costs were calculated for the second fresh IVF/ICSI treatment and for the full 12 month period for each participant. We included costs of all treatments, medication, complications and lost productivity costs. Cost-effectiveness analysis was carried out by calculating ICERs for scratch compared to control. Bootstrap resampling was used to estimate the uncertainty around cost and effect differences and ICERs. In the sensitivity and scenario analyses, various unit costs for a single scratch were introduced, amongst them, unit costs as they apply for the United Kingdom (UK). MAIN RESULTS AND THE ROLE OF CHANCE: More live births occurred in the scratch group, but this also came with increased costs over a 12-month period. The estimated chance of a live birth after 12 months of follow-up was 44.1% in the scratch group compared to 39.3% in the control group (risk difference 4.8%, 95% CI -1.6% to +11.2%). The mean costs were on average €283 (95% CI: -€299 to €810) higher in the scratch group so that the point average ICER was €5846 per additional live birth. The ICER estimate was surrounded with a high level of uncertainty, as indicated by the fact that the cost-effectiveness acceptability curve (CEAC) showed that there is an 80% chance that endometrial scratching is cost-effective if society is willing to pay ∼€17 500 for each additional live birth. LIMITATIONS, REASONS FOR CAUTION: There was a high uncertainty surrounding the effects, mainly in the clinical effect, i.e. the difference in the chance of live birth, which meant that a single straightforward conclusion could not be ascertained as for now. WIDER IMPLICATIONS OF THE FINDINGS: This is the first formal cost-effectiveness analysis of endometrial scratching in women undergoing IVF/ICSI treatment. The results presented in this manuscript cannot provide a clear-cut expenditure for one additional birth, but they do allow for estimating costs per additional live birth in different scenarios once the clinical effectiveness of scratching is known. As the SCRaTCH trial was the only trial with a follow-up of 12 months, it allows for the most complete estimation of costs to date. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organization for funding healthcare research. A.E.P.C., F.J.M.B., E.R.G. and C.B. L. reported having received fees or grants during, but outside of, this trial. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL5193/NTR 5342)