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A systematic literature review and meta-analysis was conducted to evaluate whether the administration of an oxytocin receptor antagonist (OTR-a) around embryo transfer is associated with live birth and pregnancy achievement in IVF treatment. Multiple databases were searched for randomized controlled trials (RCT) comparing the outcome of IVF treatment with administration of an OTR-a before, during or after embryo transfer versus administration of placebo/nil. The literature search identified 11 eligible RCT. The active compound was intravenous atosiban (n = 7), subcutaneous barusiban (n = 1) and oral nolasiban (n = 3). Clinical pregnancy rate was significantly higher in women receiving an OTR-a around embryo transfer (relative risk [RR] 1.31, 95% confidence interval [CI] 1.13–1.51, P = 0.0002, I2 = 61%, n = 11 studies, n = 3611); however, live birth rate was not statistically significantly affected (RR 1.09, 95% CI 0.98–1.20, P = 0.11, I2 = 25%, n = 5 studies, n = 2765). A sensitivity analysis on low risk of bias studies likewise indicates a higher clinical pregnancy chance (RR 1.11, 95% CI 1.01–1.22, P = 0.03, I2 = 5%, n = 5 RCT, n = 2765). OTR-a administration in IVF treatment has the potential to increase IVF efficacy, although the treatment effects observed so far are small and have not been sufficiently corroborated.

Research question What is the in-vitro effect of oxytocin receptor (OTR) antagonism on parameters of receptivity in human endometrial explants and endometrial stromal cell lines cultured in oestradiol-rich conditions mimicking ovarian stimulation? Design Experimental in-vitro study on endometrial tissue explants collected by aspiration biopsy from 30 women undergoing fertility treatment and cultured endometrial tHESC cell line. The study examined the effects of high oestradiol, oxytocin and OTR antagonist on parameters of decidualization (cell viability and prolactin secretion) as well as cyclooxygenase-1/2 (COX-1/2) activity and prostaglandin F2α (PGF2α) secretion. Changes in expression of OXTR and COX-2 genes were examined using quantitative polymerase chain reaction (qPCR). Results In experiments on cultured endometrial cell line, high oestradiol and oxytocin similarly limited the viability of cells. In cultured endometrial explants both also decreased the secretion of prolactin (a marker of decidualization) and augmented endometrial COX-2 activity and formation of PGF2α. Oxytocin antagonist atosiban was confirmed to reverse the above effects, both in the endometrial line and endometrial explants. Addition of atosiban to cultures acted analogously in experiments employing both oxytocin and high oestradiol. Conclusions Oxytocin antagonist reversed the effects of high oestradiol and oxytocin on parameters related to endometrial receptivity in conditions mimicking ovarian stimulation. This might point to a novel, endometrium-related mechanism to support embryo implantation achieved by the application of oxytocin antagonist prior to embryo transfer.

Introduction The breech presentation represents 4,7% of deliveries at term. There is a method of external cephalic version (ECV) performed from 36 weeks of gestation. French guidelines for the clinical practice of ECV were published in 2020. Objective To evaluate the national practices of ECV in French maternity units, especially on the use of tocolysis, 1 year after publication of the French clinical recommendations guidelines by the French national college of obstetricians and gynecologists (CNGOF). Methods Data self-reported for this national descriptive study were collected from March to May 2021 by an online questionnaire distributed to all French maternities. The 25 items of the questionnaire collected information of maternity units, the general practice of ECV, use or not of tocolysis for ECV attempt and the relevance of a prospective study. Results Of the 517 French maternity units, 150 (29%) responded to the online survey. 95,3% systematically performed ECV. A Kleihauer test was routinely performed in 71 units (49.7%). A tocolysis was associated with ECV attempt in 52.4% of cases. The drugs used were intravenous atosiban (30,7%), mainly in levels 2b and 3 maternity units, intravenous salbutamol (24%), other mode of administration of salbutamol (14,7%) and oral nifedipine (22,6%) mainly in levels 1 and 2a maternity units. Adverse effects were described in 20%, mainly with the use of salbutamol (73,3%). Conclusions 52.4% of the French maternity units surveyed used tocolysis for the ECV attempt, although it is systematically recommended. The choice of tocolytic drug differed according to the maternity units.

There is increasing evidence that oxytocin is involved in learning and memory process. This study investigated the effects of blockade of oxytocin receptors using the selective oxytocin receptor antagonist atosiban (ATO) on contextual fear memory consolidation and reconsolidation in male rats. Post-training injections of different doses of ATO (1, 10, 100 or 1000 µg/kg) impaired the 48 h retention performance in a dose-dependent manner. The same doses of ATO following memory reactivation did not impair subsequent expression of contextual fear memories which formed under low or high shock intensities and tested 24 h or one week following memory reactivation. Also, no effect was found when ATO was administrated in the absence of memory reactivation. Our finding is the first report that indicates endogenous oxytocin released during training play an important role in the consolidation, but not reconsolidation of contextual fear memory in rats.

Recent warnings postulate a possible damaging effect of volatile anesthetics on the fetus. In our archive of fetal surgeries, we found wide variation in dosing of volatile anesthetics during spina bifida surgeries. We hypothesized that there was an association between volatile anesthetic exposure and uterine activity.Sixty anesthesia records from spina bifida operations were assessed. We analyzed the course of the administered volatile anesthetic during surgery and calculated from each patient's anesthesia record the volatile anesthetic exposure expressed in vol%h. We divided the records into two post hoc groups of the 20 lowest exposure (Group L) versus the 20 highest exposure (Group H), and compared them for uterine activity and fetal heart rate.The number of contractions per hour was significantly greater in Group H (mean 1.3, SD ± 1.2) compared with Group L (mean 0.5, SD ± 0.6, P=0.049). There was no difference between the groups for the administration of the tocolytic drug atosiban (P=0.29). The course of the mean arterial pressure did not significantly differ but group H needed significantly more vasoactive medication (P0.05).We found that a lower intra-operative volatile anesthetic exposure than recommended in the MOMS-trial (i.e.2.0 minimum alveolar concentration [MAC]) was not associated with an increase in intra-operative uterine activity. This is an indication that during spina bifida surgery, 2.0 MAC may not be necessary to avoid potentially harmful uterine activity.

The reperfusion injury salvage kinase (RISK) pathway is a fundamental signal transduction cascade in the cardioprotective mechanism of ischemic postconditioning. In the present study, we examined the cardioprotective role of oxytocin as a postconditioning agent via activation of the RISK pathway (PI3K/Akt and ERK1/2). Animals were randomly divided into 6 groups. The hearts were subjected under 30 minutes (min) ischemia and 100 min reperfusion. OT was perfused 15 min at the early phase of reperfusion. RISK pathway inhibitors (Wortmannin; an Akt inhibitor, PD98059; an ERK1/2 inhibitor) and Atosiban (an OT receptor antagonist) were applied either alone 10 min before the onset of the ischemia or in the combination with OT during early reperfusion phase. Myocardial infarct size, hemodynamic factors, ventricular arrhythmia, coronary flow and cardiac biochemical marker were measured at the end of reperfusion. OT postconditioning (OTpost), significantly decreased the infarct size, arrhythmia score, incidence of ventricular fibrillation, Lactate dehydrogenase and it increased coronary flow. The cardioprotective effect of OTpos was abrogated by PI3K/Akt, ERK1/2 inhibitors and Atosiban. Our data have shown that OTpost can activate RISK pathway mostly via the PI3K/Akt and ERK1/2 signaling cascades during the early phase of reperfusion.

Ethnopharmacological relevance In folklore medicine Ananas comosus (pineapple) is reputed to act as an abortifacient and in expectant women as a means of inducing labor. Several reports have claimed abortifacient property of A. comosus fruit (ripe or unripe). Ripe fruit has been used orally as traditional medicine in inducing abortion in Kerala state of India while the juice of unripe fruit was used for abortion in Bangladesh. However, scientific evidence supporting the efficacy of pineapple extracts in inducing uterine contractions is clearly lacking. Aim of the study This study investigated the pharmacological effects of different fractions of pineapple extract with a range of maturities to identify the most potent uterotonic fraction. Materials and Methods The ethanolic crude extracts of pineapple (edible part) were prepared and fractionated through a series of liquid-liquid partitions. Fractions were separately tested on isolated uterine muscle from pregnant SD rats and human pregnant myometrium, which were cut into strips along the longitudinal axis of uterus. The strips were mounted vertically in organ baths (37 °C) and exposed to cumulative addition of fractions (0.1–10 mg ml−1), serotonin (0.05–5 µM) and different inhibitors to delineate the mechanism of action of the active ingredients of the extract. Results Aqueous fraction (F4) possesses uterine stimulant property which was blocked by verapamil but unaffected by indomethacin, prazosin and atosiban. Notably, ketanserin (10 µM) diminished the maximal contractile response induced by both F4 and 5HT by 74.3% and 92.1% respectively. Conclusions These results may indicate the presence of 5HT or 5HT-like compound(s) and serotonergic pathways may contribute to the uterotonic activity of pineapple extract.

Sildenafil is a phosphodiesterase type 5 inhibitor mainly used for male erectile dysfunction. One of rare yet serious adverse effects of Sildenafil is its potential to decrease seizure threshold. Ample evidence suggests that Sildenafil exerts central effects through induction of Oxytocin (OT) secretion and CREB phosphorylation. The aim of the present study is to evaluate potential roles of OT and CREB in the proconvulsant effects of Sildenafil. The Pentylenetetrazole-induced seizure was used as a standard convulsion model in this study. OT release and pCREB expression were evaluated in the hippocampus of mice using ELISA and western blot assays, respectively. Our results showed that Sildenafil at the dose of 10mgkg(-1) or higher, significantly decreased seizure threshold. Pretreatment with a non-effective dose of OT, potentiated while OT receptor antagonist, Atosiban, reversed fully the proconvulsant effects of Sildenafil (5mgkg(-1)). At biochemical inspection, Sildenafil markedly increased CREB which was attenuated by coadministration of Atosiban. The present study shows for the first time that OT release and the subsequent CREB phosphorylation are involved in the proconvulsant effects of acute Sildenafil treatment in an experimental model of seizure.

Nijs, K (reprint author), Jessa Hosp, Dept Anesthesiol & Pain Med, Hasselt, Belgium. Jessa Hosp, Dept Anesthesiol & Pain Med, Hasselt, Belgium.

Uterine inflammation results in a poor uterine environment and early embryonic loss in the mare due to an inhibition of maternal recognition of pregnancy caused from increased prostaglandin F2α (PGF2α). Oxytocin binds to endometrial cell receptors to activate prostaglandin synthesis. An oxytocin receptor antagonist (Atosiban) and a cyclooxygenase inhibitor (indomethacin) both decrease PGF2α production. The aim of this study was to evaluate the in vitro effects of Atosiban and indomethacin on equine uterine prostaglandin secretion. Equine endometrial explants were harvested on day two of behavioral estrus. Endometrial explant cultures were challenged with oxytocin (250nM) and PGF2α concentrations were measured over time. Explants were also cultured with Atosiban and indomethacin for 6h to determine the influence on PGF2α secretion. When endometrial explants were challenged with oxytocin, PGF2α concentrations were greater (P0.0001) at each time point over the 24h of culture as compared to controls. Oxytocin failed (P0.001) to elicit PGF2α release in explants cultured with either Atosiban or indomethacin. These findings show equine endometrial explants can be stimulated with oxytocin to increase secretion of PGF2α and this secretion can be inhibited through an oxytocin receptor antagonist and a Cox inhibitor, suggesting that this response to oxytocin involves an oxytocin receptor mediated event that activates the prostaglandin synthesis cascade through cyclooxygenase. Furthermore, this data suggests a role for the use of these inhibitors in vivo to decrease uterine PGF2α secretion and prevent early luteal regression and embryonic loss.

Background and purpose There is growing evidence that stress contributes to cardiovascular disease and triggers the release of oxytocin. Moreover previous studies confirmed oxytocin mimics the protection associated with ischemic preconditioning. The present study was aimed to assess the possible cardioprotective effects of the centrally released oxytocin in response to stress and intracerebroventricular (i.c.v.) administration of exogenous oxytocin in ischemic-reperfused isolated rat heart. Methods and subjects Rats were divided in two main groups and all of them were subjected to i.c.v. infusion of vehicle or drugs: unstressed rats [control: vehicle, oxytocin (OT; 100 ng/5 μl), atosiban (ATO; 4.3 μg/5 μl) as oxytocin antagonist, ATO + OT] and stressed rats [St: stress, OT + St, ATO + St]. After anesthesia, hearts were isolated and subjected to 30 min regional ischemia and 60 min reperfusion (IR). Acute stress protocol included swimming for 10 min before anesthesia. Myocardial function, infarct size, coronary flow, ventricular arrhythmia, and biochemical parameters such as creatine kinase and lactate dehydrogenase were measured. Ischemia-induced ventricular arrhythmias were counted during the occlusion period. Results The plasma levels of oxytocin and corticosterone were significantly elevated by stress. Unexpectedly hearts of stressed rats showed a marked depression of IR injury compared to control group. I.c.v. infusion of oxytocin mimicked the cardioprotective effects of stress, yet did not elevate plasma oxytocin level. The protective effects of both stress and i.c.v. oxytocin were blocked by i.c.v. oxytocin antagonist. Conclusions These findings suggest that i.c.v. infusion of exogenous oxytocin and centrally released endogenous oxytocin in response to stress could play a role in induction of a preconditioning effect in ischemic-reperfused rat heart via brain receptors.

Purpose Animal models have confirmed high efficiency of combined tocolytic treatment in preterm labour. In humans, the recommended doses of tocolytic drugs prolong pregnancy in threatened preterm labour. The aim of the study was to evaluate the inhibitory effect of dual combinations of atosiban, nifedipine and celecoxib on human myometrial strips contractility on the in vitro model of preterm labour. Material/methods Two groups of patients who delivered by cesarean section were involved in the study: 36 patients who delivered preterm between the 24 th and 34 th week of pregnancy and 40 patients who delivered at term. Myometrial samples were obtained from the lower uterine segment during cesarean sections. Contractile activity was recorded with digital software for each drug combination: atosiban/nifedipine; atosiban/celecoxib, nifedipine/celecoxib. Tocolytic efficiency of the drug combinations was assessed using IC 50 parameter – a molar drug concentration inhibiting 50% of contractility. Results The atosiban/nifedipine combination has shown additive tocolytic effect on myometrial strips contractility in preterm and term patients. The other combinations: atosiban/celecoxib and nifedipine/celecoxib presented only antagonistic effects in both studied groups. Conclusions The effect of the combined therapy on human myometrial contractility presented in the study could be a base for further in vivo clinical trials.

Sicilo-Sarde is a local breed from northern Tunisia resulting from crossing Sarda and Comisana dairy sheep and is traditionally used for cheese production after lamb weaning. A sample of 52 adult Sicilo-Sarde lactating ewes was used for studying their udder morphological traits and milk yield potential during weeks 4–8 (milking–suckling period) and 10 (milking period) of lactation. Daily milk yield was estimated on a daily basis by using the double oxytocin injection method 4 h after machine-milking at d 30 and 45. Udder and teat morphology were also measured at d 45 of lactation. Cisternal area (by ultrasonography) and udder compartments (cisternal and alveolar milk) were evaluated 8 h after milking by using atosiban and oxytocin on d 72 of lactation. Milk yield averaged 0.56 ± 0.10 L/d and ewes had small (volume, 496 ± 28 mL) and healthy udders (CMT

The aim of the present study is to assess the role of endogenous oxytocin (OT) in cardioprotective effects of ischemic preconditioning (IPC) in anesthetized rat.Animals were divided into five groups: 1) ischemia-reperfusion (IR); (n=6), hearts were subjected to 25 min regional ischemia and 60 min reperfusion, 2) OT; (n=6), oxytocin was administered (0.03 μg/kg i.p) 10 min prior to ischemia, 3) IPC; (n=7), IPC was induced via a 5 min regional ischemia followed by 5 min of reperfusion before IR, 4) IPC+ATO (Atosiban); (n=6), atosiban (1.5 μg/kg i.p) was used as OT receptor selective antagonist in the beginning of IPC and 5) IR+ATO; (n=6), atosiban was injected 10 min prior to ischemia-reperfusion.In our experiment, Infarct size was decreased significantly in OT and IPC groups compared to IR (23 ± 1.5% and 19 ± 0.6% vs. 45 ± 2.9% in IR group, P0.05). Administration of atosiban in IPC+ATO group increased infarct size to 39 ± 0.9% in comparison with OT and IPC groups (P0.05). The use of OT and IPC prior to ischemia significantly declined ventricular arrhythmias severity in compared to IR group (1.2 ± 0.4 and 1 ± 0.5 respectively, vs. 4 ± 0.4 in IR group, P0.05). Blockade of OT receptor by atosiban abolished the cardiopreconditioning effects of IPC.This study shows that, in part, the cardioprotective effects of IPC can be induced by endogenous OT.

Summary Objective Pregnancies with extremely preterm premature rupture of membranes (EPPROM), especially before 20 weeks of gestation, are usually considered to be a termination of pregnancy. By improvement of obstetric and neonatal care, we can prolong the pregnancy across the threshold of survival by aggressive tocolysis. Case Report Using intrauterine insemination, a 32-year-old woman became pregnant with twins (first pregnancy). Threatened abortion occured since 9 weeks of gestation and EPPROM of the upper twin was noted at 18 weeks. Massive vaginal bleeding and vigorous uterine contractions occurred at 22 weeks. Poor control of preterm labor occurred using ritodrine and MgSO 4 . Atosiban was applied to calm uterine activities. After discontinuation of atosiban at 30 weeks, the uterine contractions became severe again and an emergency cesarean section was performed to deliver two live, premature babies weighing 1,518 g and 830 g, respectively. Twin A was healthy, weighing 2,030 g at 35 days after birth and subsequently discharged. The smaller twin B was dependent on continuous positive airway pressure and died of pulmonary infection 120 days after birth. Conclusion Comparing to other tocolytic agents, Atosiban has few side effects and assisted in prolonging a pregnancy involving twins that experienced EPPROM.

Oxytocin triggers an excitatory-to-inhibitory switch in GABA (gamma-aminobutyric acid) actions in immature neurons and this was found to increase their resistance to anoxic episodes. In this study we examined the neuroprotective effect of oxytocin on immature hippocampal cultures subjected to oxygen-glucose deprivation (OGD) both immediately after the insult, as well as after 6h of reoxygenation. We measured metabolic activity fluorometrically using resazurin and found that cellular viability was increased in the oxytocin treated group both immediately after OGD, as well as after 6 h of reoxygenation. While the oxytocin receptor antagonist atosiban blocked the effect of oxytocin, the Na+-K+-2Cl(-) cotransporter (NKCC1) blocker bumetanide protected neurons after reoxygenation. The effects of oxytocin are dose-related. Our results suggest that oxytocin exerts a prolonged neuroprotective action on fetal neurons. Perinatal pharmacologic manipulation of oxytocin receptors may have detrimental effects by increasing susceptibility of the fetal brain to hypoxic-ischemic insults.

A kinetic study of atosiban was conducted following repeated intravenous administration in Wistar rats. Sample analysis was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) following full validation of an in-house method. Eptifibatide, a cyclic peptide, was used as an internal standard (IS). The analyte and internal standard were extracted using solid phase extraction (SPE) method. Chromatographic separation was carried out using an ACE C18 5 microm 50 mm x 4.6 mm column with gradient elution. Mass spectrometric detection was performed using TSQ Quantum ultra AM. The lower limit of quantification was 0.01 microg/ml when 100 microl rat plasma was used. Plasma concentrations of atosiban were measured at 0 (pre-dose), 2, 15, 30, 45, 60, 120 min at the dosage levels of 0.125 mg/kg (low dose), 0.250 mg/kg (mid dose), and 0.500 mg/kg (high dose), respectively. Atosiban plasma concentration measured at Day 1 showed mean peak atosiban concentration (C(max)) 0.40, 0.57, 1.95 microg/ml for low, mid and high dose treated animals and mean peak concentration on Day 28 was 0.41, 0.88, 1.31microg/ml on Day 28 for low, mid and high dose treated animals.

This chapter discusses the tocolytic agents currently in use for the treatment of preterm labour and considers them in light of the evidence base. These agents are the β2 sympathomimetic agonists, magnesium sulphate (MgSO 4 ), indomethacin, nifedipine and atosiban. The available evidence for these agents shows that the β2 agents are effective but have significant maternal side effects and no effect on perinatal outcome. MgSO 4 and glyceryl trinitrate are clearly ineffective. Nifedipine is effective with a low maternal side effect profile and is associated with improved perinatal outcomes. Meta-analyses of the several randomized controlled trials of atosiban show that it is no more effective than other tocolytic therapies. Possible directions for the future will be discussed.

The oxytocin receptor antagonist barusiban, currently being developed for treatment of preterm labour, was investigated in pregnant cynomolgus monkeys with a 9-month postnatal follow-up of their offspring. The nature of barusiban, its indication, and the potential exposure of pre- and postnatal infants entailed the design of a unique protocol to investigate all aspects of maternal and offspring well-being. Barusiban was administered to the mothers from gestation day 85 until delivery with daily subcutaneous dosages up to 2.5 mg/kg body weight/day. There were no test article-related effects seen in the mothers at any time during the study. The postnatal examination of offspring included routine toxicological parameters, as well as specialised investigation of the immune, cardiovascular, renal and central nervous systems, including a full behavioural assessment. A full pathology examination of offspring was performed at the end of the 9-month postnatal period. No adverse infant findings occurred.

Objective To investigate embryotoxic potential and effects on human sperm motility of the mixed vasopressin V 1a /oxytocin receptor antagonist atosiban considered for novel indication of improvement of uterine receptivity in embryo-transfer recipients. Design One-cell rabbit embryo bioassay and human sperm motility bioassay were performed in control media or in media containing atosiban. Setting Private center of reproductive medicine and academic research institute of reproduction biotechnology. Animal(s) Rabbit females (New Zealand and California, N=15) aged 4.5–6.5 months. Intervention(s) In vitro exposure of one-cell rabbit embryos and human sperm to atosiban in the range of therapeutic concentrations clinically occurring in human beings. Main Outcome Measure(s) Embryo development and sperm motility. Result(s) Preimplantation development of one-cell rabbit embryos was not affected by atosiban in the concentrations ≤15,000 nM, which was 50-fold higher than the mean plasma concentration reached during regular therapy (300 nM). Atosiban did not affect human sperm motility in concentrations of ≤3,000 nM, in other words, 10 times the human mean plasma concentration. Conclusion(s) Clinical application of atosiban in the proposed indication may be safe for embryos because it is compatible with preimplantation rabbit embryo development and human sperm motility.

The prevention of preterm birth should be one of the major aims of antenatal care. Unfortunately, identification of women who will subsequently deliver preterm is imprecise. Prevention is also difficult. Surgical prevention with cerclage may help a proportion of women. Medical prevention is currently limited to the identification and treatment of bacterial vaginosis, although recent studies have suggested that progesterone prophylaxis may be helpful in some women. Confirmation of efficacy and safety is required before progesterone is introduced as long-term prophylaxis for all women at high risk. The optimal medical treatment (rather than prevention) of threatened preterm labour is controversial. Tocolysis is generally accepted to improve neonatal outcome although this has never been convincingly demonstrated in appropriate trials. Antibiotics confer benefit in the presence of ruptured membranes but are not indicated in uncomplicated preterm labour. In future, it may be possible to identify a subgroup of women in preterm labour with intact membranes who will benefit from tocolysis. The choice of first-line tocolytic therapy is currently debated but atosiban or nifedipine are suggested in current UK guidelines. A direct comparison of these drugs is required in a clinical trial. Although indirect comparisons have been made, these are difficult to interpret due to methodological differences. Each of these drugs have their advocates. Nifedipine has been reported to delay delivery and improve outcome but there are inconsistencies in the clinical trials. Atosiban is also reported to delay delivery and is well tolerated but improved neonatal outcome may have been hidden in clinical trials due to the requirement for rescue tocolysis.

Experiments were conducted to determine if the chronic absence of the neurotransmitter oxytocin (OT) in null mice resulted in alterations in the responsiveness and abundance of central OT receptors. Self-grooming elicited by intracerebroventricularly administered OT was studied as an indicator of the activation of central OT receptors and autoradiography was used to map the distribution and density of OT receptors in OT null and wild type mice. The intracerebroventricular administration of OT, but not vehicle, artificial cerebrospinal fluid (aCSF), produced a robust increase in grooming behavior in both OT null and wild type animals, P

Objectives: (1) To determine the current use of treatment options for preterm labour and (2) to review the relative safety and efficacy of each class of tocolytic agent. Methods: MEDLINE and the Cochrane Library were searched using the terms "preterm delivery, " "preterm labour, " and "tocolysis" alone, and in combination with the terms "betamimetics, " "ritodrine, " "magnesium sulfate, " "calcium channel blockers, " "nifedipine, " "prostaglandin synthetase inhibitors, " "indomethacin, " "glyceryl trinitrate, " "nitroglycerin, " "oxytocin antagonists, " and "atosiban. " Randomized controlled trials (RCTs) that compared the effect of a tocolytic with a placebo or other tocolytic in women with preterm labour were selected. Trials were assessed according to Jadad's validated quality scale for assessing the quality of RCTs. Thirty-two RCTs retrieved met the inclusion criteria. Information not evident from RCTs was sought from non-randomized clinical trials, cohort studies, case control studies, case series, and case reports. Data from the Canadian Survey on Tocolytic Use was obtained directly from the Society of Obstetricians and Gynaecologists of Canada (SOGC). Results: The available evidence on the use of tocolytics to prolong pregnancy fails to show benefits in neonatal survival and reduced disability. This uncertainty of benefit makes the issue of fetal and maternal drug toxicity more important. There is great concern among SOGC members over the lack of effective and safe treatment options for the management of preterm labour. Conclusions: Further well-designed placebo-controlled trials are necessary to study the efficacy and safety of tocolytics in managing preterm labour

To compare the efficacy and safety of atosiban and salbutamol in the treatment of preterm labor.A multicenter, double-blind, double-placebo, randomized, controlled trial. Women (n=241) diagnosed with preterm labor at 23-33 gestational weeks were enrolled and received either atosiban (n=119) or salbutamol (n=122). At randomization, women were stratified by gestational age (or =28 weeks and28 weeks). Atosiban (i.v. bolus dose of 6.75 mg, then 300 microg/min for 3h and 100 microg/min for up to 48h) and salbutamol (2.5-45 microg/min) were administered by i.v. infusion for up to 48h. Retreatment with study drug or an alternative tocolytic agent was allowed. Main outcome measures included tocolytic effectiveness which was assessed in terms of the number of women undelivered after 48h and 7 days. Tocolytic efficacy and tolerability were assessed in terms of the proportion of women undelivered and who did not require alternative tocolytic therapy at 48h and 7 days of starting treatment. Safety was assessed in terms of maternal side effects and neonatal morbidity.Tocolytic effectiveness at 48h was 93.3 versus 95.0% (P=0.67) and after 7 days was 89.9 versus 90.1% (P=0.93) in the atosiban and salbutamol groups, respectively. Tocolytic efficacy and tolerability within 48h was 79.8 versus 75.2% (P=0.15), and after 7 days was 58.8 versus 46.3% (P=0.021) in the atosiban and salbutamol groups, respectively. Maternal adverse events, including serious events, occurred more frequently in the salbutamol group. Neonatal outcomes were comparable between the study groups.The oxytocin antagonist atosiban was found to be better tolerated by both mother and fetus than salbutamol, with a comparable neonatal and infant safety profile, and atosiban was as effective as salbutamol in delaying threatened preterm birth. This study supports the clinical use of atosiban in the treatment of preterm labor.

Beta-adrenergic receptor agonists have been used for tocolysis in the setting of preterm labor for more than three decades. One of these agents, ritodrine hydrochloride, is the only Federal Drug Administration (FDA) approved drug for the treatment of preterm labor. Despite their widespread use, only a few prospective randomized placebo-controlled trials have been performed. These agents have been shown to have more patients deliver beyond 48 hours after the onset of treatment as compared with controls, but have never shown a difference in neonatal outcomes. Because they are one of the few tocolytic agents to have been shown to make a difference when compared with controls, the beta-agonists are commonly used as the control groups in studies examining the efficacy of newer tocolytic agents. In general, agents such as nifedipine, magnesium sulfate, and atosiban have not been shown to be more efficacious than the beta-agonists. However, several studies have shown these agents to have less side effects and lower discontinuation rates than the beta-agonists.

Preterm birth at37 weeks of gestation is the most common and costly complication of pregnancy and remains the leading cause of neonatal morbidity, death, and reduced achievement in surviving infants. Magnesium sulfate is 1 class of tocolytics for threatened preterm labor; however, its clinical efficacy has been questioned. Twin pregnancies are at increased risk of preterm delivery compared with singleton gestations, which suggests that there is twin-specific risk to preterm delivery in twins. The prevention strategies that are applied to singleton pregnancies, however, have not been shown to be effective in twin pregnancies.The purpose of this study was to compare the relaxant effect of magnesium sulfate on spontaneous and oxytocin-augmented contractions of human myometrium from singleton and twin pregnancies and to examine whether the effect of oxytocin on magnesium sulfate's potency could be reversed with the use of the oxytocin receptor antagonist, atosiban.Myometrium was obtained at the time of prelabor cesarean section (36-40 weeks of gestation) from women with singleton (n=23) or twin (n=12) pregnancy. Isometric tension recordings were made on myometrial strips that were mounted in organ baths that were superfused with physiologic saline solution. Strips were exposed to rising concentrations of magnesium sulfate, and the effect on spontaneous contractions or stimulated with oxytocin (0.5 nmol/L) and in the presence or absence of atosiban (100 nmol/L) was recorded. The contractile characteristics after each application of magnesium sulfate, which included amplitude of contraction and activity integral, were measured. Concentration-response curves were fitted with the use of nonlinear regression and comparison of the negative logarithm of the 50% reduction in activity values.Magnesium sulfate exerted an equal concentration-dependent inhibitory effect on spontaneous myometrial contractions from both singleton and twin myometrium (P.05). The application of oxytocin produced a significant rightward shift in the concentration-response curves (P.0001), but no differences were found between pregnancy groups (P.05). The addition of atosiban shifted concentration-response curves significantly back to the left for amplitude of contraction and activity integral in singletons (P.0001). However, only activity integral was significantly reversed in twins (P.01).Magnesium sulfate is equipotent in suppressing contractions in singleton and twin myometrium. Oxytocin (0.5 nmol/L) significantly reduces the tocolytic potency of magnesium sulfate, which may explain, in part, magnesium sulfate's poor efficacy in vivo; however, this can be reversed partially by the use of an oxytocin receptor antagonist. Combination tocolysis that involves oxytocin receptor antagonists requires further investigation.

Objectives: Patients admitted with an acute episode of preterm labor who respond to early intravenously administered tocolysis remain at risk of having subsequent episodes of preterm labor and preterm delivery. Several pharmacologic agents have been used in an attempt to reduce subsequent episodes of preterm labor, and all are associated with significant side effects. Atosiban, an oxytocin receptor antagonist, is effective in the treatment of an acute episode of preterm labor. This study was designed to compare the efficacy and safety of atosiban with those of placebo maintenance therapy in women with preterm labor who achieved uterine quiescence with intravenous atosiban. Study Design: A multicenter, double-blind, placebo-controlled trial was designed for patients in preterm labor who responded to early intravenous treatment with atosiban. Five hundred thirteen patients were randomly assigned to receive maintenance therapy, 252 to receive atosiban, and 251 to receive matching placebo. Maintenance therapy was administered as a continuous subcutaneous infusion, via pump, of 30 μg/min to the end of 36 weeks' gestation. The primary end point was the number of days from the start of maintenance therapy until the first recurrence of labor. A secondary end point was the percentage of patients receiving subsequent intravenous atosiban therapy. Results: The time (median) from the start of maintenance treatment to the first recurrence of labor was 32.6 days with atosiban and 27.6 days with placebo ( P = .02). At least one subsequent intravenous atosiban treatment was needed by 61 atosiban patients (23%) and 77 placebo patients (31%). Except for injection site reactions, adverse event profiles of atosiban and placebo were comparable. There were 4 neonatal deaths reported in the atosiban group and 5 in the placebo group after the start of maintenance therapy. Infant outcomes (including birth weight) were comparable between maintenance and treatment groups. Conclusions: Maintenance therapy with the oxytocin receptor antagonist atosiban can prolong uterine quiescence after successful treatment of an acute episode of preterm labor with atosiban. Treatment was well tolerated. (Am J Obstet Gynecol 2000;182:1184-90.)

Objective: This study was undertaken to compare the efficacy and safety of intravenous administration of atosiban versus ritodrine for the treatment of preterm labor. Study Design: Women with preterm labor and intact membranes diagnosed at 23 to 33 gestational weeks (n = 247) were randomly assigned to treatment arms and received atosiban (6.75 mg intravenous bolus, 300 μg/min for 3 hours, then 100 μg/min intravenously) or ritodrine (0.10-0.35 mg/min intravenously) for as long as 18 hours. Tocolytic effectiveness was assessed in terms of the numbers of women who had not been delivered after 48 hours and after 7 days. Safety was assessed in terms of maternal side effects and neonatal morbidity. Secondary outcomes included mean gestational age at delivery and mean birth weight. An intent-to-treat analysis was performed with the Cochran-Mantel-Haenszel test. Results: The proportion of women who had not been delivered at 48 hours was 84.9% (n = 107) in the atosiban group and 86.8% (n = 105) in the ritodrine group. At 7 days 92 women had still not been delivered in both the atosiban (73.0%) and ritodrine (76.0%) groups. Neither of these differences was statistically significant. The incidence of maternal cardiovascular side effects was substantially lower in the atosiban group (4.0% vs 84.3%, P < .001). In addition, intravenous therapy was terminated more frequently as a result of maternal adverse events in the ritodrine group (29.8%) than in the atosiban group (0.8%). The overall occurrences of fetal adverse events in the two treatment groups were comparable. Neonatal morbidity was similar between the treatment groups after adjustment for unbalanced enrollment of women with multiple pregnancies and for gestational ages within treatment groups. Conclusion: Atosiban was comparable in clinical effectiveness to conventional ritodrine therapy but was better tolerated than ritodrine, with no evidence of significant maternal or fetal adverse events. Neonatal morbidity, which was similar between the two treatment arms, was apparently related to the gestational age of the infant rather than to the exposure to either tocolytic agent. (Am J Obstet Gynecol 2000;182:1191-9.)

OBJECTIVE: Our purpose was to evaluate the pharmacokinetics of atosiban, an oxytocin antagonist, during and after intravenous infusion in pregnant patients having at least six contractions per hour. The relationship between atosiban infusion and uterine activity was also assessed. STUDY DESIGN: Plasma samples from eight pregnant patients treated with intravenous atosiban (300 μg/min for 6 to 12 hours) were analyzed for atosiban concentration by a specific radioimmunoassay procedure. Contraction rate data were obtained by external tocodynamometry for 1 hour before the infusing and during the subsequent infusion. RESULTS: The average steady-state plasma concentrations of patients receiving intravenous atosiban were 442 ± 73 ng/ml (mean ± SD), with steady state achieved by 1 hour after the start of the infusion. After the completion of the infusion, plasma concentrations declined rapidly in a biexponential manner with initial and terminal half-life estimates of 13 ± 3 and 102 ± 18 minutes, respectively. The effective half-life was 18 ± 3 minutes. The plasma clearance of atosiban was relatively high (42 L/hr) and the volume of distribution (approximately 18 L) was consistent with distribution into extracellular fluid. Of the seven patients evaluated for uterine activity, the mean contraction rate decreased by 75% during the third hour of treatment and remained low until treatment termination. CONCLUSION: On the basis of earlier published reports, the pharmacokinetics of atosiban in pregnant patients are similar to those in nonpregnant women. Although the patient population was small, a consistent reduction in uterine activity was observed during atosiban infusion.

OBJECTIVE: Our purpose was to study myometrial oxytocin and type V1 vasopressin receptors, the in vitro contractile effects of these hormones, and the influence of an oxytocin antagonist. STUDY DESIGN: Women delivered by cesarean section preterm ( n = 51) and at term ( n = 71), with and without labor contractions, gave-myometrium for the estimation of oxytocin and V1 vasopressin receptors. The in vitro myometrial effects of the peptides and the influence on these of the competitive oxytocin receptor blocking agent 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin were also tested. RESULTS: The median concentration of oxytocin receptors was 116 fmol/mg protein (range 15 to 372 fmol/mg protein) in patients delivered preterm not in labor, 134 fmol/mg protein (27 to 1421 fmol/mg protein) in the beginning of labor, and 46 fmol/mg protein (9 to 140 fmol/mg protein) in advanced labor. At term the corresponding concentrations were 172 (25 to 629), 223 (24 to 414), and 70 (21 to 92) fmol/mg protein. The concentration of V1 vasopressin receptors also decreased in advanced labor. In advanced labor after oxytocin infusion a reduction in the concentration of the receptor for this hormone was observed, which appeared to be related to the duration and dose of treatment. Oxytocin receptors did not vary between women with different indications for cesarean section. The oxytocin effects in vitro and the degree of inhibition by the antagonist of oxytocin responses correlated with the concentration of oxytocin receptors but not with that of V1 vasopressin receptors. No correlation was seen between the response to vasopressin and concentrations of oxytocin or V1 vasopressin receptors. CONCLUSIONS: The effect of oxytocin on the myometrium in pregnancy is mediated by an oxytocin receptor; whereas vasopressin acts on both oxytocin and vasopressin receptors. The initiation of labor both preterm and at term may be primarily related to increased release of oxytocin, which is locally produced in the uterus and not detectable in the plasma, but oxytocin and vasopressin receptors may play a role in the regulation of labor. The analog 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin, which blocks both the oxytocin and the V1 vasopressin receptor, should inhibit labor both preterm and at term, the former confirming results of recent clinical studies in Sweden and the United States.

OBJECTIVE: The purpose of this study was to test the hypothesis that infusion of the oxytocin antagonist atosiban results in decreased preterm uterine activity in the human. STUDY DESIGN: A randomized, double-blind, placebo-controlled trial was performed. One hundred twenty women from 20 to 36 weeks' gestation with a complaint of labor who had more than four uterine contractions per hour after intravenous hydration but no evidence of cervical change were randomized to receive a 2-hour intravenous infusion of atosiban at a rate of 300 μg/min or placebo. One hundred-twelve subjects (56 in each arm) were suitable for analysis of efficacy. Both groups remained at bed rest and received hydration. RESULTS: The mean percent decrease in contraction frequency was greater in atosiban subjects compared with controls (55.3% ± 36.3% vs 26.7% ± 40.4%, mean ± SD, p < 0.001). A minimal (< 20%) decrease or an increase in contraction frequency was noted in 25 placebo subjects (45%) and seven atosiban subjects (13%). There was no clinically or statistically significant change in maternal blood pressure or heart rate during the infusion. The only adverse experiences possibly related to the drug were nausea and vomiting in one atosiban patient. CONCLUSION: A 2-hour infusion of the oxytocin antagonist atosiban resulted in a significantly greater decline in contraction frequency compared with controls. Oxytocin appears to play a role in the maintenance of preterm uterine activity in the human. (AM J OBSTET GYNECOL 1994;170:474-8.)

Objectives: Atosiban is a synthetic oxytocin antagonist that is currently undergoing dose-ranging clinical trials. To date, no data are available on the cardiovascular effects of combined oxytocin and vasopressin blockade during late pregnancy. Our aims were (1) to determine the effects of atosiban infusion on the maternal and fetal cardiovascular system and on uterine blood flow and (2) to determine the maternal pharmacokinetics and the rate of placental transfer of atosiban. Study Design: Five chronically catheterized pregnant sheep were treated with a 2-hour infusion of atosiban (300 μg · min −1 ) at 116 to 126 days' gestation. Maternal and fetal blood pressure and heart rate and uterine blood flow were measured before and during the infusion. Maternal and fetal arterial blood samples were obtained throughout the experiment for measurement of plasma atosiban levels and blood gas values. Results: No significant change in maternal cardiovascular parameters or uterine blood flow were observed. Similarly, no changes in fetal blood pressure and arterial blood gases were present during the infusion of the atosiban. Maternal plasma levels of atosiban reached a maximum of 585.2 ± 82.2 (ng/ml mean ± SD) at the end of the infusion and decreased biexponentially with a mean t ½α of 17 minutes and a mean t ½β of 2.2 hours. Fetal plasma levels of atosiban were at or below the detection limit. Conclusion: Atosiban does not significantly affect maternal or fetal cardiovascular parameters when it is administered for 2 hours in late-pregnant sheep. Although significant levels were measured in maternal blood, negligible transfer to the fetus occurred.

A set of oxytocin antagonists consisting of [Mpa 1 Sar 7 Arg 8 ]-oxytocin substituted by various conformationally restricted or bulky d amino acids at position 2 were synthetized and biologically tested. In in vivo pharmacological investigations, the effects of these peptides were examined on the spontaneous motor activity of postpartum rat. Three of the newly prepared peptides proved at least as effective in inhibiting uterine contractions as clinically investigated atosiban.

We wanted to determine the degree of placental transfer of atosiban (Antocin), an oxytocin antagonist, in pregnant women at term. We also assessed the effects of the infusion on umbilical cord blood gases at birth and the maternal hematocrit drop after cesarean section.Eight women undergoing elective cesarean section at term were studied. Each received an infusion of 300 micrograms/min of atosiban over 208 to 443 minutes; the infusion was continued up to the time of cord clamping. Uterine vein and umbilical blood samples were obtained simultaneously. They were assayed by specific radioimmunoassay. Cord blood gases were obtained and compared with those from a control group of women undergoing elective cesarean section.The mean (+/- SD) maternal uterine vein concentration was 331.9 +/- 42.9 ng/ml, compared with 42 +/- 13 ng/ml in the umbilical vein (p0.05). The mean maternal/fetal was 12 +/- 0.03, which was not affected by the length of infusion. There was no significant difference in the hematocrit drop between the cesarean delivery groups: 5.9 +/- 0.4 for the control group versus 5.8 +/- 1.1 for the atosiban group (p0.1). The mean cord pH was 7.27 for the atosiban group versus 7.27 for the control group (n = 141) (p0.1). One year follow-up of the infants (n = 7) was normal.Our results show minimal placental transfer of atosiban. Drug levels did not increase with longer infusions, and no effect was seen on umbilical cord gases. Administration of atosiban even at high doses up to the time of delivery did not increase maternal blood loss at cesarean section.