Study protocol: E-freeze - freezing of embryos in assisted conception: a randomised controlled trial evaluating the clinical and cost effectiveness of a policy of freezing embryos followed by thawed frozen embryo transfer compared with a policy of fresh embryo transfer, in women undergoing in vitro fertilisation.

BACKGROUND: Infertility affects one in seven couples; many of these need in vitro fertilisation (IVF). IVF involves external hormones to stimulate a woman's ovaries to produce eggs which are harvested surgically. Embryos, created in the laboratory by mixing eggs with sperm, are grown in culture for a few days before being replaced within the uterus (fresh embryo transfer). Spare embryos are usually frozen with a view to transfer at a later point in time - especially if the initial fresh transfer does not result in a pregnancy. Despite improvements in technology, IVF success rates remain low with an overall live birth rate of 25-30% per treatment. Additionally, there are concerns about health outcomes for mothers and babies conceived through IVF, particularly after fresh embryo transfer, including maternal ovarian hyperstimulation syndrome (OHSS) and preterm delivery. It is believed that high levels of hormones during ovarian stimulation could create a relatively hostile environment for embryo implantation whilst increasing the risk of OHSS. It has been suggested that freezing all embryos with the intention of thawing and replacing them within the uterus at a later stage (thawed frozen embryo transfer) instead of fresh embryo transfer, may lead to improved pregnancy rates and fewer complications. We aim to compare the clinical and cost effectiveness of fresh and thawed frozen embryo transfer, with the primary aim of identifying any difference in the chance of having a healthy baby. METHODS: E-Freeze is a pragmatic, multicentre two-arm parallel group randomised controlled trial where women aged ≥18 and < 42 years, with at least three good quality embryos are randomly allocated to receive either a fresh or thawed frozen embryo transfer. The primary outcome is a healthy baby, defined as a term, singleton, live birth with appropriate weight for gestation. Cost effectiveness will be calculated from a healthcare and societal perspective. DISCUSSION: E-Freeze will determine the relative benefits of fresh and thawed frozen embryo transfer in terms of improving the chance of having a healthy baby. The results of this pragmatic study have the potential to be directly transferred to clinical practice. TRIAL REGISTRATION: ISRCTN registry: ISRCTN61225414 . Date assigned 29/12/2015.

4-D Assessment of Endometrial Vascularity Using Spatiotemporal Image Correlation: A Study Comparing Spherical Sampling and Whole-Tissue Analysis.

Our aim in the study described here was to assess the feasibility of spatiotemporal image correlation power Doppler quantification of the endometrium with two techniques: spherical samples and whole tissue. We scanned 51 women in the midluteal phase of the menstrual cycle: STIC assessment of the whole endometrium was not possible in 10% of cases, whereas spherical analysis was possible in all. The time taken for data set analysis was much longer for the whole endometrium compared with spherical analysis (1478.9 ± 291 s vs. 266.8 ± 39.3 s, p < 0.05). Intra-class correlation coefficients for the vascularization flow index (VFI) were similar for both methods. Volumetric vascularity indices were higher when spherical sampling was conducted. Significant cycle-to-cycle variability in the vascularity indices was present, with coefficients of variation exceeding 20% for both techniques. We found that STIC power Doppler quantification of the whole endometrium is possible in the majority of cases, however, it is time consuming and limited by significant cycle-to-cycle variability.

Placental 3-D power Doppler angiography--regional variation and reliability of two ultrasonic sphere biopsy techniques.

Three-dimensional power Doppler angiography and 4D View allows quantification of placental "vascularity" using sonobiopsy or manual tracing. We used two vascular "biopsy" techniques: nontargeted sphere placement and systematic uniform random sphere placement (SURS). We hypothesised that random application of spheres would result in less reliability and the basal zone would display higher values than the chorionic zone. Forty women between 18+6 to 21+6 weeks gestation were recruited. A single volume of the placenta was acquired. Data was analysed twice by a single observer. Significantly higher values were seen for all vascular indices in the basal zone. Reliability was greatest for the whole placental technique with intraclass correlation coefficients of 0.9 and limits of agreement for flow index (FI) of -3.81 to 2.50 (equivalent to -7.8% to 5.1%) compared with 0.6 and -13.2 to 18.3 (-64.6% to 78.2%) for the nontargeted sphere technique. Whole placental values are more reliable than biopsy techniques with significantly different results seen with each technique.

Evaluating the intra- and interobserver reliability of three-dimensional ultrasound and power Doppler angiography (3D-PDA) for assessment of placental volume and vascularity in the second trimester of pregnancy.

Three-dimensional (3-D) power Doppler angiography (3-D-PDA) allows visualisation of Doppler signals within the placenta and their quantification is possible by the generation of vascular indices by the 4-D View software programme. This study aimed to investigate intra- and interobserver reproducibility of 3-D-PDA analysis of stored datasets at varying gestations with the ultimate goal being to develop a tool for predicting placental dysfunction. Women with an uncomplicated, viable singleton pregnancy were scanned at 12, 16 or 20 weeks gestational age groups. 3-D-PDA datasets acquired of the whole placenta were analysed using the VOCAL software processing tool. Each volume was analysed by three observers twice in the A plane. Intra- and interobserver reliability was assessed by intraclass correlation coefficients (ICCs) and Bland Altman plots. At each gestational age group, 20 low risk women were scanned resulting in 60 datasets in total. The ICC demonstrated a high level of measurement reliability at each gestation with intraobserver values >0.90 and interobserver values of >0.6 for the vascular indices. Bland Altman plots also showed high levels of agreement. Systematic bias was seen at 20 weeks in the vascular indices obtained by different observers. This study demonstrates that 3-D-PDA data can be measured reliably by different observers from stored datasets up to 18 weeks gestation. Measurements become less reliable as gestation advances with bias between observers evident at 20 weeks.

Three-dimensional ultrasound features of the polycystic ovary and the effect of different phenotypic expressions on these parameters.

BACKGROUND: The aim of this study was to quantify the three-dimensional (3D) ultrasound characteristics of ovaries in Caucasian women with polycystic ovarian syndrome (PCOS) and to examine if these values differed between different phenotypic forms. METHODS: 3D pelvic ultrasound was performed in 40 women with PCOS and in 40 controls. Total ovarian volume, stromal volume and echogenicity and antral follicle count (AFC) were measured and ovarian blood flow was quantified using both 3D power Doppler and two-dimensional pulsed-wave Doppler. RESULTS: Women with PCOS had a higher AFC (median 16.3 versus 5.5 per ovary, P < 0.001) and ovarian volume (12.56 versus 5.66 ml, P < 0.001). Stromal volume (10.79 versus 4.69 ml, P < 0.001) and stromal vascularization (VI: 3.85 versus 2.79%, P < 0.001; VFI: 1.27 versus 0.85, P < 0.001) were also increased in women with PCOS. There were no significant differences in stromal echogenicity or pulsed-wave Doppler indices between women with PCOS and the controls. Among the women with PCOS, ovarian vascularity was significantly higher in 30 women who were hirsute compared with normoandrogenic women (FI: 33.94 versus 29.30, P < 0.05) and in 14 women with PCOS who were of normal weight compared with obese women (VI: 4.51 versus 3.25%, P < 0.05; VFI: 1.56 versus 1.22, P < 0.05). CONCLUSIONS: Based on 3D ultrasound, women with PCOS have an increased stromal volume and vascularity. Stromal vascularity is significantly higher in women with PCOS who are hirsute and of normal weight.

In vivo perfusion, T1, and T2 measurements in the female pelvis during the normal menstrual cycle: a feasibility study.

PURPOSE: To quantify T(1), T(2), and regional tissue perfusion in uterine tissues, with MR imaging in clinically feasible imaging times, using echo planar imaging (EPI) techniques over a single menstrual cycle. MATERIALS AND METHODS: A total of 24 healthy ovulating women were scanned; however, complete data sets through the menstrual cycle were not obtained from all women. Three scans were performed to coincide prospectively with the follicular, periovulatory, and luteal phases of the cycle. T(1) and perfusion were measured simultaneously using flow alternating inversion recovery (FAIR), while T(2) was measured using a single Hahn spin-echo (SE) EPI sequence. RESULTS: Between the follicular and periovulatory phases, statistically significant increases (P < 0.05) were seen for the T(2) of the endometrium and perfusion of the myometrium as well as the T(2)/T(1) ratio for both endometrium and myometrium. A statistically significant decrease was seen in the endometrial T(2) between the periovulatory and luteal phases of the cycle. Tissue differentiation was achieved using the parameters measured, with T(1) and T(2) being statistically greater for the endometrium than for the myometrium, and endometrial perfusion being statistically lower than myometrial perfusion. CONCLUSION: These results show the feasibility of using these techniques to measure T(1), T(2), and perfusion in uterine tissues and of extending this work to study pathological conditions.

Uterine tissue development in healthy women during the normal menstrual cycle and investigations with magnetic resonance imaging.

OBJECTIVE: High-resolution magnetic resonance imaging (MRI) was used to monitor both uterine endometrial and junctional zone morphometry during the normal menstrual cycle. STUDY DESIGN: Twenty-four healthy, ovulating women were studied during a single menstrual cycle. Three scans were performed to prospectively coincide with the follicular, periovulatory, and luteal phases of the cycle. RESULTS: MRI data showed a significant increase in endometrial and junctional zone volume, between the follicular and periovulatory phases, with a significant decrease in endometrial volume observed from the periovulatory to luteal phases. The regularity index, which is a novel subjective assessment of junctional zone structure, varied significantly and demonstrated a less regular junctional zone in the luteal phase. CONCLUSION: This study has quantified the normal developmental changes of uterine tissue during the menstrual cycle with MRI. Junctional zone data from MRI may play a major role in future studies that investigate menstrual disorders, subfertility, and pathologic changes.