Third stage of labor: evidence-based practice for prevention of adverse maternal and neonatal outcomes.

The third stage of labor is defined as the time period between delivery of the fetus through delivery of the placenta. During a normal third stage, uterine contractions lead to separation and expulsion of the placenta from the uterus. Postpartum hemorrhage is a relatively common complication of the third stage of labor. Strategies have been studied to mitigate the risk of postpartum hemorrhage, leading to the widespread implementation of active management of the third stage of labor. Initially, active management of the third stage of labor consisted of a bundle of interventions including administration of a uterotonic agent, early cord clamping, controlled cord traction, and external uterine massage. However, the effectiveness of these interventions as a bundle has been questioned, leading to abandonment of some components in recent years. Despite this, upon review of selected international guidelines, we found that the term "active management of the third stage of labor" was still used, but recommendations for and against individual interventions were variable and not necessarily supported by current evidence. In this review, we: (1) examine the physiology of the third stage of labor, (2) present evidence related to interventions that prevent postpartum hemorrhage and promote maternal and neonatal health, (3) review current global guidelines and recommendations for practice, and (4) propose future areas of investigation. The interventions in this review include pharmacologic agents to prevent postpartum hemorrhage, cord clamping, cord milking, cord traction, cord drainage, early skin-to-skin contact, and nipple stimulation. Treatment of complications of the third stage of labor is outside of the scope of this review. We conclude that current evidence supports the use of effective pharmacologic postpartum hemorrhage prophylaxis, delayed cord clamping, early skin-to-skin contact, and controlled cord traction at delivery when feasible. The most effective uterotonic regimens for preventing postpartum hemorrhage after vaginal delivery include oxytocin plus ergometrine; oxytocin plus misoprostol; or carbetocin. After cesarean delivery, carbetocin or oxytocin as a bolus are the most effective regimens. There is inconsistent evidence regarding the use of tranexamic acid in addition to a uterotonic compared with a uterotonic alone for postpartum hemorrhage prevention after all deliveries. Because of differences in patient comorbidities, costs, and availability of resources and staff, decisions to use specific prevention strategies are dependent on patient- and system-level factors. We recommend that the term "active management of the third stage of labor" as a combined intervention no longer be used. Instead, we recommend that "third stage care" be adopted, which promotes the implementation of evidence-based interventions that incorporate practices that are safe and beneficial for both the woman and neonate.

Intramyometrial and intravenous oxytocin compared to intravenous carbetocin for prevention of postpartum hemorrhage in elective cesarean section-A quasi-randomized controlled phase IV non-inferiority interventional trial.

INTRODUCTION: Our objective was to assess non-inferiority of the unique approach used in our institution of combined 10 IU IM (intramyometrial) and 10 IU IV (intravenous) oxytocin to carbetocin IV in preventing severe postpartum blood loss in elective cesarean sections. The design was a prospective controlled phase IV non-inferiority interventional trial. The setting was a tertiary center at University Hospital, Zurich, Switzerland. MATERIAL AND METHODS: The population consisted of 550 women undergoing elective cesarean section after 36 completed weeks of gestation at low risk for postpartum hemorrhage (PPH). Subjects were assigned to either combined oxytocin regimen (10 IU IM and 10 IU IV) or carbetocin (100 µg IV). Non-inferiority for oxytocin for severe PPH was assessed with a 0.05 margin using the Newcombe-Wilson score method. The main outcome measures were severe postpartum blood loss defined as delta hemoglobin (∆Hb, Hb prepartum-Hb postpartum) ≥30 g/L. RESULTS: Non-inferiority of combined oxytocin (IM/IV) in preventing severe postpartum blood loss was not shown (17 women in the oxytocin group vs. 7 in the carbetocin group). The number needed to treat when using carbetocin was 28. The risk difference for ∆Hb ≥30 g/L was 0.04 (oxytocin 0.06 vs. 0.03), 95% confidence interval (CI) (0.00-0.08). No significant difference was observed for ∆Hb (median 12 [IQR 7.0-19.0] vs. 11 [5.0-17.0], p = 0.07), estimated blood loss (median 500 [IQR 400-600] vs. 500 [400-575], p = 0.38), or the PPH rate defined as estimated blood loss ≥1000 mL (12[4.5] vs. 5 [2.0], risk difference 0.03, 95% CI (-0.01 to 0.06), p = 0.16). More additional uterotonics were administered in the oxytocin group compared to the carbetocin group (15.2% vs. 5.9%, p = 0.001). Total case costs were non-significantly different in the oxytocin group (US $ 10 146 vs. 9621, mean difference 471.4, CI (-476.5 to 1419.3), p = 0.33). CONCLUSIONS: Combined (IM/IV) oxytocin is not non-inferior to carbetocin regarding severe postpartum blood loss defined as postpartum Hb decrease ≥30 g/L in elective cesarean sections. We recommend carbetocin for use in clinical practice for elective cesarean sections.

Carbetocin versus Oxytocin with or without Tranexamic Acid for Prophylactic Prevention of Postpartum Hemorrhage after a Vaginal Delivery: A Randomized Clinical Trial.

OBJECTIVE: Our study's primary objective was to examine the effects of four different prophylactic protocols on the prevention of postpartum hemorrhage following vaginal birth, including carbetocin only, oxytocin only, and a combination of carbetocin or oxytocin with tranexamic acid. DESIGN: A multicentric randomized controlled trial. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: This multicentric center prospective randomized controlled trial was conducted at the Department of Obstetrics and Gynecology of Bezmialem University and Van Health Teaching and Research Hospital from August 2022 to January 2023. The collected data included age, gravidity, parity, gestational age at birth, duration of delivery stages, prepartum hemoglobin and hematocrit concentrations, changes in hemoglobin and hematocrit concentrations, intrapartum blood loss, estimated blood loss after 2 h of vaginal delivery, Apgar scores at 1 and 5 min, birth weight, and neonatal intensive care unit (NICU) admission. Intrapartum blood loss was objectively measured in milliliters using a postpartum drape with a calibrated bag. The amount of bleeding was measured by subtracting the empty weight of the pads placed under the patient in the patient's bed within 2 h after delivery. Group I: carbetocin 100 µg/mL (n = 75), group II: oxytocin 5 IU/mL (n = 75), group III: carbetocin and tranexamic acid 50 mg/mL (n = 75), group IV: oxytocin and tranexamic acid (n = 75). RESULTS: The hemoglobin concentration decrease significantly differed between groups (1.03 ± 1.04, 1.3 ± 0.85, 1.4 ± 0.85, 1.41 ± 0.87, respectively; p < 0.001). Group 4 has the highest decrease in hemoglobin and hematocrit concentrations. When we investigated the subgroup differences, the decrease in hemoglobin concentration was significantly higher in group 2 than group 1 (1.30 ± 0.85 vs. 1.03 ± 1.04; p = 0.023), in group 2 than group 3 (1.3 ± 0.85 vs. 1.04 ± 0.9; p = 0.013), and in group 4 than group 3 (1.41 ± 0.87 vs. 1.04 ± 0.9; p < 0.001). The decrease in hematocrit level was significantly different between groups (3.07 ± 3.23, 3.55 ± 2.44, 2.13 ± 3.09, 4.25 ± 2.52; p < 0.001, respectively). No significant differences were observed in terms of mean blood loss between the four groups (277.19 ± 208.10, 294.13 ± 198.64, 274.33 ± 199.57, and 283.97 ± 178.11; p = 0.445, respectively). Furthermore, there was no significant difference between the groups in the rate of need for blood transfusion (1.3%, 5.4%, 4%, and 4%, respectively; p = 0.6). LIMITATIONS: The most important limitation of the study is a relatively small number of participants. CONCLUSION: In conclusion, our findings suggest that carbetocin may be more successful than oxytocin and oxytocin plus tranexamic acid regimens in terms of postpartum hemoglobin reduction, and there is no difference in terms of the need for blood transfusion when it is used for postpartum hemorrhage prophylaxis after vaginal delivery.

Administration of carbetocin-a long-acting oxytocin analogue-before sperm collection by transrectal ultrasound-guided massage of the accessory sex glands in bucks (Capra hircus) and ibexes (Capra pyrenaica).

Transrectal ultrasonic-guided massage of the accessory sex glands (TUMASG) is a technique that allows collecting semen requiring few electrical stimuli or even no pulse. A long-acting analogue of oxytocin (carbetocin, 0.1 mg) was i.v. administered before TUMASG in 10 conscious bucks (Experiment 1) and 10 anaesthetized Iberian ibexes (Experiment 2) to shorten the time of semen collection, decrease the number of electrical stimuli and/or improve the semen quality. The ejaculated volume, concentration, quality parameters and kinetics variables of the sperm were determined in fresh semen. The time length of the procedures and the number of electric pulses applied were recorded. Furthermore, stress response indicators (number of vocalizations in Experiment 1; heart and respiratory rates, rectal temperature, cortisol levels, totals proteins and neutrophil-to-lymphocyte ratio in Experiment 2) were documented. In bucks, the administration of carbetocin tended to shorten the time needed for semen collection but no-showed differences in the fresh seminal quality. In the Iberian ibexes, there were no significant differences between groups in the time length of procedures or in the number of animals that ejaculated. Carbetocin administration only reduced the respiratory rate, did it modify fresh semen characteristics in ibexes. In conclusion, the administration of carbetocin did not appear as a useful tool to improve welfare during semen collection with TUMASG or semen quality in conscious bucks and anaesthetized ibexes, having only slight advantages related to the procedure.

Oxytocin receptor behavioral effects and cell types in the bed nucleus of the stria terminalis.

Oxytocin is a neuropeptide that can produce anxiolytic effects and promote social approach. However, emerging evidence shows that under some conditions, oxytocin can instead induce anxiety-related behaviors. These diverse effects of oxytocin appear to be mediated by circuit-specific actions. Recent data showed that inhibition of oxytocin receptors (OTRs) in the bed nucleus of the stria terminalis (BNST) was sufficient to increase social approach and decrease social vigilance in female California mice (Peromyscus californicus) exposed to social defeat stress. As a member of the G-protein coupled receptor family, OTRs can induce distinct downstream pathways by coupling to different G-protein isoforms. We show that infusion of carbetocin, a biased OTR-Gq agonist, in the BNST reduced social approach in both female and male California mice. In both females and males, carbetocin also increased social vigilance. To gain insight into cell types that could be mediating this effect, we analyzed previously published single-cell RNAseq data from the BNST and nucleus accumbens (NAc). In the NAc, we and others showed that OTR activation promotes social approach behaviors. In the BNST, Oxtr was expressed in over 40 cell types, that span both posterior and anterior subregions of the BNST. The majority of Oxtr-expressing neurons were GABAergic. In the anterior regions of BNST targeted in our carbetocin experiments, Cyp26b1-expressing neurons had high average Oxtr expression. In the NAc, most Oxtr+ cells were D1 dopamine receptor-expressing neurons and interneurons. These differences in Oxtr cell type distribution may help explain how activation of OTR in BNST versus NAc can have different effects on social approach and social vigilance.

Preventing postpartum hemorrhage after cesarean delivery: a network meta-analysis of available pharmacologic agents.

BACKGROUND: Postpartum hemorrhage causes a quarter of global maternal deaths. The World Health Organization recommends oxytocin as the first line agent to prevent hemorrhage during cesarean delivery. However, some randomized controlled trials suggest that other uterotonics are superior. OBJECTIVE: We conducted a network meta-analysis comparing the ability of pharmacologic agents to reduce blood loss and minimize the need for additional uterotonics during cesarean delivery. DATA SOURCES: We searched the Cochrane Central Register of Controlled Trials, Embase, and MEDLINE databases from inception to May 2020. STUDY ELIGIBILITY CRITERIA: We included randomized controlled trials that compared oxytocin, carbetocin, misoprostol, ergometrine, carboprost, or combinations of these in the prevention of postpartum hemorrhage during cesarean delivery. METHODS: We performed a systematic review followed by an NMA in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Quality of the evidence was assessed with the Confidence in Network Meta-Analysis approach and Grading of Recommendations, Assessment, Development and Evaluations tool within the summary of findings table. Our primary outcomes were the estimated blood loss and need for additional uterotonics. Secondary outcomes included nausea and postpartum hemorrhage of >1000 mL. We performed sensitivity analyses to explore the influence of surgical context and oxytocin administration strategy. RESULTS: A total of 46 studies with 7368 participants were included. Of those, 21 trials (6 agents and 3665 participants) formed the "estimated blood loss" network and, considering the treatment effects, certainty in the evidence, and surface under the cumulative ranking curve scores, carbetocin was assessed to probably be superior to oxytocin, but only in reducing the estimated blood loss by a clinically insignificant volume (54.83 mL; 95% confidence interval, 26.48-143.78). Misoprostol, ergometrine, and the combination of oxytocin and ergometrine were assessed to probably be inferior, whereas the combination of oxytocin and misoprostol was assessed to definitely be inferior to oxytocin. A total of 37 trials (8 agents and 6193 participants) formed the "additional uterotonic" network and, again, carbetocin was assessed to probably be superior to oxytocin, requiring additional uterotonics 185 (95% confidence interval, 130-218) fewer times per 1000 cases. Oxytocin plus misoprostol, oxytocin plus ergometrine, and misoprostol were assessed to probably be inferior, whereas carboprost, ergometrine, and the placebo were definitely inferior to oxytocin. For both primary outcomes, oxytocin administration strategies had a higher probability of being the best uterotonic, if initiated as a bolus. CONCLUSION: Carbetocin is probably the most effective agent in reducing blood loss and the need for additional uterotonics. Oxytocin appears to be more effective when initiated as a bolus.

Carbetocin vs. oxytocin at elective caesarean delivery: a double-blind, randomised, controlled, non-inferiority trial of low- and high-dose regimens.

Carbetocin or oxytocin are given routinely as first-line uterotonic drugs following delivery of the neonate during caesarean delivery to prevent postpartum haemorrhage. Low doses may be as effective as high doses with a potential reduction in adverse effects. In this double-blind, randomised, controlled, non-inferiority trial, we assigned low-risk patients undergoing elective caesarean delivery under spinal anaesthesia to one of four groups: carbetocin 20 µg; carbetocin 100 µg; oxytocin 0.5 IU bolus + infusion; and oxytocin 5 IU bolus + infusion. The study drug was given intravenously after delivery of the neonate. Uterine tone was assessed by the obstetrician 2, 5 and 10 minutes after study drug administration according to an 11-point verbal numerical rating scale (0 = atonic, 10 = excellent tone). The primary outcome measure was uterine tone 2 min after study drug administration. The pre-specified non-inferiority margin was 1.2 points on the 11-point scale. Secondary outcomes included uterine tone after 5 and 10 minutes, use of additional uterotonics, blood loss and adverse effects. Data were available for 277 patients. Carbetocin 20 µg resulting in uterine tone of (median (IQR [range])) 8 (7-8 [1-10]) was non-inferior to carbetocin 100 µg with tone 8 (7-9 [3-10]), median (95%CI) difference 0 (-0.44-0.44). Similarly, oxytocin 0.5 IU with tone 7 (6-8 [3-10]) was non-inferior to oxytocin 5 IU with tone 8 (6-8 [2-10]), median (95%CI) difference 1 (0.11-1.89). Carbetocin 20 µg was also non-inferior to oxytocin 5 IU, and oxytocin 0.5 IU was non-inferior to carbetocin 100 µg. Uterine tone after 5 and 10 minutes, use of additional uterotonics, blood loss and adverse effects were similar in all groups.

Carbetocin versus oxytocin following vaginal and Cesarean delivery: a before-after study.

PURPOSE: A nationwide shortage of oxytocin in Canada resulted in a temporary switch from oxytocin to carbetocin for all postpartum women at our institution. This change offered a unique opportunity to conduct a pragmatic comparative assessment of the efficacy of carbetocin and oxytocin. METHODS: In a retrospective before-after study, we reviewed the medical records from 641 women in the carbetocin group and 752 women in the oxytocin group . The standard carbetocin dosing was 100 µg iv following vaginal and intrapartum Cesarean delivery, while for elective Cesarean delivery it was 50 µg, with an additional 50 µg if required. The standard oxytocin dosing was 5 IU iv followed by 2.4 IU·hr-1 for four to six hours after vaginal delivery, while for Cesarean delivery it was 1-3 IU iv, three minutes apart, up to 10 IU if required, followed by the same maintenance. In both modalities of delivery, if uterine tone was suboptimal, the maintenance dose of oxytocin could be increased to 4.8 IU·hr-1. In both groups, additional uterotonics were used as required. The primary outcome was the need for additional uterotonics. Secondary outcomes included estimated and calculated blood loss, the occurrence of postpartum hemorrhage, and the need for blood transfusion. RESULTS: The incidence of additional uterotonic use was not different between the carbetocin and oxytocin groups (12.0% vs 8.8%; P = 0.05; odds ratio, 1.39; 95% confidence interval, 0.97 to 2.00). The incidence of postpartum hemorrhage was higher in the carbetocin group than in the oxytocin group (10.3% vs 6.6%; P = 0.01). Blood transfusion was more common in the carbetocin group (1.4% vs 0.3%; P = 0.02). CONCLUSION: There was no difference in the use of additional uterotonics when carbetocin or oxytocin were used in a cohort of women undergoing vaginal deliveries and both elective and emergency Cesarean deliveries.

RéSUMé: OBJECTIF: Une pénurie nationale d'ocytocine au Canada a entraîné l'utilisation temporaire de la carbétocine en remplacement de l'ocytocine pour toutes les femmes en post-partum dans notre établissement. Grâce à cette substitution, nous avons bénéficié d'une occasion unique de mener une évaluation comparative pragmatique de l'efficacité de la carbétocine et de l'ocytocine. MéTHODE: Dans une étude rétrospective avant-après, nous avons examiné les dossiers médicaux de 641 femmes dans le groupe carbétocine et de 752 femmes dans le groupe ocytocine. Le dosage standard de carbécotine était de 100 µg iv après un accouchement vaginal et pendant un accouchement par césarienne intrapartum, tandis que pour un accouchement par césarienne élective, le dosage était de 50 µg, avec 50 µg supplémentaires au besoin. Le dosage standard d'ocytocine était de 5 UI iv suivi de 2,4 UI·h-1 pendant quatre à six heures après un accouchement vaginal, tandis que pour un accouchement par césarienne, il était de 1 à 3 UI iv, à trois minutes d'intervalle, jusqu'à 10 UI au besoin, suivi du même dosage d'entretien. Dans les deux types d'accouchement, si le tonus utérin était sous-optimal, la dose d'entretien d'ocytocine pouvait être augmentée à 4,8 UI·h-1. Dans les deux groupes, des utérotoniques supplémentaires ont été utilisés au besoin. Le critère d'évaluation principal était le besoin d'utérotoniques supplémentaires. Les critères d'évaluation secondaires comprenaient la perte de sang estimée et calculée, la survenue d'une hémorragie du post-partum et la nécessité d'une transfusion sanguine. RéSULTATS: L'incidence d'utilisation d'utérotoniques supplémentaires n'était pas différente entre les groupes carbétocine et ocytocine (12,0 % vs 8,8 %; P = 0,05; rapport de cotes,1,39; intervalle de confiance à 95 %, 0,97 à 2,00). L'incidence d'hémorragie du post-partum était plus élevée dans le groupe carbétocine que dans le groupe ocytocine (10,3 % vs 6,6 %; P = 0,01). Les transfusions sanguines étaient plus fréquentes dans le groupe carbétocine (1,4 % vs 0,3 %; P = 0,02). CONCLUSION: Aucune différence dans l'utilisation d'utérotoniques supplémentaires n'a été observée lors de l'utilisation de carbétocine ou d'ocytocine dans une cohorte de femmes accouchant par voie vaginale ou par césarienne élective ou en urgence.

Comparison of carbetocin as a bolus or an infusion with prophylactic phenylephrine on maternal heart rate during Cesarean delivery under spinal anesthesia: a double-blinded randomized controlled trial.

PURPOSE: Carbetocin, an oxytocin analog, given as a postpartum hemorrhage prophylaxis in elective Cesarean deliveries, frequently causes tachycardia and hypotension. Phenylephrine infusion has been shown to prevent spinal anesthesia-induced hypotension. The goal of this study was to evaluate if a slow infusion of carbetocin would reduce maternal heart rate variation and hemodynamic disturbances compared with a rapid bolus in parturients receiving a prophylactic phenylephrine infusion during elective Cesarean delivery. METHODS: In this double-blinded randomized controlled trial, 70 healthy parturients were allocated to either a bolus group or an infusion group. At cord clamping, participants in the bolus group received carbetocin 100 µg as a rapid intravenous bolus, while participants in the infusion group received carbetocin 100 µg over 10 min. The primary outcome was the variation in maternal heart rate from baseline during the 20 min following cord clamping. Secondary outcomes included blood pressure, cardiac output, and stroke volume variations during the study period, measured with the ClearSight™ hemodynamic monitor. RESULTS: Maximum heart rate variation was not different between the groups: bolus group, mean (standard deviation) 29.8 (25.2)% vs infusion group, 27.2 (23.3)%; P = 0.67. The increase in heart rate occurred significantly earlier in the bolus group than in the infusion group (median [interquartile range] time, 105 [69-570] sec vs 485 [255-762] sec; P = 0.02; group × time interaction: two-way repeated measures ANOVA, P = 0.04). There was no significant difference in maximum variations for the other hemodynamic parameters between the groups. CONCLUSION: Carbetocin infused over ten minutes did not reduce the magnitude of maternal heart rate variation but delayed its occurrence. This finding could be relevant to the anesthesiologist caring for parturients in whom a slight increase in maternal heart rate is clinically undesirable. STUDY REGISTRATION: www. CLINICALTRIALS: gov (NCT03404544); registered 19 January 2018.

RéSUMé: OBJECTIF: Lorsque la carbétocine, un analogue de l'ocytocine, est administrée à titre de prophylaxie pour les hémorragies du post-partum dans les accouchements par césarienne programmée, cet agent provoque fréquemment une tachycardie et une hypotension. Il a été démontré qu'une perfusion de phényléphrine prévenait l'hypotension induite par la rachianesthésie. L'objectif de cette étude était d'évaluer si une perfusion lente de carbétocine réduirait la variation de fréquence cardiaque maternelle et les perturbations hémodynamiques par rapport à un bolus rapide chez les parturientes recevant une perfusion prophylactique de phényléphrine pendant un accouchement par césarienne programmée. MéTHODE: Dans cette étude randomisée contrôlée à double insu, 70 parturientes en bonne santé ont été allouées à un groupe bolus ou à un groupe perfusion. Lors du clampage du cordon, les participantes du groupe bolus ont reçu 100 µg de carbétocine sous forme de bolus intraveineux rapide, tandis que les participantes du groupe perfusion ont reçu 100 µg de carbétocine sur dix minutes. Le critère d'évaluation principal était la variation de la fréquence cardiaque maternelle par rapport aux valeurs de base au cours des 20 minutes suivant le clampage du cordon. Les critères secondaires comprenaient la tension artérielle, le débit cardiaque et les variations du volume d'éjection au cours de la période d'étude, tels que mesurés avec le moniteur hémodynamique ClearSight™. RéSULTATS: La variation maximale de fréquence cardiaque n'était pas différente entre les groupes : groupe bolus, moyenne (écart type) 29,8 (25,2) % vs groupe perfusion, 27,2 (23,3) %; P = 0,67. L'augmentation de la fréquence cardiaque s'est produite significativement plus tôt dans le groupe bolus que dans le groupe perfusion (temps médian [écart interquartile], 105 [69-570] sec vs 485 [255-762] sec; P = 0,02;× interaction groupe x temps : ANOVA bidirectionnelle à mesures répétées, P = 0,04). Il n'y avait pas de différence significative dans les variations maximales pour les autres paramètres hémodynamiques entre les groupes. CONCLUSION: La carbétocine perfusée pendant dix minutes n'a pas réduit l'ampleur de la variation de la fréquence cardiaque maternelle, mais a retardé son apparition. Cette découverte pourrait être pertinente pour l'anesthésiologiste qui prend soin de parturientes chez qui une légère augmentation de la fréquence cardiaque maternelle serait cliniquement indésirable. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT03404544); enregistrée le 19 janvier 2018.

Cost Implications of Using Carbetocin Injection to Prevent Postpartum Hemorrhage in a Canadian Urban Hospital.

OBJECTIVE: Recent World Health Organization (WHO) recommendations regarding uterotonics for the prevention of postpartum hemorrhage (PPH) state that carbetocin should be considered a first-line prophylactic agent for all births where its cost is comparable to other effective uterotonics. This study evaluated whether a room temperature stable formulation of carbetocin met this recommendation in a Canadian urban hospital setting. METHODS: A decision tree model was developed to assess the financial implications of replacing oxytocin with carbetocin as a first-line prophylactic agent for PPH prevention in a Greater Toronto Area (GTA) hospital. The analysis accounted for the mode of delivery, efficacies of carbetocin and oxytocin in PPH prevention, occurrence of PPH-related health outcomes, and health care resource costs for PPH interventions. RESULTS: This study found that a GTA hospital, with 3242 deliveries per year, could save over CAD $349 000 annually by switching to room temperature stable carbetocin for PPH prevention. Carbetocin was able to lower institution costs by reducing the use of health care resources for PPH management in low-risk and high-risk PPH patients. The cost-saving potential of carbetocin relative to oxytocin was largely attributed to its greater efficacy in preventing the consequences of PPH. CONCLUSION: The use of room temperature stable carbetocin as a first-line prophylactic agent for PPH prevention meets WHO recommendations regarding uterotonics for PPH in a GTA hospital. The model from this study can be used to determine the financial impact of switching from oxytocin to carbetocin in other jurisdictions while diversifying a hospital's pool of PPH prophylactic agents.

Heat stable carbetocin vs. oxytocin for the prevention of post-partum hemorrhage in emergency caesarean delivery: a randomized controlled trial.

OBJECTIVES: To evaluate the uterotonic effect of carbetocin compared with oxytocin in emergency cesarean delivery in Iraq. METHODS: A double-blinded randomized noninferiority single center trial. Three-hundred patients were systematically randomized to intravenous bolus injection of 10 IU oxytocin or 100 mcg carbetocin after delivery in a ratio of 2:1. The primary outcome was additional uterotonic use when inadequate uterine tone occur in the first 24 h after delivery. Secondary outcomes include the need for blood transfusion, blood pressure and pulse rate changes within an hour of drugs administration. Noninferiority margins for the relative risks outcomes was 4%. RESULTS: Addition uterotonics use was significantly lower in carbetocin group with a risk ratio of 0.36. Carbetocin was superior to oxytocin in reducing the need for additional uterotonic drugs by 12% and non-inferior to oxytocin for blood transfusion 3.5%. Noninferiority was not shown for the outcome of sever blood loss. Miner changes in blood pressure and pulse rate were observed in carbetocin group compared to oxytocin but clinically were not significant. CONCLUSIONS: Heat stable carbetocin is effective in reducing additional uterotonics use compared to oxytocin without clinically significant change in blood pressure or pulse rate, therefore, can be a potential alternative in Iraq.

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.

Targeting the Oxytocin System to Ameliorate Early Life Depressive-Like Behaviors in Maternally-Separated Rats.

Oxytocin (OXT) -"the love hormone"- has been involved in the anti-depressant activity of some selective serotonin reuptake inhibitors (SSRIs). The exact mechanism underlying the OXT pathway in depression is not fully clear. This study aimed to investigate the effect of OXT analogue, carbetocin (CBT) and the SSRI, escitalopram (ESCIT) on depressive-like behaviors following maternal separation (MS). It is worthy to mention that intranasal CBT has been approved by U.S. Food and Drug Administration (FDA) for Prader-Willi syndrome. Adolescent Wistar albino maternally-separated rats were given CBT, (100 µg/animal/d via inhalation route), and, ESCIT, (20 mg kg-1, per os ( p.o.)) either alone or in combination for 7 d. Repeated 3-h MS demonstrated increased immobility time in forced swim test (FST) and decreased locomotor activity in open field test. MS elevated plasma level of adrenocortico-trophic hormone (ACTH) but notably reduced plasma OXT, with no effect on hippocampal OXT-R expression. Following MS, hippocampal contents of 5-hydroxytryptamine receptors (5HT1A-R), serotonin transporter (SERT) were increased. CBT and ESCIT corrected the behavioral dysfunction in FST and suppressed the high levels of ACTH. Additionally, both treatments boosted OXT level, reduced 5HT1A-R and normalized SERT contents, which reflects increased availability of serotonin. Finally, CBT markedly ameliorated the histopathological damage induced by MS and suppressed the increased glial fibrillary acidic protein. CBT and ESCIT manage depressive-like behavior by positively affecting serotonergic and oxytocinergic systems. Targeting OXT system -using CBT- ameliorated depressive like behaviors induced by maternal separation most probably via enhancing OXT plasma levels, attenuating hormonal ACTH and restoring the expression of hippocampal oxytocin and serotonin mechanisms.

Cost of hospital care of women with postpartum haemorrhage in India, Kenya, Nigeria and Uganda: a financial case for improved prevention.

OBJECTIVE: Access to quality, effective lifesaving uterotonics in low and middle-income countries (LMICs) remains a major barrier to reducing maternal deaths from postpartum haemorrhage (PPH). Our objective was to assess the costs of care for women who receive different preventative uterotonics, and with PPH and no-PPH so that the differences, if significant, can inform better resource allocation for maternal health care. METHODS: The costs of direct hospital care of women who received oxytocin or heat-stable carbetocin for prevention of PPH in selected tertiary care facilities in India, Kenya, Nigeria, and Uganda were assessed. We collected data from all women who had PPH, as well as a random sample of women without PPH. Cost data was collected for the cost of stay, PPH interventions, transfusions and medications for 2966 women. We analyzed the difference in cost of care at a facility level between women who experienced a PPH event and those who did not. Key findings The mean cost of care of a woman experiencing PPH in the study sites in India, Kenya, Nigeria, and Uganda exceeded the cost of care of a woman who did not experience PPH by between 21% and 309%. There was a large variation in cost across hospitals within a country and across countries. CONCLUSION: Our results quantify the increased cost of PPH of up to 4.1 times that for a birth without PPH. PPH cost information can help countries to evaluate options across different conditions and in the formulation of appropriate guidelines for intrapartum care, including rational selection of quality-assured, effective medicines. This information can be applied to national assessment and adaptation of international recommendations such as the World Health Organization's recommendations on uterotonics for the prevention of PPH or other interventions used to treat PPH. Trial registration HRP Trial A65870; UTN U1111-1162-8519; ACTRN12614000870651; CTRI/2016/05/006969, EUDRACT 2014-004445-26. Date of registration 14 August 2014 Access to quality, effective lifesaving medicines in low and middle-income countries remains a major barrier to reducing maternal deaths from bleeding after childbirth. Information on to what extent treatments for bleeding increases the cost of care of women after childbirth is important for informed resource allocation. We collected data from all women who had bleeding after childbirth, as well as a random sample of women without bleeding in selected hospitals in India, Kenya, Nigeria, and Uganda. Cost data was collected for the cost of stay and interventions to manage bleeding for 2966 women. We compared the difference in cost of care between women who experienced a bleeding event and those who did not. The mean cost of care of a woman with bleeding in the study sites exceeded the cost of care of a woman who did not experience PPH by between 21% and 309%. There was a large variation in cost across hospitals within a country and across countries. Our results indicate an increased cost of bleeding of up to 4.1 times that for birth without bleeding. Effective prevention reduces the cost of care. Cost information can help countries to evaluate options across different conditions and in the formulation of appropriate guidelines for intrapartum care, including rational selection of quality-assured, effective medicines. This information can be applied to national assessment and adaptation of international recommendations such as the World Health Organization's recommendations on medications for the prevention of bleeding after childbirth or other interventions used to treat bleeding.

Duration of third stage labour and postpartum blood loss: a secondary analysis of the WHO CHAMPION trial data.

BACKGROUND: Obstetric haemorrhage continues to be a leading cause of maternal mortality, contributing to more than a quarter of the 2,443,000 maternal deaths reported between 2003 and 2009. During this period, about 70% of the haemorrhagic deaths occurred postpartum. In addition to other identifiable risk factors for greater postpartum blood loss, the duration of the third stage of labour (TSL) seems to be important, as literature shows that a longer TSL can be associated with more blood loss. To better describe the association between the duration of TSL and postpartum blood loss in women receiving active management of third stage of labour (AMTSL), this secondary analysis of the WHO CHAMPION trial data has been conducted. METHODS: This was a secondary analysis of the WHO CHAMPION trial conducted in twenty-three sites in ten countries. We studied the association between the TSL duration and blood loss in the sub cohort of women from the CHAMPION trial (all of whom received AMTSL), with TSL upto 60 min and no interventions for postpartum haemorrhage. We used a general linear model to fit blood loss as a function of TSL duration on the log scale, arm and center, using a normal distribution and the log link function. We showed this association separately for oxytocin and for Heat stable (HS) carbetocin. RESULTS: For the 10,040 women analysed, blood loss rose steeply with third stage duration in the first 10 min, but more slowly after 10 min. This trend was observed for both Oxytocin and HS carbetocin and the difference in the trends for both drugs was not statistically significant (p-value = 0.2070). CONCLUSIONS: There was a positive association between postpartum blood loss and TSL duration with either uterotonic. Blood loss rose steeply with TSL duration until 10 min, and more slowly after 10 min. Study registration The main trial was registered with Australian New Zealand Clinical Trials Registry ACTRN12614000870651 and Clinical Trial Registry of India CTRI/2016/05/006969.

The duration of the third stage of labour (TSL) seems to be an important risk factor for greater postpartum blood loss, as literature shows that a longer TSL can be associated with more blood loss. Active management of third stage of labour (AMTSL), included in the WHO guidelines for prevention of postpartum haemorrhage (PPH), is effective in reducing both the amount of postpartum blood loss and the duration of the third stage. To better describe the association between duration of TSL and postpartum blood loss in women receiving AMTSL, we conducted this secondary analysis of WHO CHAMPION trial data.To assess the association between the duration of third stage of labour and postpartum blood loss, a subcohort of the CHAMPION modified ITT population was selected by excluding women with missing blood loss or missing TSL duration or TSL duration more than 60 min and women with interventions. Thus, the subcohort consisted of 10,040 women.In women with vaginal birth and not receiving interventions for treating atonic PPH or other sources of bleeding, and with TSL duration up to 60 min, there was a positive association between duration of the TSL and postpartum blood loss. The blood loss rose steeply with duration in women with TSL of 10 min or less, while in women with longer TSL duration the slope was less steep.There was no evidence of a difference between oxytocin and HS carbetocin in the pattern of association of duration of the TSL and blood loss.

Uncontrolled before-after study adding carbetocin in addition to oxytocin decreases blood loss for cesarean section in twin pregnancies.

PURPOSE: To evaluate the effectiveness of adding carbetocin to regular uterotonic agents for prevention of postpartum hemorrhage (PPH) after cesarean section for twin pregnancies. METHODS: This is a retrospective uncontrolled before-after study done in a tertiary center in Taiwan, 2010-2017. Women with twin pregnancies that underwent cesarean section were enrolled. The control group (n = 114) received oxytocin infusion and direct uterine injection. In addition to these, the study group (n = 127) received 100ug of intravenous carbetocin. Primary endpoint was the change in hemoglobin. Secondary endpoints included risk of PPH and undiagnosed PPH (Hb dropped more than 2 g/dL), blood loss, the need for additional uterotonic maneuvers, and blood transfusion. Hemodynamic changes were also investigated. RESULTS: After adjusting for confounding factors, the change in Hb (0.35 g/dL, 95% CI: -0.03∼0.74) and incidence of PPH (OR 0.30, 95% CI: 0.03∼3.28) were comparable in both groups. However, women with undiagnosed PPH decreased (OR 0.43, 95% CI:0.22∼0.85). Total blood loss in 24 h after delivery also decreased (-40.33 mL, 95%CI: -80.32∼ -0.34). The use of extra uterotonic medications and the need for blood transfusion did not differ. The systolic blood pressure 4 h after childbirth was higher in the carbetocin group (6.71, 95% CI: 2.27∼11.15). CONCLUSION: The use of carbetocin in addition to regular uterotonic agents decreased total blood loss and undiagnosed PPH. Also, systolic blood pressure 4 h after childbirth is higher in the carbetocin group. There was no significant difference in hemoglobin change and risk of PPH.

Pharmacologic intervention for the management of retained placenta: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Retained placenta affects 2% to 3.3% of all vaginal deliveries and is one of the leading causes of postpartum hemorrhage worldwide. Despite the prevalence of this condition, there is limited guidance on its management. OBJECTIVE: A systematic review and meta-analysis were performed to evaluate the efficacy of pharmacologic interventions for the management of retained placenta. STUDY DESIGN: PubMed, ClinicalTrials.gov, Cochrane Library, Web of Science, and Scopus were searched for full-text publications in English. Search terms included "retained placenta" AND "treatment" OR "therapy" OR "disease management" OR "Pitocin" OR "misoprostol" OR "Cytotec" OR "dinoprostone" OR "nitroglycerin" OR "carbetocin" OR "ergotamine," with no restriction on publication dates. Only randomized controlled trials were included. The primary outcome was the need for manual extraction of the placenta or dilation and curettage. Reviewers evaluated the quality of included articles using the Cochrane Collaboration's tool for assessing the risk of bias. Pooled risk ratios were estimated based on random- and fixed-effects analyses. Interstudy heterogeneity was considered when I2≥50%. RESULTS: The literature search identified 29 randomized controlled trials that met the inclusion criteria (2682 subjects). The most commonly used agent across the studies was oxytocin administered via umbilical vein injection; there was high heterogeneity among these studies (I2=62%). Oxytocin was inferior to carbetocin (risk ratio, 1.61; 95% confidence interval, 1.03-2.52) and prostaglandins (risk ratio, 2.63; 95% confidence interval, 1.18-5.86) for the primary outcome. For oxytocin, prostaglandin agents, and nitroglycerin, there was a trend toward favoring the study drug for the primary outcome compared with control or placebo. Compared with placebo or control, estimated blood loss was lower if pharmacologic interventions were administered, with a mean difference of 121.5 mL (95% confidence interval, -185.7 to -52.3). There was no difference in postpartum hemorrhage or the need for blood transfusion between pharmacologic interventions and placebo or control. CONCLUSION: Pooled estimates for oxytocin via umbilical vein injection, prostaglandin agents, and nitroglycerin performed favorably compared with placebo or control for the management of retained placenta. Carbetocin and prostaglandin agents were superior to oxytocin in reducing the need for manual extraction or dilation and curettage.

Carbetocin at elective caesarean section: a sequential allocation trial to determine the minimum effective dose in obese women.

Postpartum haemorrhage is a leading cause of maternal death during childbirth. There is an increasing incidence of atonic postpartum haemorrhage in developed countries, and maternal obesity has been proposed as a contributing factor. The dose-response relationship of carbetocin in obese women has not yet been determined. We conducted a double-blind, dose-finding study of carbetocin using a biased coin up-and-down design in women with a body mass index ≥ 40 kg.m-2 undergoing elective caesarean section. The determinant for a successful response was satisfactory uterine tone, with no intra-operative need for additional uterotonic drugs. Secondary outcomes included the use of additional uterotonic drugs postoperatively, estimated blood loss and adverse effects of carbetocin administration. Thirty women were recruited to the study. The median (IQR [range]) body mass index was 44.93 (41.5-55.2 [40-66.5]) kg.m-2 . The ED90 of carbetocin was estimated as 62.9 (95%CI 57.0-68.7) µg using the truncated Dixon and Mood method, and 68 (95%CI 52-77) µg using the isotonic regression method. The estimated blood loss was 880 (621-1178 [75-2442]) ml. The overall rates of hypotension and hypertension after delivery were 40% and 6.7%, respectively, while nausea occurred in 26.7% of women. The ED90 for carbetocin in obese women at elective caesarean section is lower than the dose of 100 µg currently recommended by the Society of Obstetricians and Gynaecologists of Canada, but is approximately four times higher than the previously demonstrated ED90 of 14.8 µg in women with body mass index < 40 kg.m-2 .

Carbetocin compared with oxytocin in non-elective Cesarean delivery: a systematic review, meta-analysis, and trial sequential analysis of randomized-controlled trials.

PURPOSE: Carbetocin has been shown to reduce the requirement for additional uterotonics in women exclusively undergoing elective Cesarean delivery (CD). The aim of this review was to determine whether this effect could also be demonstrated in the setting of non-elective CD. METHODS: Medline, Embase, CINAHL, Web of Science and Cochrane databases were searched for randomized-controlled trials (RCTs) in any language comparing carbetocin to oxytocin. Studies with data on women undergoing non-elective CD, where carbetocin was compared with oxytocin, were included. The primary outcome was the need for additional uterotonics. Secondary outcomes included incidence of blood transfusion, estimated blood loss (mL), incidence of postpartum hemorrhage (PPH; > 1000 mL) and mean hemoglobin drop (g·dL-1 RESULTS: Five RCTs were included, with a total of 1,214 patients. The need for additional uterotonics was reduced with carbetocin compared with oxytocin (odds ratio, 0.30; 95% CI, 0.11 to 0.86; I2, 90.60%). Trial sequential analysis (TSA) confirmed that the information size needed to show a significant reduction in the need for additional uterotonics had been exceeded. No significant differences were shown with respect to any of the secondary outcomes, but there was significant heterogeneity between the studies. CONCLUSIONS: Carbetocin reduces the need for additional uterotonics in non-elective CD compared with oxytocin. TSA confirmed that this analysis was appropriately powered to detect the pooled estimated effect. Further trials utilizing consistent core outcomes are needed to determine an effect on PPH. TRIAL REGISTRATION: PROSPERO CRD42019147256, registered 13 September 2019.

RéSUMé: OBJECTIF: Il a été démontré que la carbétocine réduisait les besoins en utérotoniques supplémentaires exclusivement chez les femmes subissant un accouchement par césarienne planifié. L'objectif de ce compte rendu était de déterminer si cela pouvait également être démontré dans le cas d'un accouchement par césarienne non planifié. MéTHODE: Les bases de données Medline, Embase, CINAHL, Web of Science et Cochrane ont été passées en revue pour en extraire les études randomisées contrôlées (ERC), toutes langues confondues, comparant la carbétocine à l'ocytocine. Les études comportant des données concernant des femmes subissant un accouchement par césarienne non planifié et comparant la carbétocine à l'ocytocine ont été incluses. Le critère d'évaluation principal était le besoin d'utérotoniques supplémentaires. Les critères secondaires comprenaient l'incidence de transfusion sanguine, la perte de sang estimée (mL), l'incidence d'hémorragie postpartum (HPP; > 1000 mL) et la baisse moyenne du taux d'hémoglobine (g·dL−1). RéSULTATS: Cinq ERC ont été retenues, incluant 1214 patientes au total. Les besoins en utérotoniques supplémentaires étaient plus faibles lors de l'utilisation de carbétocine par rapport à l'ocytocine (rapport de cotes, 0,30; IC 95 %, 0,11 à 0,86; I2, 90,60 %). L'analyse séquentielle des essais a confirmé que la taille des informations démontrant une réduction significative du besoin d'utérotoniques supplémentaires avait été dépassée. Aucune différence significative n'a été démontrée en ce qui touchait nos critères d'évaluation secondaires, mais l'hétérogénéité des études était considérable. CONCLUSION: La carbétocine réduit le besoin d'utérotoniques supplémentaires lors d'un accouchement par césarienne non planifié comparativement à l'ocytocine. L'analyse séquentielle des essais a confirmé que cette analyse disposait de suffisamment de puissance pour détecter l'effet estimé pondéré. Des études supplémentaires portant sur des critères constants sont nécessaires afin de déterminer un effet sur l'HPP. ENREGISTREMENT DE L'éTUDE: PROSPERO CRD42019147256, enregistrée le 13 septembre 2019.

Economic evaluation of carbetocin as prophylaxis for postpartum hemorrhage in the Philippines.

BACKGROUND: The World Health Organization (WHO) recommends oxytocin as the drug of choice for postpartum hemorrhage (PPH) prevention. However, the WHO has also recently considered carbetocin for PPH prevention, but only if carbetocin were a cost-effective choice in the country. Consequently, we determined the cost-effectiveness and budgetary impact of carbetocin against oxytocin in the Philippines. METHODS: A cost-utility analysis using a decision tree was done to compare the costs and outcomes of carbetocin with oxytocin for PPH prophylaxis among women undergoing either vaginal delivery (VD) or cesarean section (CS) in a six-week time horizon using a societal perspective. One-way and probabilistic sensitivity analyses were applied to investigate parameter uncertainties. Additionally, budget impact analysis was conducted using a governmental perspective. Results were presented as incremental cost-effectiveness ratio (ICER) using a 2895 United States dollar (USD) per quality adjusted life year (QALY) gained as the ceiling threshold in the Philippines. RESULTS: Carbetocin was not cost-effective given the listed price of carbetocin at 18 USD. Given a societal perspective, the ICER values of 13,187 USD and over 40,000 USD per QALY gained were derived for CS and VD, respectively. Moreover, the ICER values were sensitive to the risk ratio of carbetocin versus oxytocin and carbetocin price. On budget impact, the five-year total budget impact of a drug mix of carbetocin and oxytocin was 25.54 million USD (4.23 million USD for CS and 21.31 million USD for VD) compared with 'only oxytocin' scenario. CONCLUSION: Carbetocin is not a cost-effective choice in PPH prevention for both modes of delivery in the Philippines, unless price reduction is made. Our findings can be used for evidence-informed policies to guide coverage decisions on carbetocin not only in the Philippines but also in other low and middle-income countries.