Short-Term Outcomes of Atosiban in the Treatment of Preterm Labour at the Sultan Qaboos University Hospital, Muscat, Oman: A tertiary care experience.

OBJECTIVES: This study aimed to generate baseline evidence regarding the effectiveness of atosiban in delaying delivery by ≥48 hours among pregnant women presenting with threatened preterm labour (TPL). The secondary objective was to assess the relationship between atosiban success and various perinatal factors and neonatal outcomes. METHODS: This retrospective study was conducted between June 2008 and May 2018 at the Sultan Qaboos University Hospital, Muscat, Oman. The medical records of all pregnant women who received atosiban between 24-34 gestational weeks for TPL during this period were reviewed. RESULTS: A total of 159 women were included in the study. Atosiban was successful in delaying delivery by ≥48 hours in 130 cases (81.8%). Approximately half of the women (50.9%) achieved uterine quiescence in <12 hours. Failure to delay delivery by ≥48 hours was significantly lower among women with normal versus abnormal cervical findings (11.1% versus 25.6%; P = 0.023). Only 9.4% of women experienced minor side-effects. Mean birth weight (2,724.55 versus 1,707.59 g; P <0.001) and Apgar scores at 5 minutes (9.66 versus 8.28; P <0.001) were significantly higher among neonates delivered at ≥48 versus <48 hours post-atosiban, whereas the rate of neonatal respiratory distress syndrome was significantly lower (18.4% versus 81.6%; P <0.001). CONCLUSION: Atosiban was highly effective in delaying delivery by ≥48 hours and resulted in few adverse maternal side-effects and neonatal outcomes. To the best of the authors' knowledge, this is the first study conducted in Oman to evaluate the effectiveness of atosiban in preventing preterm labour.

Oxytocin receptor antagonists as a novel pharmacological agent for reducing smooth muscle tone in the human prostate.

Pharmacotherapies for the treatment of Benign Prostatic Hyperplasia (BPH) are targeted at reducing cellular proliferation (static component) or reducing smooth muscle tone (dynamic component), but response is unpredictable and many patients fail to respond. An impediment to identifying novel pharmacotherapies is the incomplete understanding of paracrine signalling. Oxytocin has been highlighted as a potential paracrine mediator of BPH. To better understand oxytocin signalling, we investigated the effects of exogenous oxytocin on both stromal cell proliferation, and inherent spontaneous prostate contractions using primary models derived from human prostate tissue. We show that the Oxytocin Receptor (OXTR) is widely expressed in the human prostate, and co-localises to contractile cells within the prostate stroma. Exogenous oxytocin did not modulate prostatic fibroblast proliferation, but did significantly (p < 0.05) upregulate the frequency of spontaneous contractions in prostate tissue, indicating a role in generating smooth muscle tone. Application of atosiban, an OXTR antagonist, significantly (p < 0.05) reduced spontaneous contractions. Individual tissue responsiveness to both exogenous oxytocin (R2 = 0.697, p < 0.01) and atosiban (R2 = 0.472, p < 0.05) was greater in tissue collected from older men. Overall, our data suggest that oxytocin is a key regulator of inherent spontaneous prostate contractions, and targeting of the OXTR and associated downstream signalling is an attractive prospect in the development of novel BPH pharmacotherapies.

Randomized Trials of Retosiban Versus Placebo or Atosiban in Spontaneous Preterm Labor.

OBJECTIVE: The aim of this study is to assess the efficacy and safety of retosiban in spontaneous preterm labor (sPTL). STUDY DESIGN: Two multicenter, randomized, and double-blind trials compared retosiban with placebo and retosiban with atosiban in women with a singleton pregnancy and intact membranes in sPTL at 24 to 336/7 weeks' gestation. Coprimary endpoints in the placebo-controlled trial were time to delivery (TTD) or treatment failure (whichever occurred first) and neonatal composite morbidity and mortality. The primary endpoint of the atosiban comparator trial was TTD. RESULTS: The trials were terminated early because of slow recruitment. The placebo-controlled trial enrolled 23 participants (February 2016-July 2017; 2.6% of target);the atosiban-comparator trial enrolled 97 (March 2015-August 2017; 29% of target). Baseline participant characteristics were similar between treatments. In the placebo-controlled trial, mean gestational ages at randomization were 30.8 (retosiban, n = 10) and 30.5 weeks (placebo, n = 13), and mean times to delivery/treatment failure were 18.9 days (retosiban) and 11.1 days (placebo). Two and four neonates in the retosiban and placebo groups, respectively, had ≥1 component of the neonatal composite endpoint. In the atosiban-comparator trial, mean gestational age at randomization was 31.5 weeks (for both retosiban, n = 47, and atosiban, n = 50), and adjusted mean TTDs were 32.51 days (retosiban) and 33.71 days (atosiban; p > 0.05). Adverse events were no more common with retosiban than placebo or atosiban. CONCLUSION: Despite considerable efforts to conduct two adequate and well-controlled studies in patients with sPTL, both studies were unable to recruit effectively and consequently terminated prematurely. Key factors negatively affecting participation were patient and physician resistance to use of a placebo comparator, lack of investigator consensus on diagnostic criteria and acceptance of protocol procedures, and ethics committee decisions. Meaningful cooperation between pharmaceutical companies, regulatory authorities, and the obstetric community is essential for future development of drugs to treat sPTL.

Systematic review and meta-analysis of randomized controlled trials of atosiban versus nifedipine for inhibition of preterm labor.

BACKGROUND: Two tocolytic drugs-atosiban and nifedipine-are currently used for first-line treatment of preterm labor (PTL). OBJECTIVE: To compare the efficacy and safety of atosiban with nifedipine for PTL treatment. SEARCH STRATEGY: In May 2017, we searched PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Clinical Trials with search terms including "nifedipine", "atosiban", and "preterm labor". SELECTION CRITERIA: Randomized controlled trials of women with PTL. DATA COLLECTION AND ANALYSIS: Data were extracted for study design, patient characteristics, risk of bias domains, and study outcomes. A random-effects model was used to generate pooled risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: We included seven studies that enrolled 992 patients. There was no significant difference between atosiban and nifedipine for pregnancy prolongation of 48 hours or more regarding efficacy (RR 1.06, 95% CI 0.92-1.22; P=0.440) or effectiveness (0.93, 0.84-1.03; P=0.177). Pregnancy prolongation for 7 days or more also did not differ between groups for efficacy (RR 1.04, 95% CI 0.89-1.21; P=0.656) or effectiveness (0.91, 0.79-1.05; P=0.177). Atosiban-however-was associated with fewer maternal side-effects than nifedipine. CONCLUSION: Atosiban resulted in fewer maternal side-effects than nifedipine, with no difference in pregnancy prolongation. PROSPERO registration: CRD42018090223.

Tocolysis for in utero Surgery: Atosiban Performs Distinctly Better than Magnesium Sulfate.

INTRODUCTION: To compare tocolysis with magnesium sulfate versus atosiban regarding the occurrence of short-term preterm labor and maternal side effects during and after open fetal myelomeningocele (MMC) repair. MATERIAL AND METHODS: A prospective nonrandomized cohort study was performed including 30 fetal MMC cases. The first 15 cases (group 1) received magnesium sulfate according to the MOMS protocol. In the following 15 cases (group 2), magnesium sulfate was substituted by atosiban. Chorioamniotic membrane separation (CMS), premature prelabor rupture of the fetal membranes (PPROM), preterm delivery <3 weeks after fetal MMC repair, and maternal complications due to the tocolytic medication were the major endpoints. RESULTS: In both groups, one CMS but no PPROM was diagnosed <3 weeks after fetal MMC repair. One patient of group 2 delivered <3 weeks after fetal MMC repair because of an intraoperative placental abruption at 25 weeks. All women of group 1 showed an electrolyte imbalance during magnesium sulfate administration. One woman of group 1 developed several episodes of a third-degree atrioventricular block within the first 3 days after fetal surgery. Lethargy was found in all women during magnesium sulfate therapy. No maternal side effects were found under atosiban. DISCUSSION: The use of atosiban resulted in an almost identical short-term uterine outcome without any serious maternal complications as seen when magnesium sulfate was given. Thus, the authors suggest using atosiban instead of magnesium sulfate in the context of open fetal surgery.

Association of Intraventricular Hemorrhage and Death With Tocolytic Exposure in Preterm Infants.

Importance: No trials to date have demonstrated the benefits of tocolysis on death and/or neonatal morbidity in preterm infants; tocolytics may affect the fetal blood-brain barrier. Objectives: To assess the risks associated with tocolysis in women delivering prematurely as measured by death and/or intraventricular hemorrhage (IVH) in preterm infants and to compare the association of calcium channel blockers (CCBs) nifedipine and nicardipine hydrochloride vs atosiban used for tocolysis with death and/or IVH. Design, Settings, and Participants: The French 2011 EPIPAGE-2 (Enquête Épidémiologique sur les Petits Âges Gestationnels) cohort was limited to mothers admitted for preterm labor without fever, who delivered from 24 to 31 weeks of gestation from April 1 through December 31, 2011. Groups of preterm infants with vs without tocolytic exposure and groups with atosiban vs CCB exposure were compared. Data analysis was performed from June 7, 2014, through September 3, 2017. Exposures: Tocolytics. Main Outcomes and Measures: The primary outcome was a composite of death and/or IVH in preterm infants. Secondary outcomes included death, IVH, and a composite of death and/or grades III to IV IVH. Results: A total of 1127 mothers (mean [SD] age, 25.5 [6.0] years) experienced preterm labor and gave birth to 1343 preterm infants with a male to female ratio of 1.23 and mean (SD) gestational age of 27 (2.5) weeks. Of these, 789 mothers (70.0%) received tocolytics; 314 (39.8%) received only atosiban, and 118 (15.0%) received only a CCB. In the first analysis, the primary outcome (death and/or IVH) was not significantly different in preterm infants with vs without tocolytic exposure (183 of 363 [50.4%] vs 207 of 363 [57.0%]; relative risk [RR], 0.88; 95% CI, 0.77-1.01; P = .07). The secondary outcome (death and/or grades III-IV IVH) was significantly lower in preterm infants with vs without tocolytic exposure (92 of 363 [25.3%] vs 118 of 363 [32.5%]; RR, 0.78; 95% CI, 0.62-0.98; P = .03). Other outcomes did not differ significantly. In the secondary analysis, death and/or IVH was not significantly different in preterm infants with atosiban vs CCB exposure (96 of 214 [44.9%] vs 62 of 121 [51.2%]; RR, 0.88; 95% CI, 0.70-1.10; P = .26), nor was IVH (77 of 197 [39.1%] vs 48 of 106 [45.3%]; RR, 0.86; 95% CI, 0.66-1.13; P = .29). Conclusions and Relevance: In this population-based study, findings suggest that tocolytics were associated with a reduction of death and severe IVH. Other studies are necessary to compare perinatal outcomes after use of atosiban vs CCBs.

Oxidative Stress in Women Treated with Atosiban for Impending Preterm Birth.

Preterm birth is defined as delivery before 37 completed weeks of pregnancy, and it is the leading cause of neonatal morbidity and mortality. Oxidative stress is recognized as an important factor in the pathogenesis of premature labor. We conducted this analysis to investigate the safety of administration of the tocolytic drug Atosiban-a reversible, competitive antagonist of the oxytocin receptor in the treatment of preterm birth and its impact on the level of oxidative stress in pregnant women after 48 hours of tocolytic treatment. This prospective study was conducted between March 2016 and August 2017 at the Obstetric Clinic of the Polish Mother's Memorial Hospital Research Institute. Total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) values as well as 3-nitrotyrosine, carbonyl, and thiol group levels were measured using an ELISA test in serum and plasma of 56 pregnant women before and after 48 hours of continuous administration of Atosiban. We found that TAS levels decreased almost twice after the 48-hour drug administration (0.936 ± 0.360 mmol/L vs. 0.582 ± 0.305 mmol/L, P < 0.001) while TOS increased from 18.217 ± 16.093 µmol/L to 30.442 ± 30.578 µmol/L (P < 0.001). We also found a significant increase in OSI index-almost a threefold increase from 0.022 ± 0.022 to 0.075 ± 0.085, P < 0.001. In addition, statistically significant differences in the level of carbonyl groups were found. It increased from 65.358 ± 31.332 µmol/L to 97.982 ± 38.047 µmol/L (P < 0.001), which indicates increased oxidation of plasma proteins. Furthermore, patients who gave birth prematurely had higher levels of TOS after a 48-hour drug administration than the second group with labor after 37 weeks of pregnancy (42.803 ± 34.683 µmol/L vs. 25.792 ± 27.821 µmol/L, P < 0.031). The obtained results clearly indicate that pregnant women during tocolytic treatment with Atosiban are in a state of increased oxidative stress and occurrence of preterm birth can be associated with this phenomenon. This trial is registered with NCT03570294.

Central pontine myelinolysis during pregnancy: Pathogenesis, diagnosis and management.

Central pontine myelinolysis (CPM) is a rare condition usually caused by rapid sodium correction in hyponatraemia after a severe neurological syndrome. Only few cases have been reported during pregnancy, most of which were reported in patients with hyperemesis. We describe the successful management of the first case of twin pregnancy in a patient who presented with CPM after treatment for premature labour and then review the literature on CPM in pregnancy (aetiology, diagnosis and management). Our patient required emergency delivery to achieve electrolyte and fluid balance. At six months, the twins remained asymptomatic and the mother had minor sequelae. The aetiology is not clear, and there is no evidence regarding the optimal treatment or prognosis of CPM. In our patient, desmopressin-contaminated atosiban showed a certain probability in the Karch-Lasagne algorithm of a causality relationship between hyponatraemia and the drug. To our knowledge, this is the first case of myelinolysis reported in a twin pregnancy possibly related to desmopressin-contaminated atosiban.

The safety of tocolytics used for the inhibition of preterm labour.

INTRODUCTION: Preterm birth is the major cause of neonatal mortality and morbidity worldwide and a huge cost burden on healthcare. Between 22 and 26 completed weeks of gestation, for every day that delivery is delayed, survival increases by 3%. AREAS COVERED: Following a systematic review of the literature, we have provided an overview of the use of tocolytics for the prevention of preterm birth and have examined the fetal and maternal adverse effects of the various tocolytic agents currently in use. EXPERT OPINION: No tocolytic currently in use was developed specifically to treat preterm labour so most have multi-organ side effects. ß2-agonists are relatively safe for the fetus but have rare and potentially serious maternal adverse effects. In contrast, prostaglandin synthetase inhibitors have potentially serious side effects for the fetus and neonate but have mild maternal gastrointestinal side effects. In Europe, the choice of first line therapy is either atosiban or nifedipine. The evidence base for atosiban is much more robust than for nifedipine. While their efficacy is similar, atosiban has placebo level side effects and is safer than nifedipine but is much more expensive.

Administration of atosiban in patients with endometriosis undergoing frozen-thawed embryo transfer: a prospective, randomized study.

OBJECTIVE: To examine the effects of atosiban, given before transfer of frozen-thawed embryo to women with endometriosis (EMs). DESIGN: A randomized, controlled clinical trial. SETTING: University hospital and IVF center. PATIENT(S): One hundred twenty women with endometriosis undergoing frozen-thawed embryo transfer were randomly allocated into the atosiban treatment and the control groups. Another 120 women with infertility due to tubal factor were enrolled into a tubal factor group, to compare serum oxytocin (OT) and prostaglandin (PG)F2α levels and uterine contractions with the endometriosis group. INTERVENTION(S): In the endometriosis treatment group, a single bolus (6.75 mg, 0.9 mL per vial) of atosiban was administrated before ET. MAIN OUTCOME MEASURE(S): Implantation rate and pregnancy rate. RESULT(S): Serum OT level (1.89 ± 0.33 vs. 1.66 ± 0.32 ng/L), PGF2α (2.83 ± 0.34 vs. 2.36 ± 0.35 ng/L) level, and uterine contractions (2.5 ± 1.2 vs. 1.8 ± 1.0 waves per minute) in the endometriosis group were all significantly higher than in the tubal factor group. The clinical pregnancy rate per cycle and implantation rate per transfer were 58.3% and 41.0%, respectively, in the atosiban treatment group, significantly higher than in the control group (38.3% and 23.4%, respectively). CONCLUSION(S): Women with endometriosis showed higher serum OT level, PGF2α level, and uterine contractions. Atosiban treatment before ET in endometriosis is effective in the priming of the uterus, suitable for embryo implantation. This is the first study to evaluate the effect of atosiban treatment in patients with endometriosis. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-IOQ-14005715.

[Tocolysis in preterm labour--current recommendations]. / Tokoliza w porodzie przedwczesnym--aktualne wytyczne.

Common use of tocolytic drugs in preterm labor has not been shown to reduce the rate of neonatal mortality and morbidity Currently tocolytics should be administered in the course of a 48-h administration of antepartum glucocorticoids and/or transfer of the gravida to a center with neonatal intensive care unit. Only oxytocin receptor antagonist--atosiban and short-acting beta-agonists--fenoterol are licensed to reduce preterm uterine activity Owing to its safety and efficacy atosiban should be the first-choice tocolytic, especially in women with other diseases or multiple gestations.

Therapy side-effects and predictive factors for preterm delivery in patients undergoing tocolysis with atosiban or ritodrine for threatened preterm labour.

The objective of this study was to compare the safety and efficacy of atosiban and ritodrine in the treatment of threatened preterm labour (TPL) and to analyse the predictive factors of preterm delivery. We retrospectively sampled data on 380 women hospitalised for TPL (24-35 weeks' gestation), in our clinic between 2004 and 2007. All were subjected to tocolysis with ritodrine and/or atosiban. Data were analysed using R (version 2.12.1), considering p < 0.05 as significant. We had 69 women treated with atosiban, 242 treated with ritodrine and 69 treated with ritodrine changed for atosiban, if adverse effects occurred. In the multivariate logistic regression, the use of atosiban vs ritodrine does not play any role in delaying delivery after 48 h or 7 days, whereas the cervical change at the digital examination, high contractions pre/post-therapy ratio, pPROM, cervical length and fibronectin result as predictive factors for both delivery before 48 h or 7 days. Maternal adverse drug effects were significantly more frequent in patients treated with ritodrine, and one single case of pulmonary oedema was observed. We found fewer side-effects in the atosiban than in the ritodrine group and no difference in efficacy. Moreover, the most predictive factors for preterm delivery were fibronectin test, pPROM, digital vaginal examination and uterine contraction persistence. We believe that predictive capacity of these tests could give the opportunity for targeting therapy and limiting drug side-effects and cost.

[Maternal pulmonary oedema due to the use of atosiban in cases of multiple gestation]. / Maternaal longoedeem bij gebruik van atosiban bij meerlingzwangerschap.

BACKGROUND: Nifedipine is used as a first choice tocolytic agent in many Dutch hospitals, but its use is discouraged in multiple gestations. Atosiban, a selective oxytocin receptor antagonist that rarely causes systemic side effects, is used as an alternative. CASE DESCRIPTION: A 32-year-old primigravida with spontaneous triplet pregnancy was admitted at 33 3/7 weeks for threatened preterm labour. For tocolysis, atosiban was administered for 48 hours together with betamethasone for foetal lung maturation. One day after treatment with atosiban she developed dyspnoea caused by pulmonary oedema. After a caesarean section and furosemide treatment the pulmonary oedema resolved. Analysis showed that atosiban was a likely cause of the pulmonary oedema. CONCLUSION: Every patient with multiple gestation is at increased risk of pulmonary oedema. Any tocolytic agent may elicit that response, even the relatively safe atosiban.

Atosiban and nifedipine in the suppression of pre-term labour: a comparative study.

This is a retrospective study comparing the efficacy and safety of atosiban and nifedipine in the suppression of pre-term labour. A total of 75 patients were included in this study; 34 received atosiban and 41 received nifedipine. There were no statistically significant differences in the baseline characteristics for both groups. A total of 68.3% of women in the atosiban group remained undelivered at 7 days or more, compared with 64.7% in the nifedipine group, which was not statistically significant. Average birth weight, admission to the neonatal intensive care unit and mode of delivery were similar in both groups. However, the gestational age at delivery was significantly higher in the nifedipine group. We concluded that atosiban and nifedipine are effective in delaying delivery for 7 days or more in women presenting with pre-term labour. They have the same efficacy and associated minor side-effects. However, flushing, palpitation and hypotension were significantly higher in the nifedipine group.

Elevated cardiac oxidative stress in newborn rats from mothers treated with atosiban.

PURPOSE: The purpose of this study was to evaluate the cardiac and cerebral oxidative stress in the offspings of pregnant rats treated with oxytocin antagonist atosiban. METHODS: Experimentally naive, adult female Wistar-albino rats (200-250 g) were mated with adult male rats for copulation. After confirming pregnancy, eight gravid rats were then randomly assigned into two equal groups. The animals were treated from days 15 to 20 of gestation. One group acted as a control group, and received intraperitoneal (i.p.) injections of saline in a daily dose volume of 6 mg/kg/day. The second group received 6 mg/kg/day i.p. atosiban. On day 21 of gestation, pups were delivered by cesarean. The heart and brain tissues of the newborn rats were dissected and sent for the measurement of total oxidant status, total antioxitant status and oxidative stress index. RESULTS: There was no significant difference in birthweight or in the number of pups between two groups. Newborns from atosiban-treated mothers showed significantly increased oxidative stress in the plasma and heart tissue than that of controls which was confirmed by histological examination (P < 0.05). Oxidative stress parameters and histopathological results of the brain tissues of newborns were similar between two groups (P > 0.05). CONCLUSION: Oxytocin receptor blockage for the treatment of premature delivery may be associated with increased fetal morbidity and mortality secondary to the elevated oxidative stress in the heart of the newborns.

[Atosiban treatment for preterm labor--financial considerations and savings by implementing clinical guidelines].

INTRODUCTION: Preterm delivery is a significant cause of neonatal morbidity and mortality. Pregnant women, with symptoms and signs consistent with preterm labor, can be treated with various tocolytic drugs. Atosiban is one of many drugs indicated to arrest imminent preterm labor. Various studies show that the efficacy of atosiban is similar to other tocolytic drugs. The main advantage of atosiban is a relativeLy low incidence of adverse maternal reactions. Its considerable shortcoming is the financial cost, compared to other available drugs. AIM: In view of its cost, we have decided to implement a strict protocol to direct the use of atosiban, with the intent to reduce costs, without hampering quality of care. STUDY METHODS: The protocol was implemented from July 2009, and it outlines the medical and procedural terms to use atosiban. We compared similar time periods before and after implementation of the protocol. The outcomes compared included: treatment success, rates of preterm deliveries and financial costs. RESULTS: Within the timeframe that the protocol was implemented, we have been able to demonstrate a 40% reduction in atosiban related costs, compared to a parallel period, when the clinical guidelines were not implemented. This translates into savings of about NIS 40,000 (New Israeli Shekel) (approximately $10,000). This was achieved without an increase in the rate of preterm deliveries. CONCLUSION: Implementing and enforcing a simple protocol of supervision on the use of atosiban enables a considerable reduction of financial costs related to atosiban, without hampering medical care.

Atosiban versus betamimetics in the treatment of preterm labour in Italy: clinical and economic importance of side-effects.

The aim of this study was to determine the cost effectiveness of atosiban compared to betamimetics in the treatment of preterm labour within the Italian setting. A systematic literature review identified randomised controlled trials (RCTs) comparing atosiban with betamimetics. Meta-analysis of nine RCTs determined that atosiban and betamimetics had similar efficacy in delaying preterm birth by at least 48 h (p=0.910). Use of atosiban was associated with significantly fewer adverse events (p<0.008). Results demonstrate that atosiban is cost-saving versus ritodrine or isoxuprine. Atosiban cost savings are €657 per patient from the National Health Service payer's perspective; €299 at 18 h of tocolysis to €189 at 48 h from the hospital's perspective. The respective values versus isoxuprine were €303 and €199. From the combined perspective, using atosiban versus ritodrine saved from €425 to €316; and versus isoxuprine from €429 to €326. Owing to its superior safety profile, atosiban is cost-saving versus betamimetics in the treatment of preterm labour in Italy from the payer's, hospital's and combined perspectives. With the approximate 40,000 annual preterm births in Italy the annual savings could be in excess of €13 million for the payer or €3.8-6.2 million for the hospitals.