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1.
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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2.
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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3.
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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4.
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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5.
Heat stable carbetocin or oxytocin for prevention of postpartum hemorrhage among women at risk: A secondary analysis of the CHAMPION trial
Ghosh, R., Owa, O., Santos, N., Butrick, E., Piaggio, G., Widmer, M., Althabe, F., Qureshi, Z., Lumbiganon, P., Katageri, G., et al
International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2023
Abstract
OBJECTIVE To examine whether the observed non-inferiority of heat-stable carbetocin (HSC), compared with oxytocin, was influenced by biologic (macrosomia, parity 3 or more, or history of postpartum hemorrhage [PPH]) and/or pharmacologic (induction or augmentation) risk factors for PPH. METHODS The present study is a secondary analysis of the CHAMPION non-inferiority randomized trial-a two-arm, double-blind, active-controlled study conducted at 23 hospitals in 10 countries, between July 2015 and January 2018. Women with singleton pregnancies, expected to deliver vaginally with cervical dilatation up to 6 cm were eligible. Randomization was stratified by country, with 1:1 assignment. Women in the intervention and control groups received a single intramuscular injection of 100 μg of HSC or 10 IU of oxytocin, respectively. The drugs were administered immediately after birth, and the third stage of labor was managed according to the WHO guidelines. Blood was collected using a plastic drape. For this analysis, we defined a woman as being at risk if she had any one or more of the biologic or pharmacologic risk factor(s). RESULTS The HSC and oxytocin arms contained 14 770 and 14 768 women, respectively. The risk ratios (RR) for PPH were 1.29 (95% confidence interval [CI] 1.08-1.53) or 1.73 (95% CI 1.51-1.98) for those with only biologic (macrosomia, parity 3 or more, and PPH in the previous pregnancy) or only pharmacologic (induced or augmented) risk factors, respectively, compared with those with neither risk factors. CONCLUSIONS Findings reinforce previous evidence that macrosomia, high parity, history of PPH, and induction/augmentation are risk factors for PPH. We did not find a difference in effects between HSC and oxytocin for PPH among women who were neither induced nor augmented or among those who were induced or augmented.
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6.
A Comparative Study of Sublingual Misoprostol Versus Intramuscular Oxytocin in the Active Management of Third Stage of Labor
Mishra S, Tirkey S, Prasad A, Trivedi K
Cureus. 2023;15(1):e33339
Abstract
Objective Misoprostol has attracted low-income low-resource countries for the active management of the third stage of labor. The objective of this study was to compare the efficacy of sublingual misoprostol and intramuscular oxytocin in the active management of the third stage of labor. Study design This was a prospective randomized controlled trial in which a total of 407 healthy pregnant women having singleton pregnancy, cephalic presentation, and normal vaginal delivery were divided into two groups. In the first group (n=203), women received 600 µg misoprostol tablet sublingually, and in the second group (n=204), women received 10 IU of intramuscular oxytocin, within 1 minute of the delivery of the baby during the third stage of labor. Three patients from the first group and four patients from the second group were excluded from the analysis due to traumatic postpartum hemorrhage (PPH). The primary outcome was an incidence of PPH. Secondary outcomes were the duration of the third stage of labor, amount of blood loss, fall in hemoglobin concentration after 48 hours of delivery, need for additional uterotonics, and side effects of the drugs. Data were compared using the chi-square and independent samples t-test. Results The incidence of PPH was 6.5% in the misoprostol group as compared to 2% in the oxytocin group (p=0.026). The misoprostol group also had significantly higher blood loss (293.75±125.8 mL) and a greater fall in hemoglobin level (0.58±0.25 g/dL) as compared to that in the oxytocin group (226.13±98.44 mL and 0.45±0.20 g/dL) (p<0.001). The mean duration of the third stage of labor was significantly higher in the misoprostol group (5.31±2.1 min) as compared to that in the oxytocin group (3.65±1.75 min) (p<0.001). The additional need for uterotonics was recorded in 15% of the study participants in the misoprostol group as compared to 8% in the oxytocin group (p=0.028). The incidence of side effects such as shivering and fever was significantly higher in the misoprostol group as compared to the oxytocin group. No significant difference between the two groups was observed concerning the incidence of nausea, vomiting, diarrhea, and headache. Conclusion Intramuscular oxytocin is a safe and useful alternative to sublingual misoprostol in facilitating the third stage of labor with minimal blood loss, fewer incidences of hemorrhage, and fewer adverse effects.
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7.
Maximum Dose Rate of Intrapartum Oxytocin Infusion and Associated Obstetric and Perinatal Outcomes
Son M, Roy A, Grobman WA, Miller ES, Dude A, Peaceman AM, Stetson B
Obstetrics and gynecology. 2023;141(2):379-386
Abstract
OBJECTIVE Despite lack of evidence for a safety threshold for oxytocin dose rate, many hospital protocols specify a maximum rate. We investigated whether exceeding 20 milliunits/min of oxytocin was associated with adverse outcomes. METHODS This is a secondary analysis of a double-blind, single-center, randomized controlled trial of nulliparous patients with singleton gestations at 36 weeks of gestation or later who presented in spontaneous labor randomized 1:1 to either a high-dose oxytocin titration regimen (initial-incremental rate of 6 milliunits/min) or standard-dose titration regimen (initial-incremental rate of 2 milliunits/min) for labor augmentation. A maximum oxytocin dose rate limit was not specified in the study protocol. For this secondary analysis, outcomes of participants who received oxytocin and exceeded a dose rate of 20 milliunits/min at any point in labor were compared with those whose rate remained at 20 milliunits/min or less. In addition, the cumulative proportions of labor and birth outcomes were calculated for each maximum dose rate of oxytocin reached among this study cohort. RESULTS Of the 1,003 participants in the parent trial, 955 (95.2%) received oxytocin, as planned, and were included, with 190 (19.9%) exceeding a maximum dose rate of 20 milliunits/min. Those who exceeded 20 milliunits/min were older and were more likely to have rupture of membranes as their trial entry indication, have hypertensive disorders of pregnancy, receive intrapartum magnesium sulfate infusion, and receive oxytocin for longer. Those whose maximum rates exceeded 20 milliunits/min underwent cesarean delivery more frequently, but the majority (74%) still delivered vaginally. In multivariable analyses, there were no significant associations between maximum oxytocin dose rates greater than 20 milliunits/min and cesarean delivery (adjusted odds ratio [aOR] 1.57, 95% CI 1.00-2.46), peripartum infection (aOR 0.69, 95% CI 0.41-1.19), postpartum hemorrhage (aOR 1.37, 95% CI 0.70-2.71), or neonatal intensive care unit (NICU) admission (aOR 1.72, 95% CI 0.89-3.31). Although 85% of spontaneous vaginal deliveries occurred at maximum oxytocin dose rates of 20 milliunits/min or less, vaginal deliveries continued to occur at higher maximum dose rates. The cumulative proportions of NICU admissions and composite severe neonatal morbidity and mortality cases increased with increasing oxytocin dose rates even with maximum oxytocin dose rates at 20 milliunits/min or less. CONCLUSION In multivariable analyses, there are no significant differences in maternal or perinatal adverse outcomes based on exceeding 20 milliunits/min of oxytocin. These data suggest that oxytocin dosing should be individualized to each patient and not be based on arbitrary thresholds. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov , NCT02487797.
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8.
LIBERTY Randomized Withdrawal Study: Relugolix Combination Therapy for Heavy Menstrual Bleeding Associated With Uterine Fibroids
Al-Hendy, A., Venturella, R., Arjona Ferreira, J. C., Li, Y., Soulban, G., Wagman, R. B., Lukes, A. S.
American journal of obstetrics and gynecology. 2023
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Abstract
BACKGROUND In the pivotal LIBERTY 1 and 2 trials and long-term extension (LTE) study, once-daily relugolix combination therapy (relugolix CT: relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) reduced menstrual blood loss (MBL) volume and pain in women with uterine fibroids (UF). Relugolix CT was well tolerated, with preservation of bone mineral density (BMD) through 52 weeks. OBJECTIVE To report the 2-year relugolix CT efficacy and safety results of the phase 3 LIBERTY randomized withdrawal study (RWS). STUDY DESIGN Women with UF-associated heavy menstrual bleeding (HMB) who completed the 24-week LIBERTY 1 or 2 trials followed by the 28-week LTE study (up to 52 weeks total treatment), and who met responder criteria (MBL volume <80 mL and ≥50% reduction from pivotal study baseline at week 48 (Week 24 of LTE) were randomized 1:1 to blinded treatment with relugolix CT or placebo for 52 weeks (total treatment period:104 weeks). For women who had a relapse of HMB during the study (MBL volume ≥80 mL), open-label relugolix CT was offered. Primary endpoint was the proportion of women who maintained MBL volume <80 mL through week 76 (Week 24 of RWS). Secondary endpoints included time to MBL volume ≥80 mL, proportion of women who maintained a MBL volume of <80 mL through week 104 (over the 52-week randomized treatment period), the proportion of women achieving or maintaining amenorrhea at week 76/end-of-treatment and change in UFS-Qol BPD and symptom severity scores. Analyses were performed in the modified intent-to-treat (mITT) population including all randomized women who received ≥1 dose of study drug. RESULTS Of the 229 randomized women (relugolix CT:115, placebo:114), 228 received study drug and 175 (76.7%) completed the RWS. Through week 76, 78.4% of women on relugolix CT maintained MBL volume <80 mL vs 15.1% in the placebo group difference of 63.4% [95%CI:52.9%-73.9%];p < 0.0001). At week 104, 69.8% of women on relugolix CT maintained MBL volume <80 mL vs 11.8% in the placebo group (difference of 58.0% [95%CI:47.0%-69.1%];p<0.0001 ). Through week 104, 88.3% of women on placebo relapsed with HMB (median time to relapse of 5.9 weeks). Among the 89 women in the placebo group who relapsed and received open-label rescue treatment, 87 women responded to relugolix CT, with an MBL volume <80 mL. The proportion of women who achieved or maintained amenorrhea were 57.4% vs 13.3% at week 76 (difference of 44.1% [95%CI:33.10%-55.1];p<0.0001) and 58.3% vs 10.6% at week 104 (difference 47.6% [95%CI:37.0%-58.3%];nominal p<0.0001) for relugolix CT and the placebo group, respectively. Relugolix CT was generally well tolerated; no new safety signals were identified, and the adverse event profile over the second year was consistent with that reported through the first year of treatment. BMD remained stable in women who received relugolix CT from week 52 to week 104. In women continuously treated with relugolix CT up to 2 years, BMD was generally preserved. CONCLUSIONS After 2 years of treatment with relugolix CT, there was evidence of durability of effect in maintaining low MBL volume in women with symptomatic UF. Most women had return of HMB and associated symptoms after treatment cessation, which improved upon retreatment with relugolix CT. Relugolix CT was well tolerated, the adverse event profile remained consistent and mean BMD was generally preserved through 2 years of treatment.
PICO Summary
Population
Women with uterine fibroid-associated heavy menstrual bleeding who completed the 24-week LIBERTY 1 or 2 trials (n= 229).
Intervention
Relugolix combination therapy (CT), (n= 115).
Comparison
Placebo (n= 114).
Outcome
The LIBERTY randomized withdrawal study was conducted to evaluate the 2-year relugolix CT efficacy and safety results. Relugolix CT was generally well tolerated; no new safety signals were identified, and the adverse event profile over the second year was consistent with that reported through the first year of treatment. Bone mineral density (BMD) remained stable in women who received relugolix CT from week 52 to week 104. In women continuously treated with relugolix CT up to 2 years, BMD was generally preserved.
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9.
The Effect of Oxytocin plus Carboprost Methylate in Preventing Postpartum Hemorrhage in High-Risk Pregnancy and Its Effect on Blood Pressure
Wei L, Yang H, Sun X
Evidence-based complementary and alternative medicine : eCAM. 2022;2022:9878482
Abstract
Objective. This study aimed to explore and analyze the effectiveness of oxytocin plus carboprost methylate in preventing postpartum hemorrhage in high-risk pregnancies and its effect on blood pressure. A total of 60 women with high-risk pregnancies who gave birth in our hospital from January 2020 to May 2021 were recruited and assigned via random number table method (1 : 1) to receive either oxytocin (control group) or oxytocin plus carboprost methylate (observation group). Outcome measures included hemorrhage and blood pressure. The bleeding volume of the women in the observation group (210.55 ± 45.98, 45.21 ± 9.27, and 73.74 ± 12.18) was significantly less than that in the control group during delivery and 2h and 24h after the delivery (276.91 ± 49.21, 72.98 ± 19.68, and 92.61 ± 15.67) (all P < 0.05). The observation group showed a significantly lower bleeding rate (6.67%) than the control group (16.67%) (P < 0.05). The two groups showed similar diastolic and systolic blood pressures (P > 0.05). Oxytocin plus carboprost methylate suppository effectively prevents postpartum hemorrhage in high-risk pregnancies, significantly reduces the amount of postpartum hemorrhage in high-risk pregnancies, and has little effect on the blood pressure of patients. Given its favorable treatment efficiency and high safety profile, this treatment protocol shows great potential for clinical application.
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10.
[Multicenter, Randomized, Double-Blind, and Positive Drug-Controlled Clinical Trial on Prevention of Postpartum Hemorrhage after Vaginal Delivery with Ergometrine Maleate]
Li T, Wei Q, Wu L, Chen M, Zhang LP, Zhang Q, Liu XH
Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition. 2022;53(2):316-320
Abstract
OBJECTIVE To evaluate the safety and efficacy of using ergometrine maleate injection combined with oxytocin injection, with oxytocin injection as the control, to prevent postpartum hemorrhage after vaginal delivery. METHODS A total of 305 cases who underwent vaginal delivery between December 2018 and November 2019 in 16 hospitals across China were enrolled and included in the full analysis set (FAS) and the safety analysis set (SS). Among the 299 subjects who completed the trial, 277 were included in the per protocol set (PPS). The subjects were randomly assigned by 1∶1 ratio to two groups, 152 cases in Group A, the experimental group receiving oxytocin injection plus ergometrine injection, and 153 cases in Group B, the control group, receiving oxytocin injection. The difference in total bleeding volume at 2 h, 6 h and 24 h postpartum in the two groups was documented and compared. Other measures were also compared between the two groups, including the proportion of additional use of uterotonics and hemostatic drugs or other hemostatic measures 2 h and 24 h postpartum, the proportion of subjects needing blood transfusion, the time of placenta retention, proportion of subjects with prolonged hospital stay due to uterine asthenia, the vital signs, lab test indicators and the incidence of adverse reactions in the two groups. RESULTS The total bleeding volume at 2 h, 6 h and 24 h after delivery was significantly lower in the experimental group (P<0.05). There was no significant difference between the two groups in the proportion of additional use of uterotonics and hemostatic drugs or other hemostatic measures 2 h and 24 h postpartum, the proportion of subjects needing blood transfusion and the time of placenta retention, heart rate, respiration, lab test indicators, or the incidence of adverse reaction (P>0.05). CONCLUSION Ergometrine maleate injection showed evident therapeutic efficacy in preventing hemorrhage after vaginal delivery, causing fewer adverse reactions and ensuring greater safety, and therefore, presenting promising prospects for clinical application.