Impact of discontinuing oxytocin in active labour on neonatal morbidity: an open-label, multicentre, randomised trial.

BACKGROUND: Oxytocin is effective in reducing labour duration but can be associated with fetal and maternal complications that could potentially be reduced by discontinuing the treatment during labour. We aimed to assess the impact of discontinuing oxytocin during active labour on neonatal morbidity. METHODS: STOPOXY was a multicentre, randomised, open-label, controlled, superiority trial conducted in 21 maternity units in France. Participants who received oxytocin before 4 cm dilation were randomly assigned 1:1 to either discontinuous oxytocin (oxytocin infusion stopped beyond a cervical dilation equal to or greater than 6 cm) or continuous oxytocin (administration of oxytocin continued until delivery). Randomisation was stratified by centre and parity. The primary outcome, neonatal morbidity, was assessed at birth using a composite variable defined by an umbilical arterial pH at birth less than 7·10, a base excess greater than 10 mmol/L, umbilical arterial lactates greater than 7 mmol/L, a 5-min Apgar score less than 7, or admission to the neonatal intensive care unit. Efficacy and safety was assessed in participants who were randomly assigned (excluding those who withdrew consent or were deemed ineligible after randomisation) and had reached a cervical dilation of at least 6 cm. This trial is registered with ClinicalTrials.gov, NCT03991091. FINDINGS: Of 2459 participants randomly assigned between Jan 13, 2020, and Jan 24, 2022, 2170 were eligible to receive the intervention and were included in the final modified intention-to-treat analysis. The primary outcome occurred for 102 (9·6%) of 1067 participants (95% CI 7·9 to 11·5) in the discontinuous oxytocin group and for 101 (9·2%) of 1103 participants (7·6 to 11·0) in the continuous oxytocin group; absolute difference 0·4% (95% CI -2·1 to 2·9); relative risk 1·0 (95% CI 0·8 to 1·4). There were no clinically significant differences in adverse events between the two groups of the safety population. INTERPRETATION: Among participants receiving oxytocin in early labour, discontinuing oxytocin when the active phase is reached does not clinically or statistically significantly reduce neonatal morbidity compared with continuous oxytocin. FUNDING: French Ministry of Health and the Département de la Recherche Clinique et du Développement de l'Assistance Publique-Hôpitaux de Paris.

Intranasal Oxytocin in Children and Adolescents with Autism Spectrum Disorder.

BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was -3.7 in the oxytocin group and -3.5 in the placebo group (least-squares mean difference, -0.2; 95% confidence interval, -1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.).

Oxytocin is not associated with postpartum hemorrhage in labor augmentation in a retrospective cohort study in the United States.

BACKGROUND: Previous studies reported conflicting results on the relationship between oxytocin use for labor augmentation and the risk of postpartum hemorrhage, probably because it is rather challenging to disentangle oxytocin use from labor dystocia. OBJECTIVE: This study aimed to investigate the independent association between oxytocin use for augmentation and the risk of postpartum hemorrhage by using advanced statistical modeling to control for labor patterns and other covariates. STUDY DESIGN: We used data from 20,899 term, cephalic, singleton pregnancies of patients with spontaneous onset of labor and no previous cesarean delivery from Intermountain Healthcare in Utah in the Consortium on Safe Labor. Presence of postpartum hemorrhage was identified on the basis of a clinical diagnosis. Propensity scores were calculated using a generalized linear mixed model for oxytocin use for augmentation, and covariate balancing generalized propensity score was applied to obtain propensity scores for the duration and total dosage of oxytocin augmentation. A weighted generalized additive mixed model was used to depict dose-response curves between the duration and total dosage of oxytocin augmentation and the outcomes. The average treatment effects of oxytocin use for augmentation on postpartum hemorrhage and estimated blood loss (mL) were assessed by inverse probability weighting of propensity scores. RESULTS: The odds of both postpartum hemorrhage and estimated blood loss increased modestly when the duration and/or total dosage of oxytocin used for augmentation increased. However, in comparison with women for whom oxytocin was not used, oxytocin augmentation was not clinically or statistically significantly associated with estimated blood loss (6.5 mL; 95% confidence interval, 2.5-10.3) or postpartum hemorrhage (adjusted odds ratio, 1.02; 95% confidence interval, 0.82-1.24) when rigorously controlling for labor pattern and potential confounders. The results remained consistent regardless of inclusion of women with an intrapartum cesarean delivery. CONCLUSION: The odds of postpartum hemorrhage and estimated blood loss increased modestly with increasing duration and total dosage of oxytocin augmentation. However, in comparison with women for whom oxytocin was not used and after controlling for potential confounders, there was no clinically significant association between oxytocin use for augmentation and estimated blood loss or the risk of postpartum hemorrhage.

Carvacrol-Loaded Nanoemulsion Promotes Tocolytic and Anti-Dysmenorrhea Effects in Rodents.

INTRODUCTION: Carvacrol is a phenolic constituent of essential oils that has antinociceptive, anti-inflammatory, and antioxidant activities. METHOD: This study aimed to evaluate the in vitro spasmolytic and in vivo anti-dysmenorrhea potential of a nanoemulsion-containing carvacrol (nanoCARV). RESULTS: In isolated rat uterus, nanoCARV reduced spontaneous contractions (pEC50 = 3.91 ± 0.25) and relaxed preparations pre-contracted with oxytocin (pEC50 = 3.78 ± 0.2), carbachol (pEC50 = 4.15 ± 0.4), prostaglandin F2α (pEC50 = 3.00 ± 0.36), and KCl (pEC50 = 3.98 ± 0.32). The investigation of the mechanism of action revealed significant differences (p < 0.05) between the pEC50 values of nanoCARV in the absence or presence of aminophylline or tetraethylammonium. In a primary dysmenorrhea model, treatment with nanoCARV reduced the number of oxytocin-induced abdominal writhes. CONCLUSIONS: These data indicate that the anti-dysmenorrhea effect of nanoCARV may be related to the relaxation of uterine smooth muscle, with participation of the cAMP signaling pathway and potassium channels.

Association between duration of intrapartum oxytocin exposure and obstetric hemorrhage.

PURPOSE: Prolonged duration of intrapartum oxytocin exposure is included as a risk factor within widely adopted obstetric hemorrhage risk stratification tools. However, the duration of exposure that confers increased risk is poorly understood. This study aimed to assess the association between duration of intrapartum oxytocin exposure and obstetric blood loss, as measured by quantitative blood loss, and hemorrhage-related maternal morbidity. METHODS: This was a retrospective cohort study of all deliveries from 2018 to 2019 at a single medical center. We included patients who had received any intrapartum oxytocin, and we categorized them into 1 of 5 groups: > 0-2, ≥ 2-4, ≥ 4-6, ≥ 6-12, and ≥ 12 h of intrapartum oxytocin exposure. The primary outcomes were mean quantitative blood loss, proportion with obstetric hemorrhage (defined as quantitative blood loss ≥ 1000 mL), and proportion with obstetric hemorrhage-related morbidity, a composite of hemorrhage-related morbidity outcomes. Secondary outcomes were hemorrhage-related pharmacologic and procedural interventions. A stratified analysis was also conducted to examine primary and secondary outcomes by delivery mode. RESULTS: Of 5332 deliveries between January 1, 2018 and December 31, 2019 at our institution, 2232 (41.9%) utilized oxytocin for induction or augmentation. 326 (14.6%) had exposure of > 0-2 h, 295 (13.2%) ≥ 2-4 h, 298 (13.4%) ≥ 4-6 h, 562 (25.2%) ≥ 6-12 h, and 751 (33.6%) ≥ 12 h. Across all deliveries, there was higher mean quantitative blood loss (p < 0.01) as well as increased odds of obstetric hemorrhage (adjusted odds ratio [aOR] 1.52, 95% confidence interval [CI] 1.21-1.91) for those with ≥ 12 h of oxytocin compared to all groups between > 0-12 h of exposure. In our stratified analysis, ≥ 12 h of oxytocin exposure was associated with higher mean quantitative blood loss (p = 0.04) and odds of obstetric hemorrhage in vaginal deliveries (aOR 1.47, 95% CI: 1.03-2.11), though not in cesarean deliveries (aOR 1.16, 95% CI 0.82-1.62). There were no differences in proportion with obstetric hemorrhage-related morbidity across all deliveries (p = 0.40) or in the stratified analysis. CONCLUSION: Intrapartum oxytocin exposure of ≥ 12 h was associated with increased quantitative blood loss and odds of obstetric hemorrhage in vaginal, but not cesarean, deliveries.

Assessing the effects of oxytocin in changes of core body temperature during LPS-induced endotoxemia: A novel approach using Extended Poincaré Plot Analysis.

Oxytocin has shown cardioprotective effects during inflammation and may modify the core body temperature changes in LPS-induced endotoxemia. Notably, the time series analysis of core body temperature fluctuations may indicate thermoregulation alterations. This study aims to assess the effects of oxytocin on changes in the core body temperature by analyzing the fluctuations of the temperature time series of endotoxemic rats. Twelve hours of continuous core body temperature fluctuations time series were obtained from adult male Dark Agouti rats implanted with a telemetric transmitter under the following treatment: lipopolysaccharide (LPS); oxytocin (O); lipopolysaccharide + oxytocin (LPS + O), and vehicle or control (C). The temperature fluctuations time series were analyzed using the Extended Poincaré Plot Analysis (EPPA), a novel approach for measuring nonlinear features, to compute the autocorrelation by Pearson's correlation coefficient r, the standard deviation perpendicular to the line of identity (SD1), and the standard deviation parallel to the line of identity (SD2). The autocorrelation of the temperature fluctuations assessed by Pearson's coefficient was significantly higher in the LPS group compared to control rats (C). Likewise, the co-administration of oxytocin during endotoxemia (LPS + O) significantly reduced the autocorrelation and increased the short-term variability (SD1) of temperature fluctuations compared to those recorded with a single dose of LPS. Thus, we concluded that oxytocin may introduce thermoregulatory changes under LPS-induced endotoxemia. The EPPA is a simple and powerful approach to assess physiological variability that can provide valuable insights into changes in thermoregulation.

Pharmacokinetics and safety of inhaled oxytocin compared with intramuscular oxytocin in women in the third stage of labour: A randomized open-label study.

AIMS: To compare pharmacokinetics (PK) and safety of heat-stable inhaled (IH) oxytocin with intramuscular (IM) oxytocin in women in third stage of labour (TSL), the primary endpoint being PK profiles of oxytocin IH and secondary endpoint of safety. METHODS: A phase 1, randomized, cross-over study was undertaken in 2 UK and 1 Australian centres. Subjects were recruited into 2 groups: Group 1, women in TSL; Group 2, nonpregnant women of childbearing potential (Cohort A, combined oral contraception; Cohort B, nonhormonal contraception). Participants were randomized 1:1 to: Group 1, oxytocin 10 IU (17 µg) IM or oxytocin 240 IU (400 µg) IH immediately after delivery; Group 2, oxytocin 5 IU (8.5 µg) intravenously and oxytocin 240 IU (400 µg) IH at 2 separate dosing sessions. RESULTS: Participants were recruited between 23 November 2016 to 4 March 2019. In Group 1, 17 participants were randomized; received either IH (n = 9) or IM (n = 8) oxytocin. After IH and IM administration, most plasma oxytocin concentrations were below quantification limits (2 pg/mL). In Group 2 (n = 14), oxytocin IH concentrations remained quantifiable ≤3 h postdose. Adverse events were reported in both groups, with no deaths reported: Group 1, IH n = 3 (33%) and IM n = 2 (25%); Group 2, n = 14 (100%). CONCLUSION: Safety profiles of oxytocin IH and IM were similar. However, PK profiles could not be established for oxytocin IH or IM in women in TSL, despite using a highly sensitive and specific assay.

Incidence and risk factors for postpartum hemorrhage after vaginal delivery: A systematic review and meta-analysis.

AIM: To estimate the incidence and identify risk factors of postpartum hemorrhage (PPH) after vaginal delivery. METHODS: A systematic review and meta-analysis was conducted. PubMed, Cochrane Library, CINAHL, Web of Science, EMBASE, and ClinicalTrials.gov databases were systematically searched from inception to April 30th, 2022. Cross-sectional, cohort, case-control, and secondary analysis of randomized controlled studies that reported the incidence of PPH and the related risk factors in vaginal delivery were eligible through screening of 2343 articles. The incidence, associated standard error, adjusted odds ratios, relative risks and associated 95% confidence intervals were combined in the meta-analysis. RESULTS: Thirty-six articles were included in the descriptive review. The incidence of PPH (blood loss ≥500 mL and blood loss ≥1000 mL) was 17% and 6%, respectively. Forty-one identified risk factors were divided into five categories under two criteria: history and demographics; maternal comorbidity; pregnancy-related factors; labor-related factors; delivery-related factors. CONCLUSIONS: With the increasing incidence of PPH globally, obstetric health care providers need to improve their awareness of these multi-factorial risks to optimize obstetric care and reduce maternal morbidity. This systematic review and meta-analysis have raised important questions about the nature of vaginal delivery, such as the duration of prolonged labor, details on the use of oxytocin, and the presence of genital tract trauma. There should be highlighted by obstetric personnel on these factors during a patients' labor process.

Intravenous oxytocin regimens in patients undergoing cesarean delivery: a systematic review and network meta-analysis of cluster-based groups.

Information on evaluations of different oxytocin regimens used to prevent post-partum hemorrhage during cesarean delivery is scarce, and there is a lack of statistically pooled results for comparative doses. In this review, we aimed to analyze the effectiveness of different oxytocin regimens used and rank them accordingly. We performed a meta-analysis of randomized controlled trials (RCTs) reporting the incidence of additional uterotonic (AUT) use or amount of blood loss during cesarean delivery, where different oxytocin regimens were compared. Cluster analysis was used to define different clusters of oxytocin therapy based on the identified variable regimens. During the frequentist network meta-analysis, all clusters were compared to bolus clusters of dose range 3-5 IU. Data from 33 RCTs (6741 patients) to 26 RCTs (5422 patients) were assessed for AUT use and blood loss, respectively. Pairwise meta-analysis revealed a significant reduction in the use of AUTs or blood loss was recorded for bolus-infusion combination regimens. The network meta-analysis found that combined bolus-infusion regimens of (i) 3-5 IU and 0.25-1 IU/min or (ii) 3-5 IU and < 0.25 IU/min had statistically significant results for lowest consumption of AUTs (Ranks 1 and 2, respectively); whereas with the latter's use, the lowest blood loss (Rank 2) was observed. In contrast, the dose range, > 5 IU regimen was associated with higher side effects (lowest rank). During cesarean delivery, a significant reduction in the use of AUTs or blood loss (Rank 2) was recorded for bolus-infusion combination regimens. High doses did not have enough evidence to draw meaningful conclusions.

Neuraxial analgesia interfered with the circadian rhythm of labor: a propensity score matched cohort study.

OBJECTIVES: To investigate whether neuraxial analgesia and other medical interventions have effects on the circadian rhythm of labor. METHODS: It was a retrospective propensity score matched cohort study. Parturients were recruited, who delivered term singletons in cephalic position, from seven hospitals in Harvard University Partners Healthcare Systems, 2016-2018. The parturients were divided into two groups, neuraxial analgesia delivery and spontaneous vaginal delivery, the stratification was performed according to labor induction, oxytocin, operative delivery. The parturients in each group were divided into 12 periods in every 2 h based on the birth time of babies. Cosine function fitting was used to verify whether the birth time had the characteristic of circadian rhythm. RESULTS: In spontaneous vaginal deliveries, the peak of birth time was at 2:00-4:00, and the nadir was at 14:00-16:00, this showed a circadian rhythm presented by a cosine curve fitting with the formula (y = 0.0847 + 0.01711 × cos(- 0.2138 × x + 0.4471). The labor rhythm of NAD (Neuraxial Analgesia Delivery) group changed completely, inconsistent with the cosine curve fitting of the circadian rhythm. The intervention of induction and oxytocin blurred the circadian rhythm of SVD (Spontaneous Vaginal Delivery) group and increased the amplitude of the fluctuation in NAD (Neuraxial Analgesia Delivery) group. The intervention of operative delivery had changed the distribution curve completely both in the SVD (Spontaneous Vaginal Delivery) group and the NAD (Neuraxial Analgesia Delivery) group. CONCLUSIONS: Neuraxial analgesia did affect on circadian rhythm of labor, changed the cosine rhythm of labor with spontaneous vaginal delivery, and this trend was aggravated by the use of induction, oxytocin and operative delivery.

Effectiveness and safety of carboxytocin versus oxytocin in preventing postpartum hemorrhage: A systematic review and meta-analysis.

OBJECTIVE: This study compared the effectiveness and safety of carbetocin and oxytocin in preventing postpartum hemorrhage (PPH). METHODS: A systematic literature search was performed on PubMed, Embase, and the Cochrane Library for relevant studies published up to February 2019. Next, two independent reviewers screened the studies according to the selection criteria as well as the strategies recommended by the Cochrane Collaboration. Data were then extracted and evaluated. All statistical analyses were performed using RevMan 5.1. RESULTS: A total of 24 studies involving 37 383 patients were included for analysis. For cesarean section patients, carbetocin was superior to oxytocin in reduction of the need for additional uterine contraction (odds ratio [OR] = 0.48, 95% confidence interval [CI] [0.35, 0.65], p < 0.00001), PPH (OR = 0.70, 95% CI [0.51, 0.95], p = 0.02), blood loss (mean [MD] = -64.36, 95% CI [-107.78, -20.93], p = 0.004), and transfusion (OR = 0.59, 95% CI [0.42, 0.82], p = 0.002), and there was no significant difference in severe PPH (OR = 0.84, 95% CI [0.66, 1.090], p = 0.19). For vaginal delivery patients, carbetocin was superior to oxytocin in reduction of the need for additional uterine contractions (OR = 0.48, 95% CI [0.25, 0.93], p = 0.03), PPH (OR = 0.28, 95% CI [0.09, 0.91], p = 0.03), and blood loss (MD = -63.52, 95% CI [-113.43, -13.60], p = 0.01), and there were no significant differences in severe PPH (OR = 0.82, 95% CI [0.40, 1.69], p = 0.59) and transfusion (OR = 0.60, 95% CI [0.22, 1.61], p = 0.31). With regard to safety, for cesarean section patients, carbetocin was superior to oxytocin in reduction of the incidence of headache (OR = 0.72, [0.55, 0.95], p = 0.02), and there were no significant differences in nausea, vomiting, abdominal pain, flushing, tremors, itching, dizziness, and fever. For vaginal delivery patients, there were no significant differences in nausea, vomiting, headache, abdominal pain, flushing, tremors, itching, dizziness, and fever between the two drugs. CONCLUSION: For patients undergoing cesarean section and vaginal delivery, carbetocin was superior to oxytocin in effectiveness and similar in safety. Therefore, carbetocin is expected to be an alternative uterine contraction agent for preventing PPH.

Vaginal misoprostol and intravenous oxytocin for success of termination in the second-trimester intrauterine fetal demise: A randomized controlled clinical trial.

AIM: To compare the success rate of vaginal misoprostol versus intravenous (IV) oxytocin in termination of pregnancy in the second trimester intrauterine fetal death (IUFD). METHODS: This was an open-label randomized controlled study for 106 women with second trimester IUFD. Patients were randomly divided into two groups: women given vaginal misoprostol (400 mcg every 6 h up to 48 h) versus those given IV oxytocin (starting with 50 units up to a maximum of 300 units). When the first-line treatment (as mentioned above) failed, treatment methods were replaced with each other. When the second-line treatment failed, the patients underwent dilation and evacuation. RESULTS: The first-line treatment yielded the successful rate of 88.7% versus 73.7% for misoprostol versus oxytocin, respectively (p = 0.047). Among those with first-line treatment failure, the second-line treatment yielded success rate of 85.7% versus 83.3% for misoprostol versus oxytocin (p = 0.891). The mean duration of induction to delivery in women with successful response to first-line treatment was 28.72 and 20.55 h after initially receiving misoprostol versus oxytocin, respectively (p < 0.001). While during second-line treatment, this mean interval was not significantly different among those with misoprostol versus oxytocin (p = 0.128). No severe adverse events were observed. CONCLUSION: Vaginal misoprostol was associated with higher termination rate than oxytocin without adverse events when used as the first-line treatment. Both methods yielded the same success rate when used as the second-line treatment.

[Multicenter, Randomized, Double-Blind, and Positive Drug-Controlled Clinical Trial on Prevention of Postpartum Hemorrhage after Vaginal Delivery with Ergometrine Maleate].

Objective: To evaluate the safety and efficacy of using ergometrine maleate injection combined with oxytocin injection, with oxytocin injection as the control, to prevent postpartum hemorrhage after vaginal delivery. Methods: A total of 305 cases who underwent vaginal delivery between December 2018 and November 2019 in 16 hospitals across China were enrolled and included in the full analysis set (FAS) and the safety analysis set (SS). Among the 299 subjects who completed the trial, 277 were included in the per protocol set (PPS). The subjects were randomly assigned by 1∶1 ratio to two groups, 152 cases in Group A, the experimental group receiving oxytocin injection plus ergometrine injection, and 153 cases in Group B, the control group, receiving oxytocin injection. The difference in total bleeding volume at 2 h, 6 h and 24 h postpartum in the two groups was documented and compared. Other measures were also compared between the two groups, including the proportion of additional use of uterotonics and hemostatic drugs or other hemostatic measures 2 h and 24 h postpartum, the proportion of subjects needing blood transfusion, the time of placenta retention, proportion of subjects with prolonged hospital stay due to uterine asthenia, the vital signs, lab test indicators and the incidence of adverse reactions in the two groups. Results: The total bleeding volume at 2 h, 6 h and 24 h after delivery was significantly lower in the experimental group (P<0.05). There was no significant difference between the two groups in the proportion of additional use of uterotonics and hemostatic drugs or other hemostatic measures 2 h and 24 h postpartum, the proportion of subjects needing blood transfusion and the time of placenta retention, heart rate, respiration, lab test indicators, or the incidence of adverse reaction (P>0.05). Conclusion: Ergometrine maleate injection showed evident therapeutic efficacy in preventing hemorrhage after vaginal delivery, causing fewer adverse reactions and ensuring greater safety, and therefore, presenting promising prospects for clinical application.

Heat-Stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth.

BACKGROUND: Postpartum hemorrhage is the most common cause of maternal death. Oxytocin is the standard therapy for the prevention of postpartum hemorrhage, but it requires cold storage, which is not available in many countries. In a large trial, we compared a novel formulation of heat-stable carbetocin with oxytocin. METHODS: We enrolled women across 23 sites in 10 countries in a randomized, double-blind, noninferiority trial comparing intramuscular injections of heat-stable carbetocin (at a dose of 100 µg) with oxytocin (at a dose of 10 IU) administered immediately after vaginal birth. Both drugs were kept in cold storage (2 to 8°C) to maintain double-blinding. There were two primary outcomes: the proportion of women with blood loss of at least 500 ml or the use of additional uterotonic agents, and the proportion of women with blood loss of at least 1000 ml. The noninferiority margins for the relative risks of these outcomes were 1.16 and 1.23, respectively. RESULTS: A total of 29,645 women underwent randomization. The frequency of blood loss of at least 500 ml or the use of additional uterotonic agents was 14.5% in the carbetocin group and 14.4% in the oxytocin group (relative risk, 1.01; 95% confidence interval [CI], 0.95 to 1.06), a finding that was consistent with noninferiority. The frequency of blood loss of at least 1000 ml was 1.51% in the carbetocin group and 1.45% in the oxytocin group (relative risk, 1.04; 95% CI, 0.87 to 1.25), with the confidence interval crossing the margin of noninferiority. The use of additional uterotonic agents, interventions to stop bleeding, and adverse effects did not differ significantly between the two groups. CONCLUSIONS: Heat-stable carbetocin was noninferior to oxytocin for the prevention of blood loss of at least 500 ml or the use of additional uterotonic agents. Noninferiority was not shown for the outcome of blood loss of at least 1000 ml; low event rates for this outcome reduced the power of the trial. (Funded by Merck Sharpe & Dohme; CHAMPION Australian New Zealand Clinical Trials Registry number, ACTRN12614000870651 ; EudraCT number, 2014-004445-26 ; and Clinical Trials Registry-India number, CTRI/2016/05/006969 .).

Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial.

Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18-48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P < .001) but placebo also reduced the score (8.3 to 7.2; P < .001), no between-group difference was found (effect size -0.08; 95% CI, -0.46 to 0.31; P = .69); however, plasma oxytocin was only elevated from baseline to endpoint in the oxytocin-group compared with the placebo-group (effect size -1.12; -1.53 to -0.70; P < .0001). Among the secondary endpoints, oxytocin reduced ADOS repetitive behavior (2.0 to 1.5; P < .0001) compared with placebo (2.0 to 1.8; P = .43) (effect size 0.44; 0.05 to 0.83; P = .026). In addition, the duration of gaze fixation on socially relevant regions, another secondary endpoint, was increased by oxytocin (41.2 to 52.3; P = .03) compared with placebo (45.7 to 40.4; P = .25) (effect size 0.55; 0.10 to 1.0; P = .018). No significant effects were observed for the other secondary endpoints. No significant difference in the prevalence of adverse events was observed between groups, although one participant experienced temporary gynecomastia during oxytocin administration. Based on the present findings, we cannot recommend continuous intranasal oxytocin treatment alone at the current dose and duration for treatment of the core social symptoms of high-functioning ASD in adult men, although this large-scale trial suggests oxytocin's possibility to treat ASD repetitive behavior.

The Effect of Carbetocin Dose on Transmural Dispersion of Myocardial Repolarization in Healthy Parturients Scheduled for Elective Cesarean Delivery Under Spinal Anesthesia: A Prospective, Randomized Clinical Trial.

BACKGROUND: QT interval prolongation is associated with torsade de pointes but remains a poor predictor of drug torsadogenicity. Increased transmural dispersion of myocardial repolarization (TDR), measured as the time interval between the peak and end of the T wave (Tp-e), is a more reliable predictor. Carbetocin is recommended as an uterotonic in patients undergoing cesarean delivery (CD), but its effect on Tp-e is unknown. We evaluated the effect of carbetocin dose on Tp-e and Bazett-corrected QT intervals (QTc) during elective CD under spinal anesthesia. METHODS: On patient consent, 50 healthy parturients undergoing elective CD with a standardized spinal anesthetic and phenylephrine infusion were randomized to receive an intravenous (IV) bolus of carbetocin 50 µg (C50) or 100 µg (C100) via an infusion pump over 1 minute. A 12-lead electrocardiogram (ECG) was obtained at baseline, 5 minutes after spinal anesthesia, then 5 and 10 minutes after carbetocin administration. A cardiologist blinded to group and timing of ECGs measured QTc and Tp-e using Emori's criteria. Primary outcome was the change in Tp-e at 5 minutes after carbetocin administration between the C50 and C100 groups and within each group compared to baseline values. Secondary outcomes included occurrence of arrhythmias, changes in QTc at 5 and 10 minutes after carbetocin, changes in both QTc and Tp-e after spinal anesthesia compared to baseline between and within groups. RESULTS: Data from 41 parturients with a mean (standard deviation [SD]) age of 39.0 (0.7) years and weight of 75.0 (12.0) kg were analyzed. Between groups, at 5 minutes after carbetocin administration, Tp-e in C100 was 4.1 milliseconds longer compared to C50 (95% confidence interval [CI], 0.8-7.5; P = .01). Within groups, at 5 minutes after carbetocin administration, C50 did not significantly increase Tp-e compared to baseline (mean difference [MD] 1.9 milliseconds; 95% CI, -0.95 to 4.81 milliseconds; P = .42) but C100 did (MD 5.1 milliseconds; 95% CI, 2.1-8.1; P = .003). QTc increased significantly within C50 and C100 groups at 5 and 10 minutes after carbetocin administration (all P < .001), with no between-group differences. There were no arrhythmias. CONCLUSIONS: Tp-e was unaffected by C50 IV given after CD in healthy parturients under spinal anesthesia, but minimally prolonged by C100. The increase in QTc after carbetocin administration was statistically significant, but with no apparent dose-dependent effect. The minimal Tp-e prolongation at the higher dose is unlikely to have any clinically significant impact on TDR and therefore the risk of inducing torsade de pointes is low.

Oxytocin use in trial of labor after cesarean and its relationship with risk of uterine rupture in women with one previous cesarean section: a meta-analysis of observational studies.

BACKGROUND: Trial of labor after a previous cesarean delivery (TOLAC) has reduced the rate of cesarean sections (CS). Nevertheless, the widespread use of TOLAC has been limited by an increase in adverse outcomes, the most serious one being the risk of symptomatic uterine rupture, which is possibly associated with oxytocin. In this meta-analysis, we explored the risk association between oxytocin use and uterine rupture in TOLAC. METHODS: Multiple electronic databases (PubMed, Embase, Web of Science, and Google Scholar) were searched for cross-sectional studies reporting on TOLAC, oxytocin and uterine rupture, which were published between January 1986 and October 2019. The bias-corrected Hedge's g was calculated as the effect size using the random-effects model. A two-sample Z test was used to compare the differences in synthetic rates between groups. The Newcastle-Ottawa Scale (NOS) was used to evaluate the risk of bias. Quality of the evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) certainty ratings system. RESULTS: A total of 14 studies, which included 48,457 women who underwent TOLAC, met the inclusion criteria. The pooled rate of vaginal birth after a cesarean section (VBAC) and the rate of uterine rupture in spontaneous labor were 74.3 and 0.7%, respectively. In addition, the pooled rate of VBAC and the rate of uterine rupture in the induction labor group was 60.7 and 2.2%, respectively. The women who had spontaneous labor had a significantly higher rate of VBAC (p = 0.001) and a lower rate of uterine rupture (p = 0.0003) compared to induced labor. The pooled rates of uterine rupture in women using oxytocin and women not using oxytocin in TOLAC were 1.4% and 0.5%, respectively, and the difference was significant (p = 0.0002). Also, the synthetic rate of uterine rupture in oxytocin augmentation among women with spontaneous labor and women who had a successful induction of labor were 1.7% and 2.2%, respectively, without significant difference (p = 0.443). CONCLUSIONS: Women with induced labor had a higher risk of uterine rupture compared to women with spontaneous labor following TOLAC. Oxytocin use may increase this risk, which could be influenced by the process of induction or individual cervix condition. Consequently, simplified and standardized intrapartum management, precise protocol, and cautious monitoring of oxytocin use in TOLAC are necessary.

Epidemiology of Oxytocin Administration in Out-of-Hospital Births Attended by Paramedics.

AIM: Primary postpartum hemorrhage (PPH) is a life-threatening obstetric emergency that can be mitigated through the administration of a uterotonic to actively manage the third stage of labor. This study describes the prehospital administration of oxytocin by paramedics following attendance of out-of-hospital (OOH) births. METHODS: A retrospective analysis was undertaken of all OOH births between the 1st January 2018 and 31st December 2018 attended by the Queensland Ambulance Service. The demographic and epidemiological characteristics of patients that were administered oxytocin and the occurrence of adverse side effects were described. RESULTS: In total, 350 OOH births were included in this study with the majority involving multigravidas women (94.3%) and all but two involving singleton pregnancies. Oxytocin was administered following 222 births (63.4%), while 67 patients (19.1%) declined administration preferring a physiological third stage of labor, and in 61 cases (17.4%) oxytocin was withheld by the attending paramedic. There were no documented adverse events or side effects following administration. Oxytocin administration occurred on average 14 minutes (interquartile range 9-25) following the time of birth. The median time from oxytocin administration to placenta delivery was 10 minutes (interquartile range 5-22). CONCLUSION: Oxytocin is well accepted and safe treatment adjunct for the management of the third stage of labor in OOH births and should be considered for routine practice by other emergency medical services.

Oxytocin: at birth and beyond. A systematic review of the long-term effects of peripartum oxytocin.

Oxytocin is one of the most commonly used medications during labour and delivery. Recent insights from basic neuroscience research suggest that the uterotonic effects of oxytocin may arguably be trivial when compared with its profound effects on higher-order human behaviour. The purpose of this review is to highlight the potential consequences of manipulating oxytocinergic signalling during the peripartum period and its long-term impact on the maternal-infant dyad. We identified four domains where modulation of oxytocinergic signalling might be consequential: postpartum depression; breastfeeding; neurodevelopment; and chronic pain, and performed a literature search to address the impact of peripartum oxytocin administration. We have shown modest, but inconsistent, evidence linking peripartum oxytocin administration with postpartum depression. Breastfeeding success appeared to be negatively correlated with peripartum oxytocin exposure, perhaps secondary to impaired primitive neonatal reflexes and maternal-infant bonding. The association between perinatal oxytocin exposure and subsequent development of neurodevelopmental disorders such as autism in the offspring was weak, but these studies were limited by the lack of information on the cumulative dose. Finally, we identified substantial evidence for analgesic and anti-hypersensitivity effects of oxytocin which might partly explain the low incidence of chronic pain after caesarean birth. Although most data presented here are observational, our review points to a compelling need for robust clinical studies to better dissect the impact of peripartum oxytocin administration, and as stewards of its use, increase the precision with which we administer oxytocin to prevent overuse of the drug.

High dose vs. low dose oxytocin for labor augmentation: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To compare the safety and efficacy between high dose and low dose oxytocin administration for labor augmentation. METHODS: We searched for the available studies during March 2020 in PubMed, Cochrane Library, Scopus, and ISI Web of science. All randomized clinical trials (RCTs) that assessed safety and efficacy of high dose vs. low dose oxytocin for labor augmentation were considered. The extracted data were entered into RevMan software. Dichotomous and continuous data were pooled as odds ratio (OR) and mean difference (MD) respectively, with the corresponding 95% confidence intervals (CI). Our main outcomes were cesarean delivery rate, spontaneous vaginal delivery rate, uterine hyperstimulation and tachysystole, and labor duration from oxytocin infusion. RESULTS: Eight RCTs with 3,154 patients were included. High dose oxytocin did not reduce cesarean delivery rate compared to low dose oxytocin (OR=0.76, 95% CI [0.52, 1.10], p=0.15). After solving the reported heterogeneity, high dose oxytocin did not increase the rate of spontaneous vaginal deliveries vs. low dose oxytocin (OR=1.06, 95% CI [0.84, 1.32], p=0.64). Low dose oxytocin was linked to a significant decline in uterine hyperstimulation and tachysystole (p>0.001). A reduction in labor duration was found in high dose oxytocin group over low oxytocin regimen (MD=-1.02 h, 95% CI [-1.77, -0.27], p=0.008). CONCLUSIONS: We found no advantages for high dose oxytocin over low dose oxytocin in labor augmentation except in reducing labor duration. Low dose oxytocin is safer as it decreases the incidence of uterine hyperstimulation and tachysystole. More trials are needed to confirm our findings.