Higher-Dose Oxytocin and Hemorrhage After Vaginal Delivery

A Randomized Controlled Trial
Alan T. N. Tita, MD, PhD, Jeff M. Szychowski, PhD, Dwight J. Rouse, MD, MSPH, Cynthia M. Bean, MD, Victoria Chapman, MPH, Allison Nothern, MSN, RN, Dana Figueroa, MD, Rebecca Quinn, PharmD, William W. Andrews, PhD, MD, and John C. Hauth, MD
OBJECTIVE: Higher-dose oxytocin is more effective than lower-dose regimens to prevent postpartum hemorrhage after cesarean delivery. We compared two higher-dose regimens (80 units and 40 units) to our routine regimen (10 units) among women who delivered vaginally. METHODS: In a double-masked randomized trial, oxytocin (80 units, 40 units, or 10 units) was administered in 500 mL over 1 hour after placental delivery. The primary outcome was a composite of any treatment of uterine atony or hemorrhage. Prespecified secondary outcomes included outcomes in the primary composite and a decline of 6% or more in hematocrit. A sample size of 600 per group (N 1,800) was planned to compare each of the 80-unit and 40-unit groups to the 10-unit group. At planned interim review (n 1,201), enrollment in the 40-unit group was stopped for futility and enrollment continued in the other groups. RESULTS: Of 2,869 women, 1,798 were randomized as follows: 658 to 80 units; 481 to 40 units; and 659 to 10 units. Most characteristics were similar across groups. The risk of the primary outcome in the 80-unit group (6%; relative risk [RR] 0.93, 95% confidence interval [CI] 0.62– 1.40) or the 40-unit group (6%; RR 0.94, 95% CI 0.61–1.47) was not different compared with the 10-unit group (7%). Treatment with additional oxytocin after the first hour was less frequent with 80 units compared with 10 units (RR 0.41, 95% CI 0.19 – 0.88), as was a 6% or more decline in hematocrit (RR 0.83, 95% CI 0.69 – 0.99); both outcomes declined with increasing oxytocin dose. Outcomes were similar between the 40-unit and 10-unit groups. CONCLUSION: Compared with 10 units, 80 units or 40 units of prophylactic oxytocin did not reduce overall postpartum hemorrhage treatment when administered in 500 mL over 1 hour for vaginal delivery. Eighty units decreased the need for additional oxytocin and the risk of a decline in hematocrit of 6% or more. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00790062.
(Obstet Gynecol 2012;119:293–300) DOI: 10.1097/AOG.0b013e318242da74

From the Center for Women’s Reproductive Health and Maternal-Fetal Medicine Division, Department of Obstetrics and Gynecology, Department of Biostatistics, Investigational Drug Pharmacy, University Hospital, University of Alabama at Birmingham, Birmingham, Alabama; and the Department of Obstetrics and Gynecology, Brown University, Providence, Rhode Island. Funded in part by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by a faculty development grant at the University of Alabama at Birmingham. Presented in part at the Annual Meeting of the Society of Maternal-Fetal Medicine, February 7–12, 2011, San Francisco, California. The authors thank the residents of the Department of Obstetrics and Gynecology, Janatha Grant, RN, and Mona Wallace, RN, for patient enrollment; Sarah Robertson, RN, Laura Money, RN, and the Labor and Delivery nurses at University of Alabama Birmingham Hospital for assistance with enrollment procedures; and Robin Steele and Sue Cliver for data management. Corresponding author: Alan Thevenet N. Tita, MD, PhD, 619 19th Street South, 176F, 10270, Birmingham, AL 35249; e-mail: atita@uab.edu. Financial Disclosure The authors did not report any potential conflicts of interest. © 2012 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/12


bstetric hemorrhage is the leading cause of maternal death worldwide and is among the top three causes of these deaths in the United States.1,2 Postpartum hemorrhage is the most common type of obstetric hemorrhage, and uterine atony accounts for more than 80% of postpartum hemorrhage.3 Prophylactic use of uterotonic agents prevents uterine atony and reduces the risk of postpartum hemorrhage by 40 –50%.4 –7 Compared with methylergometrine and misoprostol, oxytocin has a good safety profile and induces fewer, if any, side effects.6,8,9 In the United


VOL. 119, NO. 2, PART 1, FEBRUARY 2012



For cesarean delivery. including treatment with any uterotonic. thus ensuring equal allocation among the study arms. randomized controlled trial that included women with viable pregnancies undergoing vaginal delivery at 24 weeks of gestation or more at University Hospital. the study medication bag was then administered to the patient over 1 hour using an infusion pump for precision. clinically estimated blood loss. vasopressor treatment. If this were so. Women were randomized to one of the three study arms according to a confidential computergenerated block randomization algorithm. were numbered according to the randomization scheme provided. the optimal prophylactic oxytocin dose regimen is unknown. The investigational drug pharmacists prepared identical oxytocin bags by adding 10 units. The randomization scheme was sequentially numbered and delivered to the pharmacy. During this hour. Need to treat uterine atony or postpartum hemorrhage with uterotonics is recommended as a priority outcome measure for postpartum hemorrhage by a World Health Organization international panel. the standard dose (10 units in 500 mL) was associated with a twofold increase in the risk of uterine atony or postpartum hemorrhage requiring treatment with uterotonics (including additional oxytocin) and nearly a fivefold increase in the need for second-line uterotonics such as methergine and hemabate. double-blind.12 it remains unknown whether a higher dose of prophylactic oxytocin is similarly more effective among women who deliver vaginally. surgery.States. or blood transfusion. the protocol for postpartum hemorrhage requires routine application of fundal massage after delivery.10 The dose regimen corresponds to that routinely used after vaginal delivery at our institution: 10 units of oxytocin in 500 mL of crystalloid solution administered over 1 hour.11 Although vaginal deliveries account for more than two thirds of all births. we could have a single. The primary outcome was a composite outcome of uterine atony or hemorrhage requiring treatment. we compared the effectiveness of two higher-dose prophylactic oxytocin regimens to the standard dose regimen for vaginal deliveries. endometritis. At the time of vaginal delivery of each consented patient. On delivery of the placenta. Twenty units of oxytocin administered in 1 L of crystalloid solution “at a rate of 10 mL per minute for a few minutes to get an adequate uterine tone. use of additional oxytocin to treat uterine atony or hemorrhage was avoided (second-line uterotonics such as hemabate or methergine were used). a decline of 6% unit or more in hematocrit after delivery. At this point.11 In that study. after 1 hour). interventional radiology for uterine or other arterial embolization. The algorithm randomly allocated three women to each study dose in blocks of nine. or 80 units of oxytocin into a malleable bag of 500 mL of normal saline. oxytocin is the uterotonic routinely used for prophylaxis. The bags were prepared in advance of patient randomization. 40 units. pulmonary edema. The Institutional Review Board of the University of Alabama at Birmingham approved the study. Those who underwent cesarean delivery or who had a fetal demise. additional oxytocin could be utilized for treatment after completion of the prophylactic infusion (ie. the patient was considered randomized. The sequential drug number together with the patient’s name and medical record number were entered into the randomization log. dedicated oxytocin-dose concentration to prevent postpartum hemorrhage. and safety outcomes (need for fluid bolus. and fluid overload requiring diuretic therapy). had knowledge of the code matching the sequential number to oxytocin dose or the size of the randomized blocks. a higher dose regimen (80 units oxytocin in 500 mL of crystalloid) is used at our institution based on positive findings from a randomized trial that included 321 women who underwent cesarean delivery. Despite its widespread use. Therefore. MATERIALS AND METHODS We conducted a single-center.13 At our institution. Eligible women were approached and consented at the time of admission for delivery (spontaneous labor or induction). the next sequentially numbered oxytocin bag was dispensed to the nurse. Alabama. Key prespecified secondary outcomes included individual outcomes in the primary composite. then reduced to 1–2 mL per minute during postpartum recovery in the delivery suite and then discontinued before transfer to the postpartum suite” is a commonly recommended dose regimen. bimanual palpation is used if there is uterine atony or 294 Tita et al Prophylactic Oxytocin for Vaginal Delivery OBSTETRICS & GYNECOLOGY . However. Birmingham. Only the investigational pharmacist and one statistician. We hypothesized that higher doses of oxytocin (80 units or 40 units) as compared with the standard 10-unit dose would safely reduce uterine atony or postpartum hemorrhage requiring treatment. compared with women who received the higher dose regimen. and were stored at room temperature in a dedicated and secure research study closet on the labor and delivery unit. hospital stay. a diagnosis of coagulopathy. who had no role in patient enrollment or outcome ascertainment. or cardiomyopathy were excluded. uterine tamponade (typically with a Bakri balloon).

and KruskalWallis tests were used as applicable for baseline and outcome comparisons among the three treatment groups. fewer women in the 80-unit group. interventional treatment. At the planned interim review (n 1.05 level of significance.200 women. The Lan-DeMets spending function approximation to O’Brien-Fleming stopping boundaries14 was used to adjust the level of significance of each primary analysis at both the interim review (significance level 0. but not in the 40-unit group. 481 to the 40-unit group (discontinued) and 659 to the 10-unit group (Fig. Fisher exact and Wilcoxon rank-sum tests were used when appropriate.017) and at study termination (significance level 0. approximately two thirds of the total planned sample size. boundaries for early termination were not exceeded. We computed relative risks and 95% confidence intervals for pair-wise comparisons of outcomes. from 35% to 29%) was chosen because it corresponds on average to a 2-unit blood loss. Endometritis was based on a clinical diagnosis by the obstetric providers and the use of antibiotics for treatment. SAS 9. and enrollment was continued in the 10-unit and 80-unit dose arms to the original total sample size of 1. and a hypothesized 33% reduction in the primary outcome. The baseline rate of 18% in the 10-unit group was estimated from a review of outcomes among vaginal deliveries conducted over 1 month at our institution.869 women were screened and 1. For both primary pair-wise comparisons. Baseline characteristics including risk factors for postpartum hemor- rhage15. which we consider to be clinically significant in the context of a vaginal birth. or a total of 1. Tests for trends in dichotomous outcomes across groups were based on the Mantel Haenzsel test and tests for ordered differences in quantitative measures were based on the nonparametric Jonckheere-Terpstra test. However. did not differ by dose of prophylactic oxytocin. 2.798 were randomized as follows: 658 to 80 units of prophylactic oxytocin.ongoing hemorrhage. Overall. A 6% unit decline in hematocrit (eg. There was also a significant decreasing trend in the need for treatment with oxytocin (3% to 2% to 1%) with increasing dose of prophylactic oxytocin. Mean change in hematocrit after delivery was not significantly different between groups. with the exception of the primary outcome as previously described. and the frequency of spontaneous membrane rupture and prolonged second stage of labor was lower in the 10-unit group (Table 1). RESULTS From November 2008 through June 2010. ie. were evaluated at a 0. However.05 level of significance. Analyses were by intent-to-treat.16 and outcomes were compared between groups. higher doses of oxytocin did not significantly decrease the unadjusted risk of the primary outcome. An investigation for futility concluded that the conditional power for the 40 units compared with 10 units was less than 1%. All outcomes were ascertained by chart abstraction until discharge from hospital by trained research nurses. 80 units but not 40 units of oxytocin compared with 10 units significantly decreased the need for treatment with additional oxytocin. or blood transfusion. we planned to evaluate for trend in outcomes across 10-unit. The baseline characteristics of women were similar except the incidence of chorioamnionitis was higher. 40-unit. The 2 tests and analysis of variance were used for two group tests. All other components of the primary outcome. and 80-unit dose groups. including the rare need for tamponade. Two separate primary oxytocin dose comparisons were specified: 80 units compared with 10 units and 40 units compared with 10 units.201 randomized) by the data safety and monitoring board. 119. Need for blood transfusion was based on actual administration of whole or packed red blood cells before discharge. corresponding to a decreased need for treatment after the first hour or in the postpartum suite. 1). 80% power.800.800. As a secondary comparison. compared with the 10-unit group had a VOL. The absolute decline in hematocrit was calculated by subtracting the first postpartum hematocrit (typically collected within 8 –24 hours) from the most recent predelivery hematocrit (typically drawn at the time of admission for delivery). The need for fluid bolus and need for pressor treatment were as determined and ordered by the obstetric or anesthetic provider. FEBRUARY 2012 Tita et al Prophylactic Oxytocin for Vaginal Delivery 295 . A single interim analysis was planned at enrollment of 1. PART 1. 18% to 12% for 80 units compared with 10 units and 18% to 12% for 40 units compared with 10 units). The 40-unit arm thus was stopped for futility. NO. the primary composite outcome of treatment for hemorrhage or atony occurred in 6 –7% of the study sample. we estimated a sample size of 600 per group.05 for each comparison. there was no linear dose-response trend across groups (Table 2). Compared with the 10-unit group. analysis of variance. The 2. based on an assumed primary outcome rate of 18% in the 10-unit group (alpha of 0.033) to preserve the overall 0.2 was used for all statistical analyses.17 All statistical tests. 2. surgery. Higher doses of oxytocin did not decrease treatment of uterine atony or obstetric hemorrhage with any uterotonics.

P . Prophylactic Oxytocin for Vaginal Delivery. Obstet Gynecol 2012.013) but not with a 10% or greater decline (4% compared with 5%.0 11. The respective mean times ( SD) from delivery to postdelivery hematocrit were also similar: 15. the incidences of fluid bolus by decreasing doses of oxytocin were 0%. and 0. The mean times ( SD) between predelivery and postdelivery hematocrit revealed no differences by group: 25. for 10-unit. endometritis. fluid bolus or pressor treatment for hypotension. Other secondary outcomes including estimated blood loss (mean and clinically estimated blood loss more than 500 mL).3% (P for trend . 1. as compared with the standard dose of 10 units of oxytocin when administered in 500 mL of crystalloid over the course of 1 hour after vaginal delivery. We conducted additional (post hoc) analyses to further evaluate our findings. primarily on the postpartum floor in the postrecovery period.05). Because need for fluid bolus or pressor treatment in labor was primarily the result of epidural. However. P . and 25.5 8.3 11. respectively. 25.869 Informed consent granted and patients randomized n=1. and 16. higher doses of prophylactic oxytocin (80 units or 40 units).Patients screened N=2. Results for pressor treatment were identical. there was a reduction in the need for oxytocin to treat uterine atony or postpartum hemorrhage. There were no significant differences between higher doses (80 or 40 units) and the 10-unit standard dose oxytocin for the primary composite outcome or need for any uterotonic to treat postpartum hemorrhage.8 (P . 80 units of oxytocin reduced the frequency of two prespecified secondary outcomes: hemorrhage requiring treatment after the first postpartum hour and a decline in hematocrit more than 6% units. we restricted the study population to women who did not receive an epidural. The incidence of this clinically important decline in hematocrit decreased modestly but significantly from 28% to 23% as prophylactic oxytocin dose increased from 10 units to 80 units (P .0. Tita. There was a significant dose-response trend in these outcomes 296 Tita et al Prophylactic Oxytocin for Vaginal Delivery OBSTETRICS & GYNECOLOGY .301).891). Relative risks (95% confidence interval) for the relationship between key study outcomes and higher doses of oxytocin compared with the 10-unit dose are given (Table 4). 16. Finally. We compared the incidence of hematocrit decline greater than the prespecified 6% cut-off: 80 units compared with 10 units of prophylactic oxytocin was associated with a lower incidence of an 8% or greater decline in hematocrit (9% compared with 13%.0 8.351).1. did not significantly reduce the incidence of the primary composite outcome of uterine atony or hemorrhage requiring any treatment.3.5 hours. Flow of patients through the oxytocin trial. 40-unit.3 9. results of analyses adjusting for the baseline differences were consistent with our main findings. 0%.071 Refused consent: n=347 Ineligible: n=724 Cesarean delivery: 520 Other reasons: 204 Allocated to 80 units oxytocin n=658 Did not receive study oxytocin (cesarean delivery) n=1 Received 80 units oxytocin n=657 Allocated to 40 units oxytocin n=481 Allocated to 10 units oxytocin n=659 Did not receive study oxytocin (cesarean delivery) n=1 Received 40 units oxytocin n=481 Received 10 units oxytocin n=658 Analyzed n=658 Analyzed n=481 Analyzed n=659 Fig.0. However.798 Excluded: n=1. DISCUSSION Overall. 6% or greater decline in hematocrit (Table 3). Results for a 6% or more decline in hematocrit suggested a lower incidence with 80 units but not with 40 units compared with 10 units of oxytocin (Table 4). and prolonged hospitalization (4 or more days) did not differ by dose of prophylactic oxytocin. fluid overload. and 80-unit groups (P .2 12.999).

80 Units (n 658) 379 (58) 156 (24) 120 (18) 3 (less than 1) 30 (5) 245 (37) 360 (55) 208 (32) 90 (14) 24.5 33.000* .901 .4 5.366* 1. PART 1. decline in hematocrit.673 .691 .525 .768* Trend . these studies have associated higher doses of prophylactic oxytocin with beneficial effect on outcomes such as estimated blood loss. FEBRUARY 2012 Tita et al Prophylactic Oxytocin for Vaginal Delivery 297 .4 3. not available.408 .11.5 3.000* 1.366* .18 –20 Typically.563 .000* .559 45 (7) 45 (7) 22 (3) 42 (6) 27 (4) 23 (3) 0 (0) 0 (0) 0 (0) 1 (less than 1) 7 (1) VOL.745 .580 . or need for additional uterotonics among Table 2.533 . P Compared With 10 Units 10 Units (n 659) 80 Units .744 . * Reflects exact test.798 .000* . Results for Primary Composite Outcome and Its Components Outcome Frequency (%) Outcome Primary composite Any uterotonic Oxytocin Other uterotonics Methergine* Hemabate* Arterial ligation Hysterectomy Foley tamponade Arterial embolization Blood transfusion NA.019 . Additionally. NO.567 .4 33.Table 1. Baseline Characteristics of the Oxytocin Trial Population (n 1.5 47 (10) 50 (10) 43 (9) 406 (84) 136 (28) 270 (56) 15 (3) 23 (5) 74 (15) 412 (86) 395 (82) 41 (9) 179 (37) 477 (99) 10 Units (n 659) 404 (61) 143 (22) 106 (16) 6 (less than 1) 29 (4) 264 (40) 391 (59) 172 (26) 96 (15) 23. higher dose regimens were not associated with an increase in adverse events such as hypotension or fluid overload.595 .564 80 Units (n 658) 42 (6) 40 (6) 9 (1) 37 (6) 24 (4) 19 (3) 1 (less than 1) 1 (less than 1) 0 (0) 1 (less than 1) 5 (less than 1) 40 Units (n 481) 31 (6) 30 (6) 12 (2) 27 (6) 19 (4) 13 (3) 0 (0) 0 (0) 1 (less than 1) 0 (0) 4 (less than 1) 40 Units . 119.672 .9 5.422* 1.6 83 (13) 75 (11) 67 (10) 561 (85) 219 (33) 342 (52) 11 (2) 40 (6) 106 (16) 580 (88) 556 (85) 51 (8) 227 (35) 653 (99) 40 Units (n 481) 278 (58) 97 (20) 101 (21) 5 (1) 27 (6) 164 (34) 285 (60) 143 (30) 53 (11) 23.4 58 (9) 93 (14) 78 (12) 560 (85) 217 (33) 343 (52) 17 (3) 59 (9) 119 (18) 580 (88) 553 (84) 30 (5) 178 (27) 655 (99) (reducing incidence with increasing dose of prophylactic oxytocin).500* NA 1.018 .500* .1 33. Findings from the few available studies examining various outcomes in relation to dose regimens suggest that both dose and rate of administration (including intravenous bolus) play a role. 2.9 5.798) Characteristic Race African American White Hispanic Other Previous cesarean delivery Nulliparous Body mass index (kg/m2) Obese Overweight Normal and underweight Age (y) Hematocrit before delivery Preterm labor Preeclampsia Magnesium sulfate use Oxytocin use in labor Induction Augmentation Hydramnios Chorioamnionitis Amnioinfusion Any anesthesia Epidural Prolonged second stage of labor Spontaneous membrane rupture Singleton Data are n (%) unless or mean standard deviation.578 .453 NA NA .6 3.

80 units as compared with 10 units of prophylactic oxytocin reduced the need for any uterotonic treatment.62–1. Our original estimated sample size was based on an 18% incidence of the 298 Tita et al Prophylactic Oxytocin for Vaginal Delivery OBSTETRICS & GYNECOLOGY .79–1.617 .8 24 (5) 1 (less than 1) 10 Units (n 659) 4 (1–8) 185 (28) 116 (18) 82 (12) 0 (0) 85 (13) 3 (less than 1) 413.5 24 (4) 8 (1) 40 Units (n 481) 4 (1–8) 129 (27) 95 (20) 51 (11) 0 (0) 56 (12) 6 (1) 405.88) 0.410§ Trend .726§ .673 .046 . * Median (interdecile range).751§ . women who underwent cesarean delivery. Results for Other Key Secondary Outcomes P for Comparison to 10 Units Outcome Hematocrit change* Hematocrit decline less than 6% Hospitalization more than 4 d Fluid bolus Diuretic treatment Pressor treatment Pitocin discontinued Estimated blood loss Blood loss more than 500 mL Endometritis 80 Units (n 658) 4 (1–7) 153 (23) 109 (17) 87 (13) 1 (less than 1) 95 (14) 4 (less than 1) 401.667 .074 .50) 0.Table 3.0 137.366§ .356 . higher dose of oxytocin was associated with a higher uterine tone and a nonsignificant reduction in need for additional uterotonic. women undergoing scheduled cesarean delivery received a 5-unit intravenous bolus compared with 35 units (5 unit bolus 30 units over 4 hours) of prophylactic oxytocin. at least in part. Randomization provides balance across groups for baseline hematocrit and times to postdelivery hematocrit (a proxy for hydration during labor).75 (0.568 .61–1. in the previous trial at our institution.249† . these regimens have been generally reported to be safe.070 .1 159. the amount of blood loss needed for a 6-unit decline in hematocrit may be higher than the postulated 2 units.3 190.633 . The discrepancy in our primary outcome result could be attributed.213 .47) 0.11 It is noteworthy that women in both arms also received prophylactic low dose oxytocin (20 units in 1L) over 8 hours postparTable 4.045 . the findings for prespecified secondary outcomes (hematocrit decline of 6 units or more and need for oxytocin after the first hour) do suggest potential benefits of higher dose regimens among women after a vaginal birth.500§ . including those of concentrated oxytocin protocols for mid-trimester pregnancy termination or induction of delivery11. tum. we did not observe a significant reduction in need for any uterotonic treatment. Although contrary to the previous study. Estimates of the Primary Composite and Significant Secondary Outcomes 80 Units Compared With 10 Units 0.11.93 (0.95 (0. Mean standard deviation.409 .37–1.83 (0. Considering labor hydration.94 (0.416 . need for uterotonic treatment.11 The discrepancy may also be the consequence of our study’s limited power to discern differences in the primary outcome.5 38 (6) 5 (less than 1) 80 Units .18.377 . § Exact test.41 (0.19 Finally.18 –20 In two studies.22.623 .080‡ .19–0.229 . to differences in the risk profile of the study population and the higher rate of infusion of prophylactic dose regimens in the previous study (500 mL administered over the course of half an hour for cesarean deliveries compared with over the course of 1 hour for vaginal delivery in our study).525 . Our current study is one of the largest randomized trials comparing different doses of oxytocin to prevent postpartum hemorrhage but focuses on women who underwent vaginal delivery.072 . † Wilcoxon rank-sum test.18.40) 0.20 Women in the higher dose group had significantly lower mean estimated blood loss and lower frequencies of blood loss more than 500 ml or more than 1.346 Data are n (%) or mean standard deviation unless otherwise specified.16) Data are relative risk (95% confidence interval).21.000 mL. as well as the need for treatment with second-line agents among women who underwent cesarean delivery after labor.402 † 40 Units . Support for the safety of higher doses of oxytocin is evident from previous studies.99) Outcome Primary composite Additional oxytocin 6% or more hematocrit decline 40 Units Compared With 10 Units 0.179§ . ‡ Jonckheere-Terpstra test. or blood transfusion.69–0.20 In another small study of cesarean deliveries.339 Not available .

This is particularly applicable in settings in which the high dose is already being used for cesarean deliveries. Obstet Gynecol 2003.CD00180. McDonald S.1002/14651858. DOI: 10. Because both the dose and duration of administration may play a role. no such data are available for the 80-unit in 500 mL concentration. Although timing of administration does not appear to make a difference. Given the inherent difficulty in validly estimating postpartum blood loss. Art. Higgins SP. DOI: 10. doses as high as 80 units administered over the course of 30 minutes are used for cesarean deliveries. Elbourne DR.25. Postpartum hemorrhage. Art. 6. 3. Carroli G. ACOG Practice Bulletin No. McDonald S. we opted to continue the enrollment in the two remaining arms to the original total sample size. Prendiville WJ. Our results indicate that 51 women receiving 80 units of prophylactic oxytocin are needed to prevent one episode of use of additional oxytocin to treat hemorrhage after the first postdelivery hour. PART 1.primary outcome in the low-dose group.26 As a result. This included use of additional oxytocin to treat atony occurring while the prophylactic infusion was ongoing.24 we cannot guarantee that our results with higher doses would be the same if we initiated prophylactic oxytocin before placental delivery. the incidence of uterine atony requiring treatment was not significantly reduced when 80 units were administered over the course of 1 hour. evaluation. Therefore. NO. although we observed a reduction in the need for oxytocin in the postpartum suite and a reduction in a decrease in hematocrit more than 6 units with higher-dose oxytocin.23. At interim review. Pregnancyrelated mortality in the United States. second-line uterotonics were administered if treatment was indicated in the first hour. Issue 3. Issue 4. Prophylactic use of oxytocin in the third stage of labour. 76. and why. stability studies of highdose oxytocin regimens are needed to facilitate its efficient clinical use and evaluation. oxytocin was administered only after placental delivery. Apart from power considerations. Abbott JM. The outcome rate of 7% would have required approximately double our current sample size to be able to detect a 33% reduction in the incidence of the primary composite outcome. and reporting of this use in larger populations will be necessary to further demonstrate the safety and the effectiveness (vis-a-vis outcomes such as our pri` mary outcome and blood transfusion) of higherdose regimens for vaginal delivery. Alternatively.368:1189 –200.CD000007. Lancet Maternal Survival Series steering group. 4. The Cochrane Database of Systematic Reviews 2000.11. This would enhance efficiency by allowing for a single premixed oxytocin dose bag for prophylaxis (as opposed to one for cesarean deliveries and another for vaginal deliveries) considering the low cost of oxytocin. No.18 –20 Therefore. Prendiville WJ. We estimated that the sample size cumulated in these two groups would provide 80% power to detect a 50% reduction in the primary outcome from the new baseline of 7%. Callaghan WM. McDonald S.108:1039 – 47. FEBRUARY 2012 Tita et al Prophylactic Oxytocin for Vaginal Delivery 299 . Prophylactic ergometrineoxytocin versus oxytocin for the third stage of labour. Whitehead SJ. higher doses of prophylactic oxytocin appear to be beneficial in preventing measures of postpartum hemorrhage among women delivered by cesarean. 1991–1997.: CD000007. Nevertheless. REFERENCES 1. Although concentrations of 80 units in 1. Based on the negative findings concerning our primary outcome. Lancet 2006. Graham WJ. The smaller than expected incidence of uterotonic treatment likely reflects a higher threshold to use methergine or prostaglandins as first-line treatment for hemorrhage or atony. we used clinical outcomes as a proxy for blood loss. in our study of women undergoing vaginal delivery.000 mL or less (ie. particularly when administered within 30 minutes. Overall. where. 2. No. Elbourne D. In our protocol. 40 units in 500 mL or less) have been demonstrated to be stable for at least 7 days (and therefore a premixed bag can have a shelf-life of 7 days). Berg CJ. The VOL. Wood J. Obstet Gynecol 2006. future evaluation should also assess the effect of varying duration of administration. American College of Obstetricians and Gynecologists. Instead. practitioners may opt not to use a high dose of oxytocin after vaginal delivery. hospital pharmacies will typically accord no more than a 2-day shelf-life for premixed oxytocin concentration more than 40 units in 500 mL. However. Active versus expectant management in the third stage of labour. 2. we did not administer additional oxytocin during the first hour (concurrent with the prophylactic infusion).: CD001808. when. The Cochrane Database of Systematic Reviews 2001. However.101:289 –96. our study had other limitations. Chang J. others may choose to use 80 units considering the potential for benefits based on the positive findings for secondary outcomes. 5. based on pharmacy recommendations. considering the 80% reduction in need for second-line agents to treat from a baseline of 9% in the previous trial and the futility of the intermediate study dose for the primary outcome. 119. 21 are needed to prevent one episode of hematocrit decline more than 6% units. Maternal mortality: who. An important consideration for the efficient use of 80-unit oxytocin dose for postpartum prophylaxis concerns its stability when concentrated in 500 mL of crystalloid. Ronsmans C. ongoing monitoring.1002/14651858.

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