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1.
Effect and Safety of Diluted Vasopressin Injection for Bleeding Control During Robot-assisted Laparoscopic Myomectomy in Reproductive Women With Uterine Fibroids: A Randomized Controlled Pilot Trial (VALENTINE Trial)
Park, S. J., Lee, J. W., Hwang, D. W., Lee, S., Yim, G. W., Song, G., Lee, E. J., Kim, H. S.
In vivo (Athens, Greece). 2024;38(1):431-436
Abstract
BACKGROUND/AIM: Vasopressin injected during myomectomy is known to effectively reduce bleeding but is sometimes associated with intraoperative vasoconstriction and hypertension due to systemic absorption. Although there is a growing preference for the use of diluted vasopressin, evidence of its effect and safety is still lacking. PATIENTS AND METHODS We performed a randomized controlled pilot trial to evaluate the effect and safety of vasopressin diluted in a constant volume during robot-assisted laparoscopic myomectomy (RALM), where a total of 39 women with uterine fibroids were randomly assigned into the following three groups (group 1, 0.2 IU/ml; group 2, 0.1 IU/ml; group 3, 0.05 IU/ml with a total of 100 ml of normal saline). The primary endpoint was to compare estimated blood loss (EBL), and the secondary endpoints were to compare postoperative value and drop ratio of hemoglobin, operation time, transfusion, hospitalization, and complications among the three groups. RESULTS There were no differences in the number and largest size of uterine fibroids, total weight of uterine fibroids, console time, and volumes of intravenous fluid administered during RALM among the three groups, whereas combined operation was performed more commonly in group 2 than in groups 1 and 3 (53.9% vs. 0 to 7.7%; p=0.01). The primary and secondary endpoints were also not different among the three groups. However, two patients in group 1 (15.4%) showed vasopressin-related hypertension. CONCLUSION Vasopressin diluted in a volume of 100 ml showed an effective hemostatic effect and safety during RALM (Trial No. NCT04874246 in ClinicalTrial.gov).
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2.
Preventing postpartum hemorrhage: A network meta-analysis on routes of administration of uterotonics
Papadopoulou, A., Tournas, G., Georgiopoulos, G., Antsaklis, P., Daskalakis, G., Coomarasamy, A., Devall, A. J.
European journal of obstetrics, gynecology, and reproductive biology. 2024;295:172-180
Abstract
1. OBJECTIVE To perform a network meta-analysis to specify the route of administration that maximises the effectiveness of each of the available prophylactic uterotonics without increasing the risk for side effects. 2. DATA SOURCES Literature searches on 12th September 2022 included: CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. The reference lists of the retrieved study records were also searched. 3. STUDY ELIGIBILITY CRITERIA Population: Randomized controlled trials involving women in the third stage of labour after a vaginal or caesarean delivery in hospital or community settings. INTERVENTIONS Systemically administered prophylactic uterotonics of any route and dose for primary postpartum hemorrhage prevention. Comparison: Any other prophylactic uterotonic, or a different route or dose of a given uterotonic, or placebo, or no treatment. Outcomes (primary): postpartum hemorrhage ≥ 500 mL and ≥ 1000 mL. 4. STUDY APPRAISAL AND SYNTHESIS METHODS Risk of bias and trustworthiness assessments were performed, according to Cochrane's guidance. Direct, indirect and network meta-analyses were conducted, and results were summarized either as risk ratio or mean difference with 95% confidence intervals for dichotomous and continuous outcomes, respectively. The certainty of generated evidence was assessed according to the GRADE approach. Cumulative probabilities were calculated and the surface under the cumulative ranking curve was used to create a ranking of the available drugs. 5. RESULTS One hundred eighty-one studies involving 122,867 randomised women were included. Most studies were conducted in hospital settings in lower-middle income countries and involved women delivering vaginally. When compared with intramuscular oxytocin, carbetocin (RR 0.58, 95 % CI 0.40-0.84) and oxytocin (RR 0.75, 95 % CI 0.59-0.97) by an intravenous bolus, and intramuscular ergometrine plus oxytocin combination (RR 0.71, 95 % CI 0.56-0.91) are probably more effective in preventing primary postpartum hemorrhage. Intramuscularly administered oxytocin and carbetocin by an intravenous bolus have a favourable side effects profile. 6. CONCLUSIONS Generated evidence was generally moderate and global inconsistency was low. Carbetocin and oxytocin by an intravenous bolus, and intramuscular ergometrine plus oxytocin combination are probably the top uterotonics for primary postpartum hemorrhage prevention. Large scale studies exploring different routes of administration for available prophylactic uterotonics, and women's views should be conducted.
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3.
Low-Dose Elagolix for the Treatment of Heavy Menstrual Bleeding in Patients With Uterine Leiomyomas: A Randomized Controlled Trial
Brown, E., Kroll, R., Li, H., Ng, J., Pinsky, B., Rodriguez, J. W., Thomas, J., Snabes, M. C.
Obstetrics and gynecology. 2023
Abstract
OBJECTIVE To evaluate the safety and efficacy of elagolix 150 mg once-daily monotherapy in patients with heavy menstrual bleeding associated with uterine leiomyomas. METHODS A phase 4, randomized, double-blind, placebo-controlled, 6-month treatment study was conducted in premenopausal patients aged 18-51 years with heavy menstrual bleeding (defined as menstrual blood loss greater than 80 mL during one menstrual cycle) associated with uterine leiomyomas. Patients were randomized 2:1 to receive elagolix 150 mg once daily or placebo. The primary endpoint was reduction in menstrual blood loss volume to less than 80 mL at the final month and at least a 50% reduction in menstrual blood loss volume from baseline to the final month. RESULTS Of 82 randomized patients, 54 received elagolix 150 mg and 28 received placebo. With elagolix, 49.4% (95% CI 35.1-63.8%) of patients met the primary endpoint, compared with 23.3% (95% CI 7.2-39.5%) of patients who received placebo (P=.035). Statistically significant differences between elagolix and placebo in mean reduction of menstrual blood loss from baseline were seen as early as month 1 (P<.05 for months 1-3 and 5). Significantly more patients receiving elagolix experienced suppression of bleeding compared with placebo (P=.036). Greater improvements were observed in the elagolix group (vs placebo) in the proportion of patients with amenorrhea, in hemoglobin concentrations, and in health-related quality of life. No serious or severe adverse events were reported for elagolix, compared with 7.1% of participants in the placebo group having serious adverse events (coronavirus disease 2019 [COVID-19] n=1, enlarged uvula n=1). Three patients (5.6%) discontinued elagolix due to adverse events. CONCLUSION Elagolix 150 mg once-daily monotherapy significantly improved heavy menstrual bleeding associated with uterine leiomyomas compared with placebo in premenopausal patients. Treatment with elagolix 150 mg once daily was generally well-tolerated in this study, with no new safety signals. FUNDING SOURCE AbbVie Inc. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT03886220.
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4.
Hemodynamic Effects of Oxytocin and Carbetocin During Elective Cesarean Section in Preeclamptic Patients Under Spinal Anesthesia: A Randomized Double-blind Controlled Study
Bahr, M. H., Abdelaal Ahmed Mahmoud, M. Alkhatip A., Ahmed, A. G., Elgamel, A. F., Abdelkader, M., Hussein, H. A.
Anesthesiology and pain medicine. 2023;13(1):e128782
Abstract
BACKGROUND Oxytocin and carbetocin are uterotonic medications that are used to decrease postpartum hemorrhage (PPH). However, there are not enough clinical data about the hemodynamic side effects of carbetocin. OBJECTIVES This study aimed to compare carbetocin and oxytocin hemodynamic effects in preeclamptic patients undergoing elective cesarean section under spinal anesthesia. METHODS In this double-blind, randomized controlled trial, intravenous oxytocin or carbetocin was administered to 80 women (40 per group). The hemodynamic effects, such as blood pressure (BP), heart rate (HR), and oxygen (O(2)) saturation, were measured before the operation and after 1, 5, 10, and 15 minutes of the administration of both drugs. Intragroup and intergroup comparisons were conducted during statistical analysis. RESULTS Based on the intragroup comparison, there was a significant increase in HR and a reduction in BP from baseline to all intervals after the administration of both interventions. Moreover, based on the intergroup comparison, there was a significantly more increase in HR and a decline in BP and O(2) saturation in the oxytocin group than in the carbetocin group. There were three and seven cases that required another dose of carbetocin and oxytocin, respectively. Moreover, one case developed PPH in the carbetocin group; nevertheless, two cases developed PPH in the oxytocin group. CONCLUSIONS The minimal effect of carbetocin on patients' hemodynamics suggests extending the use of this drug instead of oxytocin as a uterotonic drug in patients with preeclampsia, hemorrhagic risk factors, and/or hypertension.
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5.
Efficacy and safety of rectal misoprostol versus intravenous oxytocin on reducing blood loss in cesarean section: A PRISMA-compliant systematic review and meta-analysis of randomized clinical trials
Albazee, E., Soliman, A., Albakri, K., Elbanna, M., Moussa, N. A., Faragalla, H. M.
Turkish journal of obstetrics and gynecology. 2023;20(2):142-153
Abstract
Blood loss is an inevitable complication and a major contributor to maternal morbidity and mortality at cesarean deliveries. We detected a potential preference regarding the efficacy and safety of rectal misoprostol over oxytocin as a uterotonic agent. We searched PubMed, Scopus, Web of Science, Cochrane, and other databases for the relevant trials from inception to September 2022. We included randomized clinical trials (RCTs) that compared rectal misoprostol versus intravenous oxytocin to control bleeding in women undergoing cesarean delivery. Our primary outcomes were the intra- and postoperative blood loss, and hemoglobin drop after delivery. Secondary outcomes included the need for blood transfusion, need for additional uterotonics, difference in operative time, as well as safety outcomes such as the incidence of shivering, pyrexia, nausea, and vomiting. Our search strategy revealed 1007 unique records, of them we retrieved full texts of 19 articles to check their adherence to our eligibility criteria. Seven RCTs with 1,090 participants were included. We found a significant reduction in postoperative blood loss [MD: -27.9; 95% confidence interval (CI): (-53.85, -2.10); p=0.03], and Hb drop after delivery [MD: -11; 95% CI: (-0.19, -0.03); p=0.01]. There is no significant difference regarding intraoperative blood loss, operative time, need for blood transfusion, or need for additional uterotonics. We could not find a significant difference between the two groups regarding safety outcomes, except for a higher shivering incidence in the misoprostol group [RR: 0.33; 95% CI; (0.16, 0.70); p=0.004]. We found a significant reduction in postoperative blood loss with a potentially favorable safety profile in women who administrated rectal misoprostol compared with oxytocin administration. Our findings recommend and prefer rectal misoprostol as a cheaper and effective uterotonic agent over oxytocin, which is expensive and requires an adequate cold chain for transportation and storage.
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6.
Desmopressin to prevent and treat bleeding in pregnant women with an inherited bleeding disorder: A systematic literature review
Al Arashi, W., Romano, L. G. R., Leebeek, F. W. G., Kruip, Mjha, van Galen, K. P. M., Turan, O., Kadir, R. A., Cnossen, M. H.
Journal of thrombosis and haemostasis : JTH. 2023
Abstract
BACKGROUND Although desmopressin (DDAVP) is an accessible and inexpensive hemostatic drug, its use in pregnancy is still debated due to safety uncertainties. OBJECTIVE We aim to review safety and effectiveness of DDAVP in women with an inherited bleeding disorder during pregnancy and delivery. METHODS Databases were searched for articles up to July 25(th) 2022, reporting maternal and/or neonatal outcomes. PRISMA methodology was followed (PROSPERO CRD42022316490). RESULTS Fifty-three studies were included, comprising 273 pregnancies. Regarding maternal outcomes, DDAVP was administered in 73 pregnancies during pregnancy and in 232 pregnancies during delivery. Safety outcome was reported in 245 pregnancies, with severe adverse event reported in two (1%; hyponatremia with neurological symptoms).Overall, DDAVP was used as monotherapy in 234 pregnancies with effectiveness reported in 153 pregnancies (82% effective; 18% ineffective). Regarding neonatal outcomes, out of 60 pregnancies with reported neonatal outcomes after DDAVP use during pregnancy, two children (3%) had a severe adverse event (preterm delivery n=1; fetal growth restriction n=1). Of the 232 deliveries, 169 neonates were exposed to DDAVP during delivery and in 114 neonates, safety outcome was reported. Two children (2%) experienced a moderate adverse event (low Apgar score n=1; transient hyperbilirubinemia not associated with DDAVP n=1). CONCLUSION DDAVP use during pregnancy and delivery seems safe for the mother with special attention to the occurrence of hyponatremia and for the child, especially during delivery. However, due to poor study designs and limited documentation of outcomes, a well-designed prospective study is warranted.
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7.
Side-effects of intravenously versus intramuscularly oxytocin for postpartum hemorrhage: a systematic review and meta-analysis of randomized controlled trials
Ai, W., Zeng, Y., Zhen, M., Lao, L., Ma, Y., Liu, L., Zhang, Y.
Frontiers in pharmacology. 2023;14:1273771
Abstract
Background: Oxytocin is the gold standard uterotonic agent for prevention of postpartum hemorrhage. However, there is no consensus with clear evidence about the side-effects of oxytocin administered intravenously or intramuscularly for management of the third stage of labor. We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the side-effects of intravenously or intramuscularly oxytocin for preventing postpartum hemorrhage in the third stage of labor. Methods: Six representative databases were searched from the inception to July 2023. Randomized controlled trials which explored the intravenously and intramuscularly oxytocin and provided at least one side-effect were included. Statistical analysis included random or fixed-effect meta-analyses using relative risk. Results: Nine studies included, involving 8,295 participants. Ten types of side-effects were reported. There was no statistical difference in hypotension (RR = 1.01, 95%CI = 0.88-1.15), anemia (0.98, 0.83-1.15), tachycardia (0.90, 0.69-1.17), shivering (0.90, 0.69-1.17), headache (0.86, 0.31-2.37), nausea (0.70, 0.20-2.42), vomiting (0.97, 0.26-3.58), uvular edema (0.82, 0.23-2.91), diarrhea (0.97, 0.26-3.58), and fever (0.97, 0.26-3.58) between intravenously or intramuscularly groups. Conclusion: There are no significant differences of side-effects between intravenously and intramuscularly administration of oxytocin for preventing postpartum hemorrhage in the third labor. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=407571.
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8.
A Comparative Study of the Efficacy of Intraoperative Intravenous Oxytocin and Intramuscular Oxytocin Versus Conventional Intramuscular Oxytocin for Third-Stage Labour in Elective Cesarean Section
Behuria S, Sahu M, Mohanty M, Behera S, Mohapatra K, Patnaik R, Jena S
Cureus. 2023;15(2):e35026
Abstract
Objective To study the efficacy of intraoperative IV oxytocin and intramuscular (IM) oxytocin versus conventional intramuscular oxytocin alone for active management of the third stage of labor in lower segment cesarean section (CS). The study was performed to determine the effect of 5 IU (International Unit) oxytocin infusion at the time of skin incision and that of 10 IU IM oxytocin infusion after delivery in reducing blood loss during and after CS, in comparison with the effect of administrating conventional 10 IU IM oxytocin in the same time period. In addition, it assessed the ability of the IV+IM oxytocin group to reduce the need for additional uterotonic as well as its safety determination and postoperative blood transfusion in CS. Materials and methods It is a randomized control study. The effect of 5 IU of oxytocin infusion at the time of skin incision and 10 IU of IM oxytocin (IV+IM) in reducing blood loss during and after the CS was compared to conventional 10 IU IM oxytocin. Results The study showed that the IV+IM group had a mean blood loss of 316.5 ± 74.36 ml, while the IM group had a mean loss of 403.90 ± 107.2 ml (p-value < 0.001) from placental delivery to the end of CS. A total of 90% of the patients in the IV+IM group had blood loss <50 ml compared to 95% of patients in the IM group who had a blood loss between 50 and 100 ml range from the end of cesarean to two hours postpartum. When total blood loss was compared in both groups, 84% of patients had a blood loss between 300 and 400 ml, compared to 81% of the patients in the IM group who had blood loss of 400-500 ml. Total blood loss in the IM group was 483.20 ± 115.86 ml, which was significantly higher compared to the IV group, 362.60 ± 78.07 ml (p-value=<0.001). Conclusion 5IU oxytocin infusion at the time of skin incision and 10 IU IM oxytocin after delivery of the baby significantly reduced the amount of blood loss, need for blood transfusion, and additional uterotonics during and after lower segment CS.
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9.
Treatment of unfavorable bleeding patterns in contraceptive implant users: a randomized clinical trial of curcumin
Edelman A, Boniface E, Schrote K, Messerle-Forbes M, O'Donnell A, Jensen JT, Han L
American journal of obstetrics and gynecology. 2023
Abstract
BACKGROUND Some users of the etonogestrel contraceptive implant experience bothersome bleeding which can reduce contraceptive satisfaction and continuation. Few strategies exist to manage this bleeding. The exact mechanism of progestin-induced bleeding is unknown but it is likely multi-factorial (e.g. impaired angiogenesis, 'leaky' fragile vasculature, and inflammation). Curcumin, the active ingredient in turmeric, has anti-inflammatory, anti-proliferative, and anti-angiogenic proprieties which may make it a useful agent for implant-associated bothersome bleeding. OBJECTIVE To evaluate whether curcumin decreases frequent or prolonged bleeding or spotting in contraceptive implant users. STUDY DESIGN The study was a randomized, double blind, placebo-controlled trial. We enrolled etonogestrel implant users with frequent or prolonged bleeding or spotting and randomized them to either 600 mg Theracumin HP (Immunovites, Las Vegas, NV) or placebo daily for 30 days. We defined "frequent" as two or more independent bleeding or spotting episodes and "prolonged" as 7 or more consecutive days of bleeding or spotting in a 30-day interval. Implant use was confirmed by clinical exam as well as a negative gonorrhea/chlamydia and pregnancy test. Enrolled participants initiated study treatmentfollowing three consecutive days of bleeding or spotting; if no bleeding or spotting occurred within 30-days of enrollment, subjects were withdrawn from the study. Study treatments were encapsulated to maintain a similar appearance. Participants used text messages to record daily bleeding patterns and study drug compliance. We defined bleeding as a day that required the use of protection with a pad, tampon, or liner, and spotting as a day with minimal blood loss that did not require the use of any protection. Our primary outcome was the total number of days without bleeding or spotting during the 30 days of study drug or placebo exposure. Secondary outcomes including total number of bleeding-free days, bleeding episodes, and satisfaction. A sample size of 22 per group provided 80% power at an alpha 0.05 to demonstrate a 6-day difference between groups. RESULTS From February 2021 to November 2022, 58 individuals enrolled in the study with 93% (n=54) completing 30 days of treatment (curcumin 26, placebo 28). One individual in the curcumin arm did not experience a qualifying bleeding event and thus never initiated treatment and, per protocol, was withdrawn from the study. Participant characteristics did not differ between groups including length of implant use at study enrollment [placebo: 521 days (SD 305), curcumin 419 days (SD 264)]. Study groups did not differ in regard to any bleeding-related outcome [mean days without bleeding or spotting: curcumin 16.7 (SD 6.9), placebo 17.5 (SD 4.8), p = 0.62; mean bleeding-free days: curcumin 23.4 (SD 4.9), placebo 22.4 (SD 4.5), p = 0.44; bleeding episodes: curcumin 2.0 (SD 0.8), placebo 2.1 (SD 0.8), p = 0.63]. Satisfaction with the implant as contraception and acceptability of bleeding over the study period also did not differ by study group (p = 0.54 and p = 0.30, respectively). CONCLUSION Daily use of curcumin did not improve bleeding patterns in users of the etonorgestrel contraceptive implant experiencing frequent or prolonged bleeding patterns.
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10.
The efficacy of three regimes of uterotonic agents for prevention of postpartum blood loss at undergoing cesarean section: a prospective randomized clinical trial
Çetin, Ç, Dural, H. R., Özcan, P., Tanoğlu, F. B., Kütük, M. S., Pasin, Ö, Ateş, S.
Ginekologia polska. 2023
Abstract
OBJECTIVES To compare the efficacy of three regimes of uterotonic agents on PPH in women undergoing cesarean section in our RCT. MATERIAL AND METHODS This study was a randomized controlled study (NCT05083910) performed at the Bezmialem Vakif University between July 2021 and January 2022. All women were randomly allocated into three groups: Group I (n = 52) - oxytocin only; Group II (n = 52) - the combination of oxytocin plus intrauterine misoprostol; Group III (n = 52) - carbetocin only. The primary outcome measures were: PPH to evaluate with the change between the concentrations of preoperative and postoperative hemoglobin, hematocrit and intraoperative blood loss. RESULTS The blood loss characteristics, including the change in hemoglobin and the change in hematocrit concentration, intraoperative blood loss, intraoperative additional hemostatic uterine sutures and the need for additional uterotonics, were lowest in group III, although all groups were comparable in terms of blood loss parameters. Group III had the highest blood loss ratio, exceeding 1000 mL. For the combination of oxytocin and intrauterine misoprostol, the ARR was 3.8% (95% CI 20.02-12.33), with a RR of 1.18 (95% CI 0.58-2.39) and a NNT of 26 (95% CI 8.1-4.9); for carbetocin, the ARR was 5.8% (95% CI 22.15-10.61), with a RR of 1.27 (95% CI 0.63-2.53) and a NNT of 17 (95% CI 9.41-4.51). CONCLUSIONS Our results demonstrate that carbetocin shows no superiority in the prevention of PPH in women undergoing cesarean section. Oxytocin still seems to be a highly effective alternative to prevent PPH.