P–362 The effect of nolasiban on uterine contractility at the time of embryo transfer in in vitro fertilisation patients

Study question What is the effect of nolasiban on the uterine contractility of in-vitro fertilisation (IVF) patients prior to embryo transfer (ET) ? Summary answer A single oral dose of nolasiban 900 mg administered 4 h before ET significantly decreased contraction frequency and increased coordination compared to placebo. What is known already Nolasiban is an investigational oral oxytocin receptor antagonist (OTRa) being developed to improve the chance of pregnancy following ET. Increased uterine contraction frequency can influence embryo implantation, and the coordination of these uterine contractions is equally important. OTRa have been shown to decrease uterine contractions and increase endometrial perfusion. Recently, an automated and quantitative measurement tool using transvaginal ultrasound (TVUS) to better characterise uterine contractility has been developed which can be used to quantify the effect of nolasiban on uterine contractility. Study design, size, duration This study is part of a completed multi-centre randomised placebo-controlled trial (IMPLANT 1 – NCT02310802) in IVF patients (n = 247) carried out in 2015. Our study retrospectively assessed a sub-set of patients with good quality TVUS recordings to evaluate their mechanical uterine motion that were randomised to receive either nolasiban 900mg (n = 39) or placebo (n = 42). Participants/materials, setting, methods Subjects were < 37 years, undergoing ET on Day 3 following IVF/ICSI and with evidence of uterine contractions 4 h before ET. Nolasiban was administered 4 h before ET. Patients underwent TVUS immediately before drug administration and again immediately before ET. Uterine contraction frequency, amplitude, power and coordination were measured by applying dedicated speckle tracking and strain analysis. The Shapiro–Wilk test, followed by the Wilcoxon rank-sum test were applied to compare features between treatment groups. Main results and the role of chance The mean (SD) frequency of uterine contractions was 1.54 (0.25) in the nolasiban group versus 1.57 (0.12) in the placebo group (p = 0.016). The mean (SD) coordination was 0.10 (0.17) in the nolasiban group versus 0.02 (0.16) in the placebo group (p = 0.034). The coordination feature was measured by assessing the presence of simultaneous movements of the anterior and posterior uterine walls, a higher value reflects increased coordination. There was no difference in contraction amplitude or power. Limitations, reasons for caution This was a retrospective analysis of TVUS videos. The small sample size limits the generalisability of the findings. Furthermore, our initial results do not show how the changes in uterine motion may affect pregnancy rate after ET, meaning that the clinical relevance of our results remains to be proven. Wider implications of the findings: Our results show that in patients taking one 900mg dose of nolasiban prior to ET, beneficial uterine contractions are seen, which could be promising for embryo implantation and pregnancy in IVF patients. Our quantitative TVUS measurement tool can be applied to different patient populations to accurately quantify uterine motion. Trial registration number NCT02310802

Effects of Hypoxic Acclimation, Muscle Strain and Contraction Frequency on Nitric Oxide-Mediated Myocardial Performance in Steelhead Trout (Oncorhynchus mykiss)

Whether hypoxic acclimation influences nitric oxide (NO)-mediated control of fish cardiac function is not known. Thus, we measured the function / performance of myocardial strips from normoxia and hypoxia-acclimated (40% air saturation; ~ 8 kPa O2) trout at several frequencies (20 - 80 contractions min-1) and two muscle strain amplitudes (8 and 14%) when exposed to increasing concentrations of the NO donor sodium nitroprusside (SNP) (10-9 to 10-4 M). Further, we examined the influence of: 1) nitric oxide synthase (NOS) produced NO (by blocking NOS with 10-4 M L-NMMA); and 2) soluble guanylyl cyclase mediated, NOS-independent, NO effects (i.e., after blockade with 10-4 M ODQ), on myocardial contractility. Hypoxic acclimation increased twitch duration by 8-10% and decreased mass-specific net power by ~35%. However, hypoxic acclimation only had minor impacts on the effects of SNP and the two blockers on myocardial function. The most surprising result of this study was the degree to which contraction frequency and strain amplitude influenced NO-mediated effects on myocardial power. For example, at 8% strain 10-4 SNP resulted in a decrease in net power of ~30% at 20 min-1 but an increase of ~20% at 80 min-1, and this effect was magnified at 14% strain. This study: suggests that hypoxic acclimation has only minor effects on NO-mediated myocardial contractility in salmonids; is the first to report the highly frequency- and strain-dependent nature of NO effects on myocardial contractility in fishes; and supports previous work showing that NO effects on the heart (myocardium) are finely tuned spatio-temporally.

Experimental faecal peritonitis alters response to 5-hydroxytryptamine in mesenteric lymphatic vessels

Aim. To compare the reactions to 5-hydroxytryptamine (5-HT, serotonin) in the mesenteric lymphangions upon endothelial denudation and during experimental faecal peritonitis as compared with the control lymphangions. Materials and Methods. Experiments were performed on the intestinal lymph trunk lymphangions of rats using a pressure myograph system. We examined the changes in contraction frequency and amplitude as well as tonic reactions upon the addition of 5-HT (10-8-10-4 M). Experimental peritonitis was caused by an intraperitoneal injection of feces. Results. Faecal peritonitis reduced contraction frequency and amplitude in mesenteric lymphangions. 5-HT increased contraction amplitude only at low concentration (10-8 M) and did not alter the tonic reactions. Upon endothelial denudation, serotonin inhibited contraction frequency and amplitude in the lymphangions. As 5-HT stimulates motility through 5-НТ2 receptors and α2-adrenoceptors on endothelial cells, faecal peritonitis abates the sensitivity of such receptors to 5-HT. Conclusion. In experimental faecal peritonitis, alterations in lymphatic vessels are reminiscent of those in blood vessels. Endothelial dysfunction disturbs the response of lymphatic vessels to 5-HT.

Uterine Activity Impacts Fetal and Neonatal Outcomes

Uterine activity impacts fetal and neonatal outcomes. The value of analysis of contraction frequency and the duration of the resting interval were underappreciated until the last two decades. Misconceptions about electronic fetal monitoring and the cesarean section rate may be related to the lack of early research on the significant impact of abnormal uterine activity.

Assessing Peristalsis at the Endometrial–Myometrial Junctional Zone: A Reproducible Ultrasound Technique?

Background: Uterine peristalsis occurs in the endometrial–myometrial junctional zone. It is involved in sperm transport and embryo implantation in spontaneous and in vitro fertilization (IVF) cycles. We investigated the reproducibility of transvaginal assessment of peristalsis and endometrial combined thickness (ECT) as a surrogate marker for contraction frequency and directionality. Methods: We studied 74 women undergoing IVF between 2015 and 2018. On day 9 of stimulation, participants had a transvaginal ultrasound to assess follicular development and ECT. Women proceeding to fresh embryo transfer had an ultrasound preprocedure. A videoclip was analyzed for frequency (total contractions per minute) and directionality of contractions (cervical to fundal [CF] and fundal to cervical [FC]). Anonymized images were reviewed on three separate occasions by a single observer. Intraclass correlation (ICC with 95% CI) and Bland–Altman plots were constructed to assess intraobserver agreement. Secondary analysis was performed to assess peristalsis with ECT and pregnancy rates. Results: Between the first and second observations, there was suboptimal correlation between visual assessment of contraction frequency and directionality (ICC–total 0.67 (0.43–0.80) p < 0.001, ICC–CF 0.62 (0.35–0.78), p < 0.001, ICC–FC 0.74 (0.55–0.85), p < 0.001. Correlation for both frequency and directionality significantly improved between second and third viewing (ICC–total 0.97 (0.95–0.98), p < 0.001, ICC–CF 0.84 (0.73–0.91), p < 0.001, ICC–FC 0.89 (0.81–0.94), p < 0.001). Good agreement was seen on Bland–Altman plots with narrower limits of agreement on second and third viewing. Median ECT was 10 mm (interquartile range [IQR] 8–12 mm). Women with ECT [Formula: see text] 10 mm versus <10 mm demonstrated more contractions per minute (2.2 ± 0.7 vs. 1.7 ± 0.6, p = 0.02). The clinical and ongoing pregnancy rates were 33% (20/60) and 22% (13/60), respectively. There was no association between pregnancy and peristalsis frequency or directionality. Conclusion: Uterine peristalsis is a reproducible observation displaying a learning curve to achieve excellent agreement. Endometrial thickness [Formula: see text]10 mm was associated with increased contraction frequency. There was no association between contraction frequency and/or directionality and clinical pregnancy rates.

TRPV4 channels’ dominant role in the temperature modulation of intrinsic contractility and lymph flow of rat diaphragmatic lymphatics

The present work addresses the putative receptor system that enables diaphragmatic lymphatics to change intrinsic contraction frequency and thus lymph flow according to the changes in temperature of the surrounding environment, showing that this role can be sustained by TRPV4 channels alone.