Does route matter? Impact of route of oxytocin administration on postpartum bleeding: A double-blind, randomized controlled trial.

OBJECTIVE: We assessed the impact of intravenous (IV) infusion versus intramuscular (IM) oxytocin on postpartum blood loss and rates of postpartum hemorrhage (PPH) when administered during the third stage of labor. While oxytocin is recommended for prevention of PPH, few double-blind studies have compared outcomes by routes of administration.
METHODS: A double-blind, placebo-controlled randomized trial was conducted at a hospital in Argentina. Participants were assigned to receive 10 IU oxytocin via IV infusion or IM injection and a matching saline ampoule for the other route after vaginal birth. Blood loss was measured using a calibrated receptacle for a 1-hour minimum. Shock index (SI) was also calculated, based on vital signs measurements, and additional interventions were recorded. Primary outcomes included: the frequency of blood loss ≥500ml and mean blood loss.
RESULTS: 239 (IV infusion) and 241 (IM) women were enrolled with comparable baseline characteristics. Mean blood loss was 43ml less in the IV infusion group (p = 0.161). Rates of blood loss ≥500ml were similar (IV infusion = 21%; IM = 24%, p = 0.362). Women in the IV infusion group received significantly fewer additional uterotonics (5%), than women in the IM group (12%, p = 0.007). Women with PPH in the IM group experienced a larger increase in SI after delivery, which may have influenced recourse to additional interventions.
CONCLUSIONS: The route of oxytocin administration for PPH prevention did not significantly impact measured blood loss after vaginal birth. However, differences were observed in recourse to additional uterotonics, favoring IV infusion over IM. In settings where IV lines are routinely placed, oxytocin infusion may be preferable to IM injection.

RCT Entities:   Population Interventions Outcomes

Introduction

Postpartum hemorrhage (PPH) is a major cause of maternal death and morbidity worldwide and is most commonly a result of uterine atony [1,2]. The administration of oxytocin during the third stage of labor is widely promoted to support uterine contractions after childbirth and reduce the risk of bleeding [3]. Comparative studies of oxytocin either in combination with other components of active management or alone show that it is safe and effective in reducing PPH [4]. While obstetric guidelines universally recommend oxytocin as the uterotonic of choice to prevent PPH, questions remain regarding the optimal route for its administration. Indeed, a comparison of guidelines, released by professional associations and leading health authorities, reveals significant heterogeneity in the recommendations for administering prophylactic oxytocin [5]. For instance, some guidelines specify only intramuscular (IM) administration for prevention of PPH [6-8], whereas others, including the World Health Organization, recommend both IM injection and intravenous (IV) routes as equal alternatives to deliver oxytocin during the third stage of labor [3,9].

The administration of oxytocin via IM injection has become increasingly widespread due to its favorable safety profile and the practical advantages over IV administration, particularly in lower levels of care where IV placement may be less feasible. Yet, evidence also supports IV administration, and some researchers report improved clinical outcomes that favor IV routes over IM [10-13], including the authors of a large systematic review of comparative studies on prophylactic oxytocin [4]. An earlier pharmacokinetic investigation, published in 1972, on circulating oxytocin levels, also found that plasma levels rose more rapidly following IV administration in the third stage of labor and reached a higher peak than after IM [14]. Importantly though, a 2018 Cochrane review identified a lack of randomized controlled trials that compared the safety and effectiveness of prophylactic oxytocin when administered via different routes [15]. It is also noted that relatively few studies of prophylactic oxytocin have been blinded [4]. The authors of both systematic reviews called for more high quality research to determine if route of administration matters [4,15].

To address this gap in the evidence, we evaluated the effect of route of prophylactic administration of oxytocin on PPH outcomes, and, more specifically, whether IV infusion results in less postpartum blood loss than IM injection.

Materials and methods

A double-blind, placebo-controlled randomized trial was conducted to compare IV infusion and IM injection of 10 IU oxytocin during the third stage of labor after vaginal delivery to assess the impact of route on postpartum blood loss and rates of PPH. A local ethics committee (Centro Rosarino de Estudios Perinatales) in Argentina approved the study prior to its implementation in a public, tertiary-level hospital in Corrientes, Argentina (Hospital Materno Neonatal E.T. de Vidal). The trial was registered with Clinical trials.gov (NCT02954068) on 3 Nov. 2016 (URL: https://clinicaltrials.gov/ct2/show/NCT02954068).

Participants and enrollment

All women presenting in active labor with a live fetus at the study hospital were invited to participate in the study and screened for eligibility. Women were ineligible if they had a cesarean delivery or were unable to give informed consent for any reason. There were no other exclusion criteria based on risk factors or delivery complications. Women were asked to confirm their willingness to respond to a few questions about their pregnancy history, have their hemoglobin measured with a Hemocue® (Angelholm, Sweden) device, and have an IV line in place at delivery (standard at this hospital). Participants’ background characteristics and baseline assessments prior to delivery were documented only after written informed consent was obtained. Data collection was undertaken by trained maternity ward staff.

Study interventions, randomization, and blinding

Ampoules of oxytocin and matching placebo (saline solution) were supplied for the study by a local pharmaceutical company (Instituto Biologico Argentino S.A.I.C., CABA, Argentina). Consecutively numbered study packets were prepared to maintain blinding; each packet included two identical ampoules–one 10 IU oxytocin ampoule and a matching placebo ampoule, one of which was labeled for IV infusion and the other for IM administration in accordance with the randomization scheme. The computer-generated randomization code in blocks of ten was created by Gynuity Health Projects in New York and not revealed until after data collection and database cleaning were completed. The study packets were labeled with a unique identification number, placed in sequential order in a dispenser, allowing individual extraction, and kept in a locked refrigerator per recommended storage requirements for oxytocin to maintain its quality and effect. The randomization code was not shared with hospital staff or local investigators, and regular monitoring ensured that packets were used in sequential order.

When birth was imminent, the next packet was removed from the dispenser and the woman was randomized to the study group. Staff was trained to remove both ampoules and prepare them for immediate administration after the birth of the baby per the labeled route on each ampoule. Because medicines given via IM injection are absorbed more slowly, staff was trained to administer the IM ampoule first, usually in the thigh. The second ampoule labeled for IV infusion was mixed in a 500cc bag of saline solution and initiated immediately after the IM injection and administered with an 18–20 gauge needle at a rate of approximately 12cc per minute for 40 minutes.

Post-randomization study procedures

Immediately after the birth of the baby, postpartum blood loss was measured using a polyurethane receptacle (Brasss-V Drapes®, Excellent Fixable Drapes, India) with calibrated markings in increments of 100cc. Blood, along with any clots, was funneled into the drape for a minimum of 1 hour or until active bleeding ceased. Pulse and blood pressure were measured at 15-minute intervals for one hour postpartum, using an automated blood pressure instrument (Omron BP785, Omron Healthcare Co., Ltd.).Women who were diagnosed with PPH were treated according to standard hospital protocol. Blood loss was measured at the time of PPH diagnosis and again when active bleeding stopped. Irrespective of PPH diagnosis, blood loss amounts were systematically recorded for all women at 30 and 60 minutes postpartum.

All actions taken to manage bleeding were documented, and the woman’s general condition was noted prior to discharge. A second hemoglobin assessment was conducted and documented 24–48 hours postpartum, and when possible, at least 12 hours after removal of any IV line.

Study outcomes and sample size

The primary outcomes were the proportion of women with a blood loss of 500ml or greater and mean total blood loss, based on objective measurement. Secondary outcomes included: average blood loss at 30 and 60 minutes postpartum, average vital sign measures, including shock index, the rate of severe PPH ≥1000ml, administration of additional uterotonics and/or other interventions, change in hemoglobin from pre- to post-delivery, and any adverse effects reported. Shock index (SI), defined as the ratio of pulse to systolic blood pressure, was analyzed at study completion and interpreted based on normal (SI<0.90) and abnormal (SI≥0.90 values described in the literature for obstetric populations [Int J Gynaecol Obstet. 2014 ">16-17].

Prior to this study, research examined the effect of oxytocin route on postpartum blood loss [10-11], including a secondary analysis that explored the effectiveness of active management interventions on postpartum blood loss when used in combination or alone. That analysis found that IV administration of oxytocin alone (i.e. in the absence of other active management components performed), compared to IM oxytocin alone, was associated with a 76% reduction in the rate of PPH (p<0.001) [11]. However, when IV or IM oxytocin was given during the third stage of labor, in combination with other interventions, such as controlled cord traction, the effect of route became negligible. Another small randomized trial was conducted to directly compare the effect of oxytocin infusion vs. IM injection on measured blood loss following vaginal deliveries that had other components of the active management of the third stage of labor performed and documented a statistically significant reduction in measured blood loss ≥ 500ml (IV infusion: 9% (15/161) and IM: 20% (32/161); RR 0.47 95% CI 0.25–0.85) [11]. Based on this evidence[10-11], we hypothesized that administration of oxytocin via IV infusion would result in a 50% lower rate of PPH (defined as blood loss ≥500ml) than IM administration and a difference of 50ml when comparing average total blood loss between study groups. According to available information from the site on their PPH rate and knowledge that PPH rates are highly variable [18] and are influenced by other practices during the third stage of labor [10], we selected an 18% PPH ≥500ml rate for sample size calculation. Assuming that IV infusion would be associated with 50% less PPH than IM injection, 442 randomized cases (221 per group) were required, based on alpha = 0.05, power = 0.80, and a two-tailed test. The sample was increased by 10% to account for any loss to follow-up or missing data that would impact the assessment of the main outcomes, resulting in a minimum enrollment of 486 women. This sample size was also sufficient to detect a difference in mean total blood loss of 50ml or greater in the two study groups.

Statistical methods

All study forms were translated into Spanish, and data from completed study forms were entered into a Microsoft Access database (version 2007). Data were then exported to SPSS 19.0 (IBM, Chicago, IL, USA) for analysis, using an intention-to-treat approach. Descriptive statistics for categorical variables were summarized as numbers and percentages and for continuous variables as means (standard deviation). Medians (interquartile ranges) were calculated for continuous variables that were determined not to be normally distributed based on skewness and kurtosis z-values (<-1.96 or >+1.96) and a Shapiro-Wilk’s test (p<0.05). Group differences for outcomes based on categorical variables were assessed using Pearson χ2 or Fisher’s exact tests (as appropriate). Continuous variables were analyzed using Independent t-tests, or if not normally distributed, using non-parametric tests (Mann-Whitney U). The relative risk and risk difference (and 95% confidence intervals) were calculated for the main study outcomes, as appropriate. Statistical significance was defined as p-value <0.05. Analyses were not adjusted for any confounders.

Results

From Dec. 2016 to Sept. 2017, 543 women presenting in labor at the study hospital were screened for eligibility and gave consent to participate (Fig 1). Following enrollment, 60 women were transferred for cesarean delivery and were withdrawn from the study. Three additional cases were excluded prior to randomization due to staff error and missing post-delivery measurements. In total, 480 women who delivered vaginally were randomized to receive 10 IU oxytocin as prophylaxis against PPH either intravenously or intramuscularly and had adequate data for analysis. The IV infusion and IM study groups consisted of 239 and 241 women, respectively, and had comparable baseline characteristics at enrollment (Table 1).

Fig 1

Consort flow diagram: Trial profile.

Table 1

Baseline characteristics by study group.

Baseline characteristics	IV infusion group (n = 239)	IM group (n = 241)
Woman’s age, mean ± SD	24.1 ± 5.2	24.3 ± 5.7
Education level, n (%)
None	4 (1.7)	0 (0)
Primary	81 (33.9)	87 (36.1)
Secondary or higher	154 (64.4)	154 (63.9)
# of pregnancies, mean ± SD	2.3 ± 1.5	2.4 ± 1.8
Primigravida, n (%)	93 (38.9)	92 (38.2)
Gestational age, mean ± SD	38.6 ± 2.1	38.9 ± 1.9
Had previous PPH, n (%)	2 (0.8)	4 (1.7)
Hb pre-partum, mean ± SD a	11.8 ± 1.5	11.7 ± 1.5
Pre-delivery Hb < 11.0 g/dL, n (%) a	61 (25.6)	68 (28.2)
Pre-delivery shock index, mean ± SD	0.75 ± 0.2	0.75 ± 0.2
Labor induced with uterotonics, n (%)	16 (6.7)	25 (10.4)
Labor augmented with uterotonics, n (%)	40 (16.7)	27 (11.2)
Singleton, n (%)	237 (99.2)	238 (98.8)
Episiotomy, n (%)	104 (43.5)	111 (46.1)

a N = 238 in the IV infusion group– 1 case had missing data on pre-partum Hb.

All randomized participants were administered both study ampoules from the study packets per the labeled routes. The IM-labeled ampoule was given within 1 minute of the birth of the baby for nearly all women (93%) in both study arms (Table 2). The average time to complete the IV infusion was 40 minutes in both randomized groups. Difficulties administering the IV infusion occurred in two cases (one in each study group)–one was an infiltrated line and the other was a dislodged IV during delivery. There were no reports of problems occurring with the IM injection. Rates of controlled cord traction and uterine massage were similar among study groups (Table 2).

Table 2

Active management of the third stage of labor by study group.

Delivery characteristics a	IV infusion group (n = 239)	IM group (n = 241)
Prophylaxis initiated within 1 minute of birth of baby, n (%) b	221 (92.5)	225 (93.8)
IV infusion time (min.) c
mean ± SD	40.1 ± 8.9	40.3 ± 9.7
(range)	(10–100)	(15–90)
Controlled cord traction, n (%)	229 (95.8)	237 (98.3)
Uterine massage, n (%)	91 (38.1)	81 (33.6)
Time (min.) to placental delivery d
mean ± SD	6.4 ± 5.7	6.6 ± 7.2
(range)	(0–40)	(0–62)

a No statistically significant differences measured; p>0.05 for all variables.

b N = 240 in the IM group– 1 case missing data on time of IM injection administration.

c N = 236 in the IV infusion group and N = 240 in the IM group due to missing data on time of infusion completion.

d N = 239 in the IM group– 2 cases missing data on time of placental expulsion.

Objective blood loss measurement revealed similar rates of PPH ≥500ml in both study arms (IV infusion: 20.6% and IM: 23.8%, p = 0.392) (Table 3). Although mean blood loss was 42ml less in the IV infusion group, compared to the IM group, this difference was not statistically significant (p = 0.161). Median total blood loss was confirmed to be 300ml in each study arm. Average blood loss (recordings at 30 min and at 60 min postpartum), as well as systolic and diastolic blood pressure and pulse readings were also similar in the two groups at all times measured.

Table 3

Trial outcomes by study group.

Outcomes	IV infusion group (n = 239)	IM group (n = 241)	Relative Risk / Estimate (95% CI)	p-value
Primary outcomes
Blood loss ≥ 500 ml, n (%) a	49 (20.6)	57 (23.8)	0.86 (0.62, 1.21)	0.392
Total blood loss, mean ± SD a	364 ± 323	406 ± 344	-42.8 ml (-102.8, 17.2)	0.161
PPH rates
PPH diagnosed, n (%)	48 (20.1)	57 (23.7)	0.85 (0.61, 1.19)	0.344
Time (min.) to diagnosis b
median (IQR)	30.0 (15, 41)	25.0 (15, 30)		0.174
Primary cause due to atony, n (%)	19 (39.6)	25 (43.9)	0.90 (0.57, 1.43)	0.658
Blood loss ≥ 750 ml, n (%) a	21 (8.8)	31 (13.0)	0.68 (0.40, 1.15)	0.146
Blood loss ≥ 1000 ml, n (%) a	14 (5.9)	18 (7.5)	0.78 (0.40, 1.53)	0.472
Additional interventions
Suturing and/or tear repair, n (%)	92 (38.5)	100 (41.5)	0.93 (0.75, 1.16)	0.502
Manual removal of placenta, n (%)	0 (0)	3 (1.2)	Cannot estimate	0.248
Bimanual compression, n (%)	0 (0)	3 (1.2)	Cannot estimate	0.248
Exploration under anesthesia, n (%)	1 (0.4)	5 (2.1)	0.20 (0.02, 1.71)	0.216
Additional uterotonics, n (%) c	13 (5.4)	30 (12.4)	0.44 (0.23, 0.82)	0.007
Oxytocin IV (10–20 IU), n c	12	28
Ergonovine IM (0.2–0.8), n c	3	5
Blood transfusion, n (%)	4 (1.7)	6 (2.5)	0.67 (0.19, 2.35)	0.751
Plasma expanders, n (%)	7 (2.9)	11 (4.6)	0.64 (0.25, 1.63)	0.346
Hysterectomy or other surgery d, n (%)	0 (0)	1 (0.4)	Cannot estimate	1.00
Hemoglobin outcomes e
Hb post-partum, median (IQR) b	10.5 (9.6, 11.2)	10.5 (9.6, 11.2)		0.453
(range)	(5.9–14.7)	(5.5–15.4)
Hb drop ≥ 2g/dL or given blood transfusion, n (%) e	79 (33.5)	74 (30.8)	1.09 (0.84, 1.41)	0.537

a Analysis of outcomes based on blood loss excludes three women whose measurement of blood was discontinued when transferred to the operating theatre for additional care (1 woman in the IV infusion group received suturing for grade IV tear; in the IM group, 1 woman received suturing for grade III tear and 1 woman was transferred for management of retained placenta). Baseline characteristics for these three women were not different from other cases included in analysis.

b Mann-Whitney U tests were calculated for secondary outcomes that were not normally distributed, including time to PPH diagnosis from delivery of baby and postpartum Hb.

c Administration of both uterotonics listed occurred in two women in the IV infusion group and three in the IM group.

d Other surgery refers to 1 woman in the IM group who received curettage for uterine evacuation due to incomplete placental expulsion.

e N = 236 in the IV infusion group and N = 240 in IM group due to missing postpartum Hb outcomes.

Shock index (SI) was also analyzed at 15-minute intervals postpartum. Fig 2 shows that women without PPH (n = 375) had relatively stable SI levels with a median of 0.74 pre-delivery and median SIs of 0.78, 0.75, 0.75, and 0.74 at 15, 30, 45, and 60-minutes postpartum, respectively, without any differences noted between study arms. Among those who developed PPH (Fig 2), median SI values were statistically significantly higher at each interval during the first hour postpartum, compared to women without PPH. This pattern was consistent irrespective of the study group. Median SI values at all time points, including changes in SI between the intervals, were comparable between study groups among PPH and non-PPH cohorts with one exception (S1 Fig). Women in the IM group who developed PPH experienced a sharp rise in SI from pre-delivery to 15-minutes postpartum (median Δ 0.20, IQR 0.08, 0.33), which was higher than in the IV infusion group (median Δ 0.13 IQR -0.02, 0.22, p = 0.048). Overall, the proportion of women with an elevated SI ≥ 0.9 at 15-minutes postpartum was higher in the IM group (80/241; (33%), compared to 25% in the IV infusion group (60/239) (p = 0.051) (S2 Fig).

Fig 2

Median shock index values pre-delivery and during the first hour postpartum for PPH cases and non-PPH cases by study group.

*Among PPH cases, median SIs were not statistically different between study groups at any time postpartum (p>0.05). ^Among non-PPH cases, median SIs were not statistically different between study groups at any time postpartum (p>0.05).

While blood loss outcomes were not clinically or statistically different between study groups, women in the IV infusion group received significantly fewer additional uterotonics (5%), compared to women randomized to IM injection (12%, p = 0.007) (Table 3). Also, fewer women received other interventions in the IV infusion group, including exploration under anesthesia, administration of plasma expanders, and blood transfusion, though none were statistically significant (Table 3). The median amount of IV fluids infused over the course of delivery was 1500 ml in both arms, and postpartum hemoglobin outcomes were similar between study groups (Table 3).

A closer examination of PPH cases in this study (n = 105) confirms that uterine atony (41.9%) and episiotomy (34.3%) were the most frequently reported causes of PPH; their occurrence was similar across study arms. All women made a full recovery from their bleeding, and no maternal deaths or severe outcomes occurred in the entire study population. There were also no reports of any adverse effects associated with prophylactic oxytocin administration in either study group.

Discussion

This double-blind, randomized controlled trial found that rates of PPH and the average volume of total blood loss were similar whether oxytocin (10 IU) was given during the third stage of labor by IV infusion or IM injection. While there were no differences in the study’s two primary outcomes based on blood measurement, the infusion of prophylactic oxytocin intravenously was associated with a clinically and statistically significant reduction in the use of additional uterotonics when compared to its administration via IM injection (IV: 5% vs. IM: 12%; RR 0.44 95% CI 0.22–0.85). The provision of other interventions was also lower in the IV infusion group, compared to IM injection, although none were found to be statistically significant except for recourse to therapeutic uterotonics (Table 3).

An analysis of bleeding patterns by study group provides insight into reasons for less frequent use of additional uterotonics in the IV infusion group than the IM group. For instance, in the IV infusion group, median blood loss at 30 minutes postpartum was 50ml less than among women randomized to IM injection. Although this finding lacks statistical significance, it suggests that women in the IM group bled more initially after childbirth. This trend is further supported by results from a post-hoc cohort analysis of atonic PPH cases showing that despite comparable blood loss at the time of PPH diagnosis, women in the IM group were diagnosed earlier (median: 18 min) after delivery, compared to women who received oxytocin via IV infusion (median: 30 min, p = 0.011). These results may be explained by the slower absorption and onset of action of IM oxytocin (i.e. 3–7 minutes) versus intravenously, with an almost immediate effect [3,19].

A similar effect was also reflected in an analysis of shock index (SI) levels by study group, particularly among women diagnosed with PPH, independent of cause. Concordant with the literature [20], the PPH cases in the present study had higher SI values in than women without PPH (Fig 2). Previous studies have shown that SI increases when a woman’s vital signs are compromised from bleeding, and when a rise in the pulse rate and a decline in systolic BP occur [16,17,21,22]. In Fig 2, a sharper rise in SI is seen among PPH cases in the IM group from before delivery to 15-minutes postpartum, compared to the IV infusion group (p = 0.048). This finding reinforces the evidence that women with PPH in the IM group likely experienced more blood loss after delivery than women in the IV infusion group.

Notably, contemporaneous findings from two large randomized controlled trials found PPH rates, based on objective measurement, to be significantly reduced when oxytocin prophylaxis was given via IV routes compared to IM injection after vaginal delivery [12-13]. The study by Charles et al, a three-arm trial conducted in Egypt, documented a significantly lowered risk of PPH (≥500mL) following administration of 10 IU prophylactic oxytocin via IV infusion, compared to IM injection (Relative Risk of 0.50, 95% CI 0.27–0.91), but did not confirm any difference in PPH rates when comparing IV bolus to IM injection [13]. Another large trial conducted in Ireland confirmed a significantly lower rate of severe PPH ≥1000mL following its IV bolus administration vs. IM injection (Odds Ratio of 0.54 95% CI 0.32–0.91) [12].

Both the Adnan and Charles studies had sample sizes that were more than twice the size of our study, which may have enabled the detection of a statistical difference in PPH rates between IV and IM routes [12-13]. It is also plausible that the faster infusion rate of IV oxytocin in the Egypt study or that administration in bolus improved outcomes in the IV groups of these trials. Our study had a mean IV infusion time of 40 minutes, whereas the time to completion of the IV infusion in the Egypt study was 28 minutes [13]. Rates of labor induction and augmentation also varied between studies. In the Egypt study, women who were pre-exposed to uterotonics in labor were excluded from participating in order to evaluate the impact of route of prophylactic oxytocin after delivery on an unexposed uterus [13]. In contrast, over half the sample enrolled in the Ireland trial had their labor induced. In fact, a subgroup analysis of these women showed an even larger reduction in the rate of severe PPH associated with IV bolus, compared to IM injection (Odds Ratio of 0.34 95% CI 0.16–0.72) [12]. Thus, both studies affirmed reductions in blood loss associated with IV routes, compared to IM injection, among women exposed and unexposed to uterotonics prior to the third stage of labor. A meta-analysis of the Adnan and Charles studies together with our findings shows that IV routes, compared to IM injection, were associated with a 23% reduction in the rate of PPH (i.e. ≥500ml) and a 41% reduction in the rate of severe PPH (i.e. ≥1000ml) (Fig 3 and Fig 4).

Fig 3

Meta-analysis of three randomized controlled trials comparing IV and IM routes of oxytocin administration for PPH prevention (Outcome: Measured blood loss ≥500ml).

Fig 4

Meta-analysis of three randomized controlled trials comparing IV and IM routes of oxytocin administration for PPH prevention (Outcome: Measured blood loss ≥1000ml).

Despite cumulative evidence favoring IV routes over IM injection for administration of oxytocin to prevent excessive blood loss after childbirth, other factors including provider skill- levels, available resources, and women’s preferences, warrant consideration when deciding which route to use. For instance, if an IV line is already in place prior to delivery, use of the same route for administering prophylaxis would be easiest and may reduce the subsequent need for additional uterotonics, based on the findings from this trial. Conversely, if there is no IV line established, IM administration is likely the most efficient way to administer oxytocin safely after delivery of the baby. Of note, in this study, there were no problems reported when administering the study medicine via IM injection; however, two problems did occur during IV infusion. Overall, difficulties with administration of oxytocin were infrequent but may be more common in other delivery environments with less skilled providers. Importantly, many guidelines on prevention of PPH only recommend the IM route of administration for oxytocin during the third stage of labor [6-8]. Yet, the inclusion of both routes in guidelines would allow for greater flexibility in the clinical care offered to women.

An important study limitation is that the acceptability to women of each route was impossible to evaluate. Due to the fact that the study was placebo-controlled, and each participant received an IM injection and had an IV line in place to administer, it was not possible to ask women to rate their experience with one route over the other—an area that deserves further exploration. Based on the findings from this study and others [12-13], it would be prudent to know whether the clinical advantages of administering prophylactic oxytocin via IV infusion should supersede women’s preferences for a less medicalized experience during childbirth. An additional study limitation is that over one-third of the PPH cases diagnosed in our study were due to trauma from episiotomy, which may affect the generalizability of our findings. When designing this study, the underlying assumption was that approximately 90% of PPH cases would be attributable to uterine atony [2,18]. Thus, our sample of atonic PPH, the specific type of PPH that can be prevented by oxytocin during the third stage of labor, might not have been adequate to detect real differences. A larger sample size might have helped compensate for this issue and future studies should modify their assumptions accordingly.

Conclusions

This study shows that IV infusion and IM injection routes of oxytocin administration did not significantly alter final blood loss outcomes or PPH incidence among participants. Nevertheless, the two routes appear to have resulted in different bleeding patterns immediately after childbirth, which likely triggered the provision of additional uterotonics to those in the IM group. These women appeared to bleed faster and have higher SI values soon after delivery, compared to women who received an infusion of prophylactic oxytocin. Greater awareness of the different clinical effects of IM and IV routes on early bleeding patterns and associated clinical signs may result in more effective tailoring of care during the immediate postpartum period. Importantly though, improvement to prophylactic regimens may have minimal impact on outcomes that matter most to women. More attention is needed to address other clinical practices that may be contributing to an increased bleeding and rates of intervention, including the performance of episiotomy, which was one of the main causes of PPH in this study. Furthermore, efforts to minimize bleeding after childbirth must prioritize access to high quality oxytocin and its proper cold chain storage.

CONSORT checklist.

(DOC)

Click here for additional data file.

Median change in SI from pre-delivery to each 15-minute time interval during the first hour postpartum for PPH cases and non-PPH cases by study group.

*Among the PPH cases, the median change in SI from pre-delivery to 15-minutes postpartum was higher in the IM group (median Δ 0.20, IQR 0.08, 0.33), compared to the IV infusion group (median Δ 0.13 IQR -0.02, 0.22; p = 0.048); change in SI between study groups were comparable at all other time intervals (p>0.05). ^Among the non-PPH cases, the median changes in SIs were not statistically different between study groups at any time postpartum (p>0.05).

(TIF)

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Proportion of women with SI ≥ 0.9 at each 15-minute time interval during the first hour postpartum by study group.

(TIF)

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Research protocol (Original in Spanish).

(DOC)

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Research protocol (English translation).

(DOC)

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23 Jul 2019

PONE-D-19-16212

Does route matter? Impact of route of oxytocin administration on postpartum bleeding: A double-blind, randomized controlled trial

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Reviewer #3: Yes

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Reviewer #1: This manuscript reports the impact of route of oxytocin administration on postpartum bleeding based on a double-blind, randomized trial. The following are my minor comments.

Table 3, IV group, the n and % should be exchanged for PPH diagnosed. Please indicate if the three excluded women are different from others on baseline characteristics.

Line 191, according to the table, should women (35) be women (53)? Please indicate which group the patients belong for those who received ergonovine.

Fig 2. For SI, it will be more informative to report and compare the average change (with SD) from pre-delivery or median change (with IQR) at each time point and report sample size for each subgroup. Authors may also consider mixed effects model to analyze the trend of SI.

Reviewer #2: In this manuscript, the authors compare intramuscular versus intravenous infusion prophylactic oxytocin for the third stage of labor.

The manuscript is written in standard English. The study objective clearly defined and corresponds to a relevant topic due to a lack of literature on the subject (see Cochrane Oladapo OT 2018: Three studies with 1306 women). However, the study is monocentric and with a sample size not permitting significant results.

Title and Keywords are clear, accurate and matching.

The abstract is accurate and complete. Nevertheless, it seems to me important to specify "IV infusion" in the method paragraph to prevent any potential confusion with the "IV bolus" route. This proposal could be usefully repeated throughout the manuscript.

Regarding the Method section:

Random sequence generation is well described. The blinding of participants and staff seems to be well respected. Research ethics are described (local ethics committee, registered with clinical trials.gov).

However, I have a few comments/questions for the authors.

- The sample size calculation is based on a strong, very optimistic hypothesis: “we hypothesized that administration of oxytocin via IV infusion would result in a 50% lower rate of PPH than IM administration”. This could explain the sample size and the non-significant outcomes.

- Confounders and their management are not described, they should be detailed in statistical analysis

- It would be easier to read the method section if structured according to CONSORT Reporting Guidelines.

- Oxytocin dose should be specified in the International Unit. It is specified "1ml" in the method section.

Regarding the Results section:

- It would seem that the numbers (n) and percentages have been inverted in tables 2 and 3: sometimes it is the number that is in brackets (for example for "uterine massage": "38.1(91)" instead of "91 (38.1)")

- Adverse effects are not described in result section.

- The results describing post-hoc analysis: PPH by uterine atony (l.219-229) do not respond to the research objective described in the method.

Discussion and conclusions are justified by the results. However, study limitations like sample calculation could be also discussed.

Reviewer #3: This randomized study tried to assess the best route of delivery of oxytocin to prevent PPH.

The background is well described and there is a lack of data regarding this question that may be of importance in countries where women do not have intra venous infusion during the third stage of labor.

The study is a well conducted double blind randomized study including 480 women delivering vaginally.

Since Adnan et al Published a larger well conducted randomized trial in 2018, these data are however less “new”.

The main concern is the number of subjects and the hypothesis used to calculate the number of subjects. As there was no real data regarding oxytocin route and that current recommendations do not provide a preferred route of administration, assuming that IV would reduce from 50% the rate of PPH is a very strong hypothesis: the use of oxytocin reduce by 50% the rate of PPH…

I would suppress the post hoc analysis conducted on a selected group of women that can be biased and do not add substantially to the paper.

There are only two or three well randomized trial comparing IV and IM. A metaanalysis of these studies as a last table would really add something to this paper.

In the discussion:

You cannot insist on the contradiction between your results and those previously published (adnan et al) as you results are actually very close : you just have a lack of power and this is what you write in the next chapter of your discussion.

Minor comments:

A detailed flow chart would be useful.

There are some inversion on the tables between n and % (able 2 line 1 , table 3 line 5 …)

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

15 Aug 2019

Responses below to Editor Comments and Reviewers’ Comments

Additional Editor Comments (if provided):

Although the topic is not original, the manuscript is technically sound and well written

Please, carefully consider the comments to improve this manuscript

Response: Thank you for your thorough review of our paper. We believe that the manuscript is significantly improved and are grateful to you and the reviewers who took the time to carefully read it.

Journal Requirements:

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1) Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response: We have improved the formatting of our manuscript, tables, and figures according to the guidance that was shared.

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In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

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Response: We are planning to post the dataset to Harvard’s dataverse as soon as the paper is accepted for publication. We will happily provide the DOI at that time.

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Response: We have included captions for the Supporting Information files at the end of our manuscript.

Reviewer #1:

This manuscript reports the impact of route of oxytocin administration on postpartum bleeding based on a double-blind, randomized trial. The following are my minor comments.

Table 3, IV group, the n and % should be exchanged for PPH diagnosed. Please indicate if the three excluded women are different from others on baseline characteristics.

Response: Thank you for noticing this error. We have corrected the n (%) for the IV group for PPH diagnosed in Table 3 and have corrected similar errors in Table 2.

Regarding the three women excluded from the analysis of postpartum blood loss outcomes, we have expanded the footnote to explain the specific reasons why their blood loss could not be measured for each case (see Lines 211-213). We also have confirmed that their baseline characteristics were not different from other cases included in the analysis. Lastly, we have revised the last two boxes of the Consort Flow Chart to reflect this information regarding the three excluded cases from the primary analysis.

Line 191, according to the table, should women (35) be women (53)? Please indicate which group the patients belong for those who received ergonovine.

Response: Thank you for asking this question. We have shifted the data from the footnote to the table (see Table 3) and list the Ns of those given additional IV oxytocin and/or ergonovine. We have modified the footnote to clarify that more than one uterotonic could be given, which occurred in only 5 cases (see Line 216). We hope the information is now more clearly presented in the table. In total, 3 women in the IV group and 5 women in the IM group were given ergonovine as an additional uterotonic.

Fig 2. For SI, it will be more informative to report and compare the average change (with SD) from pre-delivery or median change (with IQR) at each time point and report sample size for each subgroup. Authors may also consider mixed effects model to analyze the trend of SI.

Response: We have modified Fig 2 to include the sample size for each subgroup. We have opted to keep Fig 2 in the manuscript because it provides a useful overview of the SI trends for non-PPH cases and PPH cases, which support recently published findings on the topic, but are still not widely known among all audiences. We also believe that this analysis provides useful insight into the hemodynamic patterns that likely influenced providers’ decisions to offer additional uterotonics. Our finding of more frequent use of additional uterotonics in the IM group than in the IV infusion group, was the main motivation for exploring SI trends by study group among the PPH and non-PPH cohorts.

We also conducted the analysis suggested by the reviewer to look at the change in SI from before delivery to each time interval measured postpartum. We have added this figure as a supplement to the manuscript. Please see S1 Fig, which is referenced in the Results section in Lines 225-227. While we agree that this new figure provides useful information, we believe that the absolute SI values, as opposed to the delta SI values, were more likely to have influenced provider practices to offer additional care. For one, the baseline SI value may not have been known to the delivery attendant when caring for the woman during the first hour after childbirth. Also, the study team and providers were familiar with new information coming from other studies on the relationship between SI and PPH that showed SI ≥ 0.9 to be a potentially useful marker of PPH and could help aid in determining the need for treatment. Indeed, some of the previous studies on SI (Le Bas et al 2015, Nathan et al 2016, and El Ayadi et al 2016) were included as references in our study protocol to justify data collection on SI and postpartum blood loss. After giving further consideration to all of the above, we have added an additional figure to our manuscript as supplemental to show the proportion of women who had SI ≥ 0.9 by study arm at each time interval postpartum (see S2 Fig and also Lines 234-35 in the Results section).

We thank the reviewer for suggesting that we consider a mixed effects model to conduct an overall trend analysis of SI. While we think this suggestion is interesting, it would require a deeper dive into the data that is outside the scope and aims of this paper. It is also worth mentioning that we are in the process of preparing a separate manuscript that analyzes the SI findings from this study along with data on SI from other studies to enable a more complete analysis with a larger sample.

Reviewer #2:

In this manuscript, the authors compare intramuscular versus intravenous infusion prophylactic oxytocin for the third stage of labor. The manuscript is written in standard English. The study objective clearly defined and corresponds to a relevant topic due to a lack of literature on the subject (see Cochrane Oladapo OT 2018: Three studies with 1306 women). However, the study is monocentric and with a sample size not permitting significant results.

Response: Thank you for this feedback. Although our study’s sample size is small in comparison to recent trials conducted by Charles et al (2019) and Adnan et al (2018), we believe that these findings fill an important gap in the evidence and call attention to the need for greater consideration of the role that route plays in the delivery of oxytocin to reduce postpartum bleeding after childbirth. Our study is the only double-blind RCT to date that compares a prophylactic dose of oxytocin given via IV infusion compared to IM injection. The Adnan trial is the only other double-blind study which tested the bolus route versus IM injection. Although our study findings were not statistically significant, which was likely due to the small size, we believe they provide important information that helps support the findings from the recent larger trials conducted by Adnan et al and Charles et al.

Title and Keywords are clear, accurate and matching. The abstract is accurate and complete. Nevertheless, it seems to me important to specify "IV infusion" in the method paragraph to prevent any potential confusion with the "IV bolus" route. This proposal could be usefully repeated throughout the manuscript.

Response: Thanks you for this suggestion. We have specified “IV infusion” in the methods section of the abstract (see Line 24). We have taken the Reviewer’s suggestion to specify IV infusion throughout the paper where relevant.

Regarding the Method section: Random sequence generation is well described. The blinding of participants and staff seems to be well respected. Research ethics are described (local ethics committee, registered with clinical trials.gov). However, I have a few comments/questions for the authors. - The sample size calculation is based on a strong, very optimistic hypothesis: “we hypothesized that administration of oxytocin via IV infusion would result in a 50% lower rate of PPH than IM administration”. This could explain the sample size and the non-significant outcomes.

Response: We thank the reviewer for sharing these important observations about our study design. We agree that our sample size calculation was optimistic. We based our hypothesis on results from previous research, including those from an earlier RCT (un-blinded) that randomized participants after vaginal delivery to receive either 10 IU oxytocin via IV infusion or IM injection. This study documented a statistically significant reduction in measured blood loss ≥ 500ml (IV infusion: 9% (15/161) and IM: 20% (32/161); RR 0.47 95% CI 0.25-0.85) and helped to inform our hypothesis for our present study. The results from this prior research can be found online in a published conference abstract from the FIGO World Congress XX held in Rome in October 2012. https://www.sciencedirect.com/science/article/pii/S0020729212606377 We have modified our Methods section (see Lines 137-149) to provide further detail about this prior study and its findings, which provided the basis for the development of our study’s hypothesis.

Upon further reflection, we could have selected a smaller difference, but that choice might have been criticized for being arbitrary and not clinically significant. Related to the latter point, we specifically aimed to test a large difference between the two routes of administration, so if proven, this difference would signify a clear clinical benefit of one route over the other and one that would supersede programmatic advantages associated with the different routes. We also took into consideration that the study’s primary outcome (blood loss ≥ 500ml) and the fact that it does not necessarily represent an outcome of clinical consequence for all women. For instance, many women tolerate well this level of blood loss after childbirth. And while this outcome is standardly used in PPH prevention trials (Meher S BJOG 2018) and is referred to in international guideline to define PPH, a reduction of its occurrence may be viewed as clinically unimportant if the effect is small-to-moderate. In sum, we believed that a large difference might warrant a change in practices for this prophylactic intervention, but a small-to-moderate difference may not, given that the two routes have different practical advantages in different settings.

- Confounders and their management are not described, they should be detailed in statistical analysis

Response: We thank the reviewer for raising this question. As we did not find any significant imbalance between the IM and IV study groups with regard to baseline characteristics at enrollment or rates of other AMTSL practices during the third stage of labor, we did not adjust for any confounders in our analysis.

However, we did complete several sensitivity analyses to explore if our main study outcomes were different among particular subgroups of women (similar to the analyses presented in Table 5 of the published study by Adnan and colleagues). We ran these analyses (post-hoc) to assess outcomes for women who were primigravida; women whose labor was induced; women whose labor was induced/augmented; women who had episiotomy performed; women who had a pre-delivery Hb level < 11 g/dL. None of these analyses produced results that would modify our study conclusions. Also, it is difficult to draw any firm conclusions due the small sample size included in these subgroup analyses. We are happy to share these results with the reviewer below for his/her reference in this response document; however, we do not think they belong in our paper.

We also ran logistic regression to explore if any of the aforementioned variables has a confounding effect on our study’s primary outcomes. Our main findings remain unchanged after adjusting for potential confounders, including labor induction, primigravida, and episiotomy.

Summary of sensitivity analyses completed:

IV infusion IM injection P value

No induction/augment. (n=186) (n=193)

Blood loss ≥ 500mL 18.8% (35) 20.2% (39) P=0.733

Blood loss ≥ 1000mL 5.4% (10) 5.2% (10) P=0.932

Labor induced (n=16) (n=25)

Blood loss ≥ 500mL 18.8% (3) 44.0% (11) P=0.096

Blood loss ≥ 1000mL 12.5% (2) 20.0% (5) P=0.534

Labor induced/augmented (n=52) (n=46)

Blood loss ≥ 500mL 26.9% (14) 39.1% (18) P=0.198

Blood loss ≥ 1000mL 7.7% (4) 17.4% (8) P=0.144

Primigravida (n=93) (n=90)

Blood loss ≥ 500mL 30.1% (28) 34.4% (31) P=0.530

Blood loss ≥ 1000mL 9.7% (9) 14.4% (13) P=0.322

Pre-delivery Hb<11 g/dL (n=61) (n=68)

Blood loss ≥ 500mL 24.6% (15) 29.4% (20) P=0.539

Blood loss ≥ 1000mL 9.8% (6) 8.8% (6) P=0.843

No episiotomy performed (n=135) (n=130)

Blood loss ≥ 500mL 11.1% (15) 14.6% (19) P=0.394

Blood loss ≥ 1000mL 3.0% (4) 2.3% (3) P=0.739

Episiotomy performed (n=103) (n=109)

Blood loss ≥ 500mL 33.0% (34) 34.9% (38) P=0.776

Blood loss ≥ 1000mL 9.7% (10) 13.8% (15) P=0.360

- It would be easier to read the method section if structured according to CONSORT Reporting Guidelines.

Response: We have added subheadings to the Methods section to help orient the reader. We would welcome confirmation and further instructions from the journal if these types of sub-headings are allowed.

- Oxytocin dose should be specified in the International Unit. It is specified "1ml" in the method section.

Response: Thank you for sharing this observation. We have changed it to say 10 IU in the Methods section (see Line 96).

Regarding the Results section:

- It would seem that the numbers (n) and percentages have been inverted in tables 2 and 3: sometimes it is the number that is in brackets (for example for "uterine massage": "38.1(91)" instead of "91 (38.1)")

Response: Thank you for noticing these errors, which have been corrected in Tables 2 and 3.

- Adverse effects are not described in result section.

Response: Thank you for asking this question. Providers were asked to document any adverse effect that occurs since administration of the prophylactic regimen and none were reported. We have added at sentence to the Results section confirming that there were no adverse effects reported in our study (see Lines 264-265).

- The results describing post-hoc analysis: PPH by uterine atony (l.219-229) do not respond to the research objective described in the method.

Response: Thank you for this feedback. In light of your comment and feedback from another reviewer suggesting that we omit this post-hoc analysis, we have decided to remove this analysis from the Results section (removed Lines 252-263). We agree that it does not add substantially to the paper and main findings.

Discussion and conclusions are justified by the results. However, study limitations like sample calculation could be also discussed.

Response: We thank the reviewer for this comment. We have added more detail to the Methods section to explain the rationale for our study hypothesis and sample size calculation (see Lines 137-149), which we hope is helpful. While we agree that our study assumption was ambitious, we do not necessarily consider it a limitation of our study. The real limitation, we believe, is that our sample was diluted by PPH caused by episiotomy, for which prophylactic oxytocin is likely to have no effect, and that we incorrectly assumed that the majority of PPH cases would be attributable to uterine atony. We agree that a larger sample size may have helped to compensate for this issue and that future studies should modify their assumptions accordingly.

Reviewer #3:

This randomized study tried to assess the best route of delivery of oxytocin to prevent PPH.

The background is well described and there is a lack of data regarding this question that may be of importance in countries where women do not have intra venous infusion during the third stage of labor. The study is a well conducted double blind randomized study including 480 women delivering vaginally. Since Adnan et al Published a larger well conducted randomized trial in 2018, these data are however less “new”.

Response: We believe our study findings and design are complementary to the large trial conducted by Adnan et al. Our study is the only double-blind RCT to date that compares a prophylactic dose of oxytocin given via IV infusion compared to IM injection. The Adnan trial is the only other double-blind study which tested its IV bolus administration versus IM injection. Together we believe these results fill an important void in the evidence on the effect of IV routes of oxytocin administration on postpartum blood loss.

The main concern is the number of subjects and the hypothesis used to calculate the number of subjects. As there was no real data regarding oxytocin route and that current recommendations do not provide a preferred route of administration, assuming that IV would reduce from 50% the rate of PPH is a very strong hypothesis: the use of oxytocin reduce by 50% the rate of PPH…

Response: In response to a similar comment by Reviewer #2, we have modified our Methods section (see Lines 137-149) to provide further detail on the research findings that served as the basis for the development of our study’s hypothesis.

I would suppress the post hoc analysis conducted on a selected group of women that can be biased and do not add substantially to the paper.

Response: We appreciate this feedback Reviewer #2 had a similar comment and we agree that it does not add substantially to the paper. See Lines 252-263 in the Results section that has been removed in tracked changes. Please note that we have retained one sentence in the Discussion section that reports on the timing of PPH diagnosis among women with atonic PPH.

There are only two or three well randomized trial comparing IV and IM. A meta-analysis of these studies as a last table would really add something to this paper.

Response: We thank the reviewer for this suggestion. We agree that a meta-analysis of the three recent studies that our discussed in our paper would fit well in our manuscript, including our study, the Adnan trial and the 3-arm trial by Charles et al. Please note that we also had considered if the other three studies from the 2018 Cochrane review should be included in this meta-analysis, but identified numerous differences between the studies with regard to their study design and how the outcomes were reported, resulting in the decision to only include the most recent studies. Of note, none of the studies in the last Cochrane review were double-blinded. Please see Lines 321-28 where we report on the meta-analysis findings and have added the new figures (Fig 3 and 4).

In the discussion:

You cannot insist on the contradiction between your results and those previously published (adnan et al) as your results are actually very close : you just have a lack of power and this is what you write in the next chapter of your discussion.

Response: Thank you for this observation. We agree that our results were very close to previously published results by Adnan et al and Charles et al and have removed the sentence in our Discussion section that describes our findings as contradictory (see Lines 296-298). We agree that our study lacks power and while our sample size could have been larger, the lack of power in our study might be due in part to the unexpectedly high rate of traumatic cases of PPH due to episiotomy, which may have prevented us from seeing any real differences between the study arms. See Lines 351-352 in our Discussion where we raise this issue as a study limitation.

Minor comments:

A detailed flow chart would be useful.

Response: We are not certain what level of detail is being requested or suggested by this comment. Our manuscript was accompanied by Figure 1: Consort Flow Chart that describes the enrollment process and total number of cases analyzed. In response to feedback received by other reviewers, we have added more detail to the Consort Flow Chart. It would be helpful to know if the Reviewer has had a chance to see this flow chart and if the information presented is sufficient. We kindly request further instructions on what type of flow chart and additional detail would be useful and if it is still recommended after reviewing our revisions to the manuscript, including the addition of subheadings to the Methods section.

There are some inversion on the tables between n and % (able 2 line 1 , table 3 line 5 …)

Response: Thank you for noticing these errors, which have been corrected in Tables 2 and 3.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

12 Sep 2019

Does route matter? Impact of route of oxytocin administration on postpartum bleeding: A double-blind, randomized controlled trial

PONE-D-19-16212R1

Dear Dr. Durocher,

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Additional Editor Comments (optional):

Reviewers' comments:

20 Sep 2019

PONE-D-19-16212R1

Does route matter? Impact of route of oxytocin administration on postpartum bleeding: A double-blind, randomized controlled trial

Dear Dr. Durocher:

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