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). Participants 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.

Trends and regional variations in prescriptions dispensed to stimulate uterine contractions at the end of pregnancy in Belgium: A community-based study from 2003 to 2018.

PURPOSE: To investigate trends and regional variations in uterotonics dispensed around birth between 2003 and 2018 in Belgium. METHODS: Data, including outpatient and inpatient prescriptions were extracted from a nationally representative prescription database. The prevalence of uterotonics dispensed during a period including the 7 days before birth, the delivery day and the 7 days after birth was computed over three 4-year-long study periods from 2003 to 2018. The trends between periods and associations between the use of at least one uterotonic and maternal age, region of residence, delivery type and social status were assessed using logistic regression. RESULTS: In total, 31 675 pregnancies were included in the study. The proportion of pregnancies exposed to at least one uterotonic decreased significantly from 92.9% (95%CI, 92.3-93.4) in 2003-2006 to 91.4% (95%CI, 90.7-92.0) in 2015-2018 for vaginal births and from 95.5% (95%CI, 94.5-96.4) to 93.7% (95%CI, 92.6-94.7) for caesarean sections. However, for vaginal births, the proportion of oxytocin increased from 84.5% (95%CI, 83.7-85.2) to 89% (95%CI 88.3-89.7). A significant association was found between uterotonic agent use and maternal age, region of residence, and delivery type. The dispensation of some uterotonic agents differed significantly between the regions. CONCLUSIONS: The proportion of pregnancies exposed to at least one uterotonic was high across the study period but decreased slightly between 2003 and 2018. Important variations in uterotonic use between regions highlight the need for improved national guidance.

Effect of an oxytocin protocol on secondary uterotonic use in patients undergoing Cesarean delivery.

PURPOSE: Protocol-driven oxytocin regimens can reduce oxytocin administration compared with a nonprotocol free-flow continuous infusion. Our aim was to compare secondary uterotonic use between a modified "rule of threes" oxytocin protocol and a free-flow continuous oxytocin infusion after Cesarean delivery. METHODS: We conducted a retrospective before-and-after study to compare patients who underwent Cesarean delivery between 1 January 2010 and 31 December 2013 (preprotocol) with patients who underwent Cesarean delivery between 1 January 2015 and 31 August 2017 (postprotocol). The preprotocol group received free-flow oxytocin administration and the postprotocol group received oxytocin according to a modified rule of threes algorithm. The primary outcome was secondary uterotonic use and the secondary outcomes included blood transfusion, hemoglobin value < 8 g·dL-1, and estimated blood loss. RESULTS: In total, 4,010 Cesarean deliveries were performed in 3,637 patients (2,262 preprotocol and 1,748 postprotocol). The odds of receiving secondary uterotonic drugs were increased in the postprotocol group (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.04 to 1.70; P = 0.02). Patients in the postprotocol group were less likely to receive a blood transfusion. Nevertheless, the two groups were similar for the composite end point of transfusion or hemoglobin < 8 g·dL-1 (OR, 0.86; 95% CI, 0.66 to 1.11; P = 0.25). The odds of an estimated blood loss greater than 1,000 mL were reduced in the postprotocol group (OR, 0.64; 95% CI, 0.50 to 0.84; P = 0.001). CONCLUSIONS: Patients in the modified rule of threes oxytocin protocol group were more likely to receive a secondary uterotonic than those in the preprotocol group. Estimated blood loss and transfusion outcomes were similar.

RéSUMé: OBJECTIF: Les schémas thérapeutiques d'ocytocine basés sur un protocole peuvent réduire l'administration d'ocytocine par rapport à une perfusion continue en débit libre hors protocole. Notre objectif était de comparer l'utilisation secondaires d'agents utérotoniques entre un protocole modifié d'ocytocine en « règle de trois ¼ et une perfusion continue d'ocytocine à débit libre après un accouchement par césarienne. MéTHODE: Nous avons mené une étude rétrospective avant-après pour comparer les personnes ayant bénéficié d'une césarienne entre le 1er janvier 2010 et le 31 décembre 2013 (pré-protocole) avec les personnes ayant subi une césarienne entre le 1er janvier 2015 et le 31 août 2017 (post-protocole). Le groupe pré-protocole a reçu une administration d'ocytocine en débit libre et le groupe post-protocole a reçu de l'ocytocine selon un algorithme de règle de trois modifié. Le critère d'évaluation principal était l'utilisation secondaire d'agents utérotoniques et les critères d'évaluation secondaires incluaient la transfusion sanguine, un indice d'hémoglobine < 8 g·dL­1 et les pertes de sang estimées. RéSULTATS: Au total, 4010 accouchements par césarienne ont été réalisés chez 3637 patient·es (2262 pré-protocole et 1748 post-protocole). Les chances de recevoir des médicaments utérotoniques secondaires étaient plus élevées dans le groupe post-protocole (rapport de cotes [RC], 1,33; intervalle de confiance [IC] à 95 %, 1,04 à 1,70; P = 0,02). Les patient·es du groupe post-protocole étaient moins susceptibles de recevoir une transfusion sanguine. Néanmoins, les deux groupes étaient similaires en ce qui touchait au critère d'évaluation composite de transfusion ou d'hémoglobine < 8 g·dL­1 (RC, 0,86; IC 95, 0,66 à 1,11; P = 0,25). Les risques d'une perte de sang estimée supérieure à 1000 mL ont été réduits dans le groupe post-protocole (RC, 0,64; IC 95 %, 0,50 à 0,84; P = 0,001). CONCLUSION: Les patient·es du groupe du protocole d'ocytocine en règle de trois modifiée étaient plus susceptibles de recevoir un utérotonique secondaire que les personnes du groupe pré-protocole. Les pertes sanguines estimées et les résultats transfusionnels étaient similaires.

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.

Patients with resolution of low-lying placenta and placenta previa remain at increased risk of postpartum hemorrhage.

OBJECTIVE: To determine whether women who experience resolution of low placentation (low-lying placenta or placenta previa) are at increased risk of postpartum hemorrhage compared to those with normal placentation throughout pregnancy. METHODS: This was a retrospective cohort study of women who delivered at Mount Sinai Hospital between 2015 and 2019, and who were diagnosed with low-lying placenta or placenta previa on transvaginal ultrasound at the time of the second-trimester anatomical survey, with resolution of low placentation on subsequent ultrasound examination. Women undergoing second-trimester anatomical survey who had normal placentation on transvaginal ultrasound 3 days before or after the cases were randomly identified for comparison. The primary outcome was the rate of postpartum hemorrhage. Secondary outcomes included the need for a blood transfusion, use of additional uterotonic medication, the need for additional procedures to control bleeding, and maternal admission to the intensive care unit. Outcomes were assessed using a multivariable logistic regression model. RESULTS: A total of 1256 women were identified for analysis, of whom 628 had resolved low placentation and 628 had normal placentation. Women with resolved low placentation, compared to those with normal placentation throughout pregnancy, had significantly higher mean age (33.0 ± 5.4 years vs 31.9 ± 5.5 years; P < 0.01) and lower mean body mass index at delivery (27.9 ± 5.5 kg/m2 vs 30.2 ± 5.7 kg/m2 ; P < 0.01), and were more likely to have undergone in-vitro fertilization, be of non-Hispanic white race, have posterior placental location (all P < 0.01) and have private/commercial health insurance (P = 0.04). Patients with resolved low placentation vs normal placentation had greater odds of postpartum hemorrhage (adjusted odds ratio (aOR), 3.5 (95% CI, 2.0-6.0); P < 0.01), use of additional uterotonic medication (aOR, 2.2 (95% CI, 1.5-3.1); P < 0.01) and increased rates of additional procedures to control bleeding (aOR, 4.0 (95% CI, 1.3-11.9); P = 0.01). CONCLUSION: Despite high rates of resolution of low-lying placenta and placenta previa by term, women with resolved low placentation remain at increased risk of postpartum hemorrhage compared to those with normal placentation throughout pregnancy. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Does simulation improve clinical performance in management of postpartum hemorrhage?

BACKGROUND: Although simulation is now widely used to improve teamwork and communication, data demonstrating improvement in clinical outcomes are limited. OBJECTIVE: This study aimed to examine the clinical performance and outcomes associated with postpartum hemorrhage because of uterine atony following the implementation of a multidisciplinary simulation program. STUDY DESIGN: This was a prospective observational study of response to postpartum hemorrhage because of uterine atony in an academic medical center before (epoch 1: July 2017-June 2018) and after (epoch 2: July 2019-June 2020) implementing a multidisciplinary simulation program. A total of 22 postpartum hemorrhage simulations were performed from July 2018 to June 2019 involving more than 300 nursing, obstetrical, and anesthesia providers. The simulation program focused on managing postpartum hemorrhage events and improving teamwork and communication of the multidisciplinary teams. To evaluate the clinical effectiveness of the simulation program, the primary outcome was response to postpartum hemorrhage defined as the time from the administration of uterotonic medications to transfusion of the first unit of blood in the first 12 hours following delivery, comparing epoch 2 to epoch 1 following the implementation of a simulation program. Statistical analysis included the use of the Pearson chi-square test, Wilcoxon rank-sum test, Hodges-Lehmann statistic for differences, and bootstrap methods with a P value of <.05 considered significant. RESULTS: Between July 1, 2017, and June 30, 2018, there were 12,305 patients who delivered, of which 495 patients (4%) required transfusion. Between July 1, 2019, and June 30, 2020, there were 12,414 patients who delivered, of which 480 patients (4%) required transfusion. When isolating cases of postpartum hemorrhage because of uterine atony in both transfused groups, there were 157 women in the presimulation group (epoch 1) and 165 women in the postsimulation group (epoch 2), respectively. There was no difference in age, race, parity, or perinatal outcomes between the 2 epochs. Women in epoch 2 began receiving blood products significantly earlier in the first 12 hours following delivery compared with women in epoch 1 (51 [range, 28-125] minutes vs 102 [range, 32-320] minutes; P=.005). In addition, there was a significantly decreased variation in the time from the administration of uterotonic medications to transfusion of blood in epoch 2 (P=.035). Furthermore, women in epoch 2 had significantly lower estimated blood loss than women in epoch 1 (1250 [range, 1000-1750] mL vs 1500 [range, 1000-2000] mL; P=.032). CONCLUSION: The implementation of a multidisciplinary simulation program at a large academic center focusing on the management of postpartum hemorrhage was associated with an improved clinical response. Specifically, there were significantly faster times from the administration of uterotonic medications to transfusion of blood, decreased variance in the time from the administration of uterotonic medications to transfusion of blood, and lower estimated blood loss following the implementation of a simulation program. Because delay in treatment is a major cause of preventable maternal death in obstetrical hemorrhage, the results in our study provided clinical evidence that a simulation program may improve patient outcomes in such emergencies.

Intramuscular oxytocin versus Syntometrine® versus carbetocin for prevention of primary postpartum haemorrhage after vaginal birth: a randomised double-blinded clinical trial of effectiveness, side effects and quality of life.

OBJECTIVE: To compare intramuscular oxytocin, Syntometrine® and carbetocin for prevention of postpartum haemorrhage after vaginal birth. DESIGN: Randomised double-blinded clinical trial. SETTING: Six hospitals in England. POPULATION: A total of 5929 normotensive women having a singleton vaginal birth. METHODS: Randomisation when birth was imminent. MAIN OUTCOME MEASURES: Primary: use of additional uterotonic agents. Secondary: weighed blood loss, transfusion, manual removal of placenta, adverse effects, quality of life. RESULTS: Participants receiving additional uterotonics: 368 (19.5%) oxytocin, 298 (15.6%) Syntometrine and 364 (19.1%) carbetocin. When pairwise comparisons were made: women receiving carbetocin were significantly more likely to receive additional uterotonics than those receiving Syntometrine (odds ratio [OR] 1.28, 95% CI 1.08-1.51, P = 0.004); the difference between carbetocin and oxytocin was non-significant (P = 0.78); Participants receiving Syntometrine were significantly less likely to receive additional uterotonics than those receiving oxytocin (OR 0.75, 95% CI 0.65-0.91, P = 0.002). Non-inferiority between carbetocin and Syntometrine was not shown. Use of Syntometrine reduced non-drug PPH treatments compared with oxytocin (OR 0.64, 95% CI 0.42-0.97) but not carbetocin (P = 0.64). Rates of PPH and blood transfusion were not different. Syntometrine was associated with an increase in maternal adverse effects and reduced ability of the mother to bond with her baby. CONCLUSIONS: Non-inferiority of carbetocin to Syntometrine was not shown. Carbetocin is not significantly different to oxytocin for use of additional uterotonics. Use of Syntometrine reduced use of additional uterotonics and need for non-drug PPH treatments compared with oxytocin. Increased maternal adverse effects are a disadvantage of Syntometrine. TWEETABLE ABSTRACT: IM carbetocin does not reduce additional uterotonic use compared with IM Syntometrine or oxytocin.

The new clinical application of bilateral-contralateral cervix clamp in postpartum hemorrhage: a retrospective cohort study.

BACKGROUND: To assess the efficacy and safety of bilateral-contralateral cervix clamp firstly applied in postpartum hemorrhage caused by uterine tony of lower segment. METHODS: Totally 47 pregnant women with postpartum hemorrhage secondary to lower uterine segment atony in vaginal delivery or after caesarean delivery were included from March 1, 2020 to May 31, 2020. According to patient's informed consent, 22 women accepted cervical clamp to treat and 25 only used uterotonics in control group. Then hemostatic efficacy and safety of bilateral-contralateral cervix clamp were assessed by retrospective analysis. RESULTS: It was found that mean blood loss in clamp group was much less during vaginal delivery (656.2±72.79 g vs 811.8±86.07 g, p = 0.001) or after caesarean delivery (42.8±6.60 g vs 126.3±86.97 g, p = 0.007), and incidence of uterotonic repeated usage (81.8% vs 36, 18.2% vs 64%, p = 0.001) or side effect (18.2% vs 48.0%, p = 0.031) appeared less than control group, but there was no statistical differences on hospital stay (4.1±1.57 days vs 3.8±1.61 days, p = 0.535), hemoglobin (119±4.10 g vs 121.4±4.19 g, p = 0.058), blood transfusion (9.1% vs 12%,p = 0.746), surgical procedures (4.5% vs 4.0%, p = 0.93), also no clamp complications occurred. CONCLUSIONS: The bilateral-contralateral cervix clamp was effective and safe, this new technique could be a complementary treatment for postpartum hemorrhage.

Oxytocin at elective caesarean delivery: a dose-finding study in women with obesity.

Prophylactic oxytocin administration at the third stage of labour reduces blood loss and the need for additional uterotonic drugs. Obesity is known to be associated with an increased risk of uterine atony and postpartum haemorrhage. It is unknown whether women with obesity require higher doses of oxytocin in order to achieve adequate uterine tone after delivery. The purpose of this study was to establish the bolus dose of oxytocin required to initiate effective uterine contraction in 90% of women with obesity (the ED90 ) at elective caesarean delivery. We conducted a double-blind dose-finding study using the biased coin up-down design method. Term pregnant women with a BMI ≥ 40 kg.m-2 undergoing elective caesarean delivery under regional anaesthesia were included. Those with conditions predisposing to postpartum haemorrhage were not included. Oxytocin was administered as an intravenous bolus over 1 minute upon delivery of the fetus. With the first woman receiving 0.5 IU, oxytocin doses were administered according to a sequential allocation scheme. The primary outcome measure was satisfactory uterine tone, as assessed by the operating obstetrician 2 minutes after administration of the oxytocin bolus. Secondary outcomes included the need for rescue uterotonic drugs, adverse effects and estimated blood loss. We studied 30 women with a mean (SD) BMI of 52.3 (7.6) kg.m-2 . The ED90 for oxytocin was 0.75 IU (95%CI 0.5-0.93 IU) by isotonic regression and 0.78 IU (95%CI 0.68-0.88 IU) by the Dixon and Mood method. Our results suggest that women with a BMI ≥ 40 kg.m-2 require approximately twice as much oxytocin as those with a BMI < 40 kg.m-2 , in whom an ED90 of 0.35 IU (95%CI 0.15-0.52 IU) has previously been demonstrated.

Efficacy and safety of controlled-release dinoprostone vaginal delivery system (PROPESS) in Japanese pregnant women requiring cervical ripening: Results from a multicenter, randomized, double-blind, placebo-controlled phase III study.

AIM: To evaluate the efficacy and safety of dinoprostone vaginal insert (PROPESS) in pregnant post-term Japanese women requiring cervical ripening. METHODS: This randomized, double-blind, placebo-controlled study included 114 pregnant Japanese women at term (41 weeks of gestation) requiring cervical ripening (baseline Bishop score (BS) ≤ 4). The primary end-point was the proportion of subjects with successful cervical ripening defined as BS ≥ 7 or vaginal delivery in 12 h. The secondary end-points were changes in BS, proportion of women with vaginal delivery, proportion of women receiving mechanical cervical ripening procedure and use of oxytocic drugs. RESULTS: PROPESS administration for a maximum of 12 h showed significantly higher successful cervical ripening rate (47.4% vs 14.3%, respectively; treatment contrast [TC]: 33.1%; P = 0.0002). The median time from administration to vaginal delivery was significantly shorter in the PROPESS group than in the placebo group (26.18 h vs 33.02 h; OR 2.51; 95% CI [1.60-3.92]; P < 0.0001). In the PROPESS group, the dosage of uterotonic drugs, such as oxytocin, decreased, and the number of patients who used these drugs also decreased. CONCLUSION: PROPESS administration for a maximum of 12 h was an effective and well-tolerated treatment for pregnant Japanese women post-term requiring cervical ripening.

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 .

A Comparative Study of Vaginal Labor and Caesarean Section Postpartum Uterine Myoelectrical Activity.

Postpartum hemorrhage (PPH) is one of the major causes of maternal mortality and morbidity worldwide, with uterine atony being the most common origin. Currently there are no obstetrical techniques available for monitoring postpartum uterine dynamics, as tocodynamometry is not able to detect weak uterine contractions. In this study, we explored the feasibility of monitoring postpartum uterine activity by non-invasive electrohysterography (EHG), which has been proven to outperform tocodynamometry in detecting uterine contractions during pregnancy. A comparison was made of the temporal, spectral, and non-linear parameters of postpartum EHG characteristics of vaginal deliveries and elective cesareans. In the vaginal delivery group, EHG obtained a significantly higher amplitude and lower kurtosis of the Hilbert envelope, and spectral content was shifted toward higher frequencies than in the cesarean group. In the non-linear parameters, higher values were found for the fractal dimension and lower values for Lempel-Ziv, sample entropy and spectral entropy in vaginal deliveries suggesting that the postpartum EHG signal is extremely non-linear but more regular and predictable than in a cesarean. The results obtained indicate that postpartum EHG recording could be a helpful tool for earlier detection of uterine atony and contribute to better management of prophylactic uterotonic treatment for PPH prevention.

Comparative analysis of myometrial and vascular smooth muscle cells to determine optimal cells for use in drug discovery.

Novel therapeutic regulators of uterine contractility are needed to manage preterm labor, induce labor and control postpartum hemorrhage. Therefore, we previously developed a high-throughput assay for large-scale screening of small molecular compounds to regulate calcium-mobilization in primary mouse uterine myometrial cells. The goal of this study was to select the optimal myometrial cells for our high-throughput drug discovery assay, as well as determine the similarity or differences of myometrial cells to vascular smooth muscle cells (VSMCs)-the most common off-target of current myometrial therapeutics. Molecular and pharmacological assays were used to compare myometrial cells from four sources: primary cells isolated from term pregnant human and murine myometrium, immortalized pregnant human myometrial (PHM-1) cells and immortalized non-pregnant human myometrial (hTERT-HM) cells. In addition, myometrial cells were compared to vascular SMCs. We found that the transcriptome profiles of hTERT-HM and PHM1 cells were most similar (r = 0.93 and 0.90, respectively) to human primary myometrial cells. Comparative transcriptome profiling of primary human myometrial transcriptome and VSMCs revealed 498 upregulated (p ≤ 0.01, log2FC≥1) genes, of which 142 can serve as uterine-selective druggable targets. In the high-throughput Ca2+-assay, PHM1 cells had the most similar response to primary human myometrial cells in OT-induced Ca2+-release (Emax = 195% and 143%, EC50 = 30 nM and 120 nM, respectively), while all sources of myometrial cells showed excellent and similar robustness and reproducibility (Z' = 0.52 to 0.77). After testing a panel of 61 compounds, we found that the stimulatory and inhibitory responses of hTERT-HM cells were highly-correlated (r = 0.94 and 0.95, respectively) to human primary cells. Moreover, ten compounds were identified that displayed uterine-selectivity (≥5-fold Emax or EC50 compared to VSMCs). Collectively, this study found that hTERT-HM cells exhibited the most similarity to primary human myometrial cells and, therefore, is an optimal substitute for large-scale screening to identify novel therapeutic regulators of myometrial contractility. Moreover, VSMCs can serve as an important counter-screening tool to assess uterine-selectivity of targets and drugs given the similarity observed in the transcriptome and response to compounds.

Development and stability of a heat-stable formulation of carbetocin for the prevention of postpartum haemorrhage for use in low and middle-income countries.

Postpartum haemorrhage is a leading cause of maternal death worldwide. Oxytocin, currently the drug of choice for prevention of PPH, requires constant refrigeration. In pursuit of an alternative medicine, Ferring Pharmaceuticals have developed a heat-stable formulation of carbetocin, an oxytocin analogue. This study aimed to define that formulation, and to investigate its stability under ICH climate zone IV conditions (30°C/75% relative humidity) for at least 3 years and at extreme temperatures, such as 60°C, for shorter periods of time. The development resulted in a heat-stable carbetocin formulation consisting of 0.1 mg/mL carbetocin in sodium succinate buffer, mannitol, and methionine. The optimum pH was determined to be pH 5.45 (5.25-5.65). The generated stability data of this formulation show that ≥95% purity of the peptide was maintained for a minimum of 3 years at 30°C, 6 months at 40°C, 3 months at 50°C and 1 month at 60°C. In addition, the heat-stable carbetocin formulation was not sensitive to freezing or light. The reported highly stable peptide formulation facilitates the distribution in low and middle-income countries, where maintaining cold chain distribution is difficult. Ferring Pharmaceuticals, the World Health Organization, and MSD for Mothers have established a collaboration to develop this heat-stable formulation of carbetocin for the prevention of post-partum hemorrhage in women after vaginal childbirth, with the aim of making the medicine available in the public sector of developing countries that have a high burden of maternal mortality.

Improvement in the active management of the third stage of labor for the prevention of postpartum hemorrhage in Tanzania: a cross-sectional study.

BACKGROUND: Tanzania has a maternal mortality ratio of 556 per 100,000 live births, representing 21% of all deaths of women of reproductive age. Hemorrhage, mostly postpartum hemorrhage (PPH), is estimated to cause at least 25% of maternal deaths in Tanzania. In 2008, the Ministry of Health, Community Development, Gender, Elderly and Children launched interventions to improve efforts to prevent PPH. Competency-based training for skilled birth attendants and ongoing quality improvement prioritized the practice of active management of the third stage of labor (AMTSL). METHODS: A cross-sectional study was conducted in 52 health facilities in Tanzania utilizing direct observations of women during labor and delivery. Observations were conducted in 2010 and, after competency-based training and quality improvement interventions in the facilities, in 2012. A total of 489 deliveries were observed in 2010 and 558 in 2012. Steps for AMTSL were assessed using a standardized structured observation checklist that was based on World Health Organization guidelines. RESULTS: The proportion of deliveries receiving all three AMTSL steps improved significantly by 19 percentage points (p < 0.001) following the intervention, with the most dramatic increase occurring in health centers and dispensaries (47.2 percentage point change) compared to hospitals (5.2 percentage point change). Use of oxytocin for PPH prevention rose by 37.1 percentage points in health centers and dispensaries but remained largely the same in hospitals, where the baseline was higher. There was substantial improvement in the timely provision of uterotonics (within 3 min of birth) across all facilities (p = 0.003). Availability of oxytocin, which was lower in health centers and dispensaries than hospitals at baseline, rose from 73 to 94% of all facilities. CONCLUSION: The quality of PPH prevention increased substantially in facilities that implemented competency-based training and quality improvement interventions, with the most dramatic improvement seen at lower-level facilities. As Tanzania continues with efforts to increase facility births, it is imperative that the quality of care also be improved by promoting use of up-to-date guidelines and ensuring regular training and mentoring for health care providers so that they adhere to the guidelines for care of women during labor. These measures can reduce maternal and newborn mortality.

Drug delivery to the human and mouse uterus using immunoliposomes targeted to the oxytocin receptor.

BACKGROUND: The ability to provide safe and effective pharmacotherapy during obstetric complications, such as preterm labor or postpartum hemorrhage, is hampered by the systemic toxicity of therapeutic agents leading to adverse side effects in the mother and fetus. Development of novel strategies to target tocolytic and uterotonic agents specifically to uterine myocytes would improve therapeutic efficacy while minimizing the risk of side effects. Ligand-targeted liposomes have emerged as a reliable and versatile platform for targeted drug delivery to specific cell types, tissues or organs. OBJECTIVE: Our objective was to develop a targeted drug delivery system for the uterus utilizing an immunoliposome platform targeting the oxytocin receptor. STUDY DESIGN: We conjugated liposomes to an antibody that recognizes an extracellular domain of the oxytocin receptor. We then examined the ability of oxytocin receptor-targeted liposomes to deliver contraction-blocking (nifedipine, salbutamol and rolipram) or contraction-enhancing (dofetilide) agents to strips of spontaneously contracting myometrial tissue in vitro (human and mouse). We evaluated the ability of oxytocin receptor-targeted liposomes to localize to uterine tissue in vivo, and assessed if targeted liposomes loaded with indomethacin were capable of preventing lipopolysaccharide-induced preterm birth in mice. RESULTS: Oxytocin receptor-targeted liposomes loaded with nifedipine, salbutamol or rolipram consistently abolished human myometrial contractions in vitro, while oxytocin receptor-targeted liposomes loaded with dofetilide increased contraction duration. Nontargeted control liposomes loaded with these agents had no effect. Similar results were observed in mouse uterine strips. Following in vivo administration to pregnant mice, oxytocin receptor-targeted liposomes localized specifically to the uterine horns and mammary tissue. Targeting increased localization to the uterus 7-fold. Localization was not detected in the maternal brain or fetus. Targeted and nontargeted liposomes also localized to the liver. Oxytocin receptor-targeted liposomes loaded with indomethacin were effective in reducing rates of preterm birth in mice, whereas nontargeted liposomes loaded with indomethacin had no effect. CONCLUSION: Our results demonstrate that oxytocin receptor-targeted liposomes can be used to either inhibit or enhance human uterine contractions in vitro. In vivo, the liposomes localized to the uterine tissue of pregnant mice and were effective in delivering agents for the prevention of inflammation-induced preterm labor. The potential clinical advantage of targeted liposomal drug delivery to the myometrium is reduced dose and reduced toxicity to both mother and fetus.

Customised management of the third stage of labour.

BACKGROUND: Postpartum haemorrhage (PPH) rates are increasing worldwide. The rate is particularly high in women undergoing an induced or augmented labour. In response to this, we altered our hospital's protocol for the management of the third stage of labour to recommend Syntometrine, in preference to oxytocin alone, for women being induced or augmented. We set out to assess the impact of the protocol change on the PPH rate. MATERIALS AND METHODS: A random sample of 1200 women who had a singleton, term vaginal birth before and after the protocol change was taken. Exclusion criteria were then applied to match PPH risk status. Using a quasi-experimental study design, PPH rates were compared between women who had received oxytocin or Syntometrine for third stage management. RESULTS: Five hundred and forty-nine women received oxytocin prior to the protocol change and were compared with 333 women who received Syntometrine after protocol change. There was no difference in the PPH rate with respect to uterotonic used (P = 0.9). There was no evidence of an interaction between labour type, third stage uterotonic and PPH (P = 0.4). PPH rates were lowest for women who laboured spontaneously and received Syntometrine (19% oxytocin, 14% Syntometrine). The PPH rate was unchanged by uterotonic in women whose labour was augmented (34% for both). PPH was more common in women being induced who received Syntometrine (22% oxytocin, 27% Syntometrine). None of these differences were statistically significant. CONCLUSION: Compared to oxytocin, Syntometrine did not reduce the rate of PPH in women with augmented or induced labour. Other approaches to reducing PPH rates are required.

An exploration of village-level uterotonic practices in Fenerive-Est, Madagascar.

BACKGROUND: Pharmaceutical uterotonics are effective for preventing postpartum hemorrhage and complications related to unsafe abortion. In Madagascar, however, traditional birth attendants (Matrones) commonly administer medicinal teas for uterotonic purposes. Little is known about Matrone practices and how they might coincide with efforts to increase uterotonic coverage. The aims of this study were to: 1) identify indications for presumed uterotonic plant use by Matrones, 2) explore uterotonic practices at the village level, and 3) describe the response of health practitioners to village-level uterotonic practices. METHODS: Twelve in-depth interviews with health practitioners, Matrones and community agents were conducted in local dialect. All interviews were audio-recorded, transcribed, and translated into English for analysis using Atlas.ti. Medicinal plant specimens were also collected and analyzed for the presence of uterotonic peptides. RESULTS: While Matrones reported to offer specific teas for uterotonic purposes, health practitioners discussed providing emergency care for women with complications associated with use of specific teas. Complications included retained placenta, hypertonic uterus, hemorrhage and sepsis. Chemical analysis indicated the presence of cysteine-rich peptides in the Dantoroa/Denturus plant used in some Matrones' teas. CONCLUSIONS: The presence of uterotonic peptides in one plant used by Matrones may indicate that Matrones intend to administer uterotonics for safer childbirth. This finding, combined with practitioner reports of complications related to some medicinal teas, points to a need for availability of an evidence-based uterotonic at the village level, namely, misoprostol pills or oxytocin in the form of uniject.

Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design.

Cyclotides are plant peptides comprising a circular backbone and three conserved disulfide bonds that confer them with exceptional stability. They were originally discovered in Oldenlandia affinis based on their use in traditional African medicine to accelerate labor. Recently, cyclotides have been identified in numerous plant species of the coffee, violet, cucurbit, pea, potato, and grass families. Their unique structural topology, high stability, and tolerance to sequence variation make them promising templates for the development of peptide-based pharmaceuticals. However, the mechanisms underlying their biological activities remain largely unknown; specifically, a receptor for a native cyclotide has not been reported hitherto. Using bioactivity-guided fractionation of an herbal peptide extract known to indigenous healers as "kalata-kalata," the cyclotide kalata B7 was found to induce strong contractility on human uterine smooth muscle cells. Radioligand displacement and second messenger-based reporter assays confirmed the oxytocin and vasopressin V1a receptors, members of the G protein-coupled receptor family, as molecular targets for this cyclotide. Furthermore, we show that cyclotides can serve as templates for the design of selective G protein-coupled receptor ligands by generating an oxytocin-like peptide with nanomolar affinity. This nonapeptide elicited dose-dependent contractions on human myometrium. These observations provide a proof of concept for the development of cyclotide-based peptide ligands.

Rectally administrated misoprostol as an alternative to intravenous oxytocin infusion for preventing post-partum hemorrhage after cesarean delivery.

AIM: With the increasing rate of cesarean delivery (CD) worldwide, there is a need for a revision of practices to prevent post-partum hemorrhage (PPH) after CD. In search of a safe, cheap and effective alternative to oxytocin for prevention of PPH during the postoperative period of CD, the present study aimed to compare rectally administrated misoprostol with i.v. oxytocin infusion. METHODS: A randomized, placebo-controlled, double-blind prospective trial was undertaken on 192 women who did not have risk factors for PPH and who had an uneventful emergency CD under spinal anesthesia. They were randomly allocated to receive either 800 mg of rectal misoprostol or an i.v. infusion of oxytocin at the end of operation. Primary outcome measures were the amount of postoperative (24 h) blood loss and incidence of PPH during the postoperative period. The secondary outcome measures were the postoperative drop in hemoglobin concentration after 24 h, need for additional uterotonic and blood transfusion, and side-effects/complications during the 24-h observation period. RESULTS: There was a significant reduction of blood loss in the misoprostol group compared with the oxytocin group (144.5 ± 100.1 vs 191.7 ± 117.1, P < 0.0001). The two groups were similar in terms of the secondary outcome parameters. CONCLUSION: Rectally administrated 800-mg misoprostol may be an effective alternative to oxytocin infusion to prevent PPH after CD.