Intramuscular injection, intravenous infusion, and intravenous bolus of oxytocin in the third stage of labor for prevention of postpartum hemorrhage: a three-arm randomized control trial

Active management of the third stage of labor (AMTSL) is recommended to prevent postpartum hemorrhage (PPH), with uterotonics considered the most important component [1], and oxytocin the uterotonic of choice [1–6]. In most hospital settings, oxytocin is used for this indication, but with much variation in route, dose, and timing [3, 7–10]. Oxytocin is commonly administered either intramuscularly (IM) or intravenously (IV). International guidelines, including the World Health Organization, currently recommend both routes equally [1, 11].

There are potential advantages to each route. IV administration may have a clinical advantage, as it leads to a faster response and a higher peak in plasma oxytocin levels [12–14]; however, IM injection confers practical advantages, requiring fewer skills and less equipment to administer, making it a more serviceable option in a wider array of settings [9, 15]. Despite many discussions of the clinical importance of route [9, 15–25], differences in efficacy remain largely uninvestigated. The few published studies investigating route are inconsistent, with two showing reduced blood loss associated with IV administration [24, 25] and two others showing no difference between IV and IM administration [20, 21].

Clinical effects may also be different if intravenous oxytocin is delivered via bolus push or over a longer duration via dilute infusion. While there is some evidence that the more immediate, higher concentration of bolus delivery could lead to stronger effect on uterine contractions [23], this route is less frequently used due to fear of hypotension, although this problem has only been noted in case studies of women under general anesthesia during caesarean section [26–28]. Two studies conducted among women who received oxytocin following vaginal delivery showed no side effects or adverse outcomes associated with IV bolus administration and somewhat worse clinical outcomes associated with IV infusion [22, 23]. Despite this evidence, hesitation persists regarding oxytocin via IV bolus.

To help inform best practices in clinical care and address inconsistencies and gaps in the literature, we conducted a three-arm study to compare the clinical effectiveness and safety of IM injection to both IV infusion and IV bolus of 10 IU oxytocin administered during the third stage of labor.

Pregnant women presenting for vaginal delivery in two tertiary Egyptian hospitals were screened for participation in this open-label, three-arm, parallel, randomized controlled trial. Approval was obtained from the research ethics committees of both hospitals: El Galaa Teaching Hospital in Cairo (the largest maternity hospital in Cairo), and Shatby Maternity Hospital in Alexandria (the university hospital of Alexandria University), where all three routes of oxytocin administration were routinely used.

Women were eligible to participate if they delivered a live birth vaginally, did not receive pre-delivery uterotonics to induce or augment labor, and were able to provide informed consent. Written consent was obtained after admission, upon arrival to the labor ward. Blood pressure and pre-delivery hemoglobin were subsequently measured and recorded, the latter using HemoCue® hb 201+ (HemoCue, Ängelholm, Sweden).

Women were randomized to receive 10 IU of oxytocin by IM injection, IV infusion, or IV bolus immediately after delivery of the baby. IM injection was usually administered in the thigh. For IV infusion, oxytocin was mixed in 500 ml of fluid and administered through gravity-driven infusion with the roller clamp fully open, most often using an 18 gauge needle. IV bolus was pushed directly into the IV port over approximately 1 min.

Information on other prophylactic measures provided in the third stage of labor, including controlled cord traction and uterine massage, was recorded on standardized data collection forms. Postpartum blood pressure and any side effects or adverse events experienced after oxytocin administration were also recorded. Postpartum blood loss was measured at 1 h post-delivery using a plastic blood collection drape funneled into a calibrated container. For women diagnosed with PPH, blood loss was also recorded at the time of PPH diagnosis and at active bleeding cessation. Women diagnosed with PPH received standard of care treatment at each hospital. Interventions, including administration of additional uterotonics or blood transfusion, were documented. Postpartum hemoglobin was measured at least 24 h after delivery and at least 12 h after removal of the IV for women receiving IV fluids, if possible, or just before discharge if women were discharged sooner.

Our primary outcomes were mean blood loss and proportion of women with blood loss ≥500 ml. Secondary outcomes included proportion of women with blood loss ≥350 ml and ≥ 1000 ml, change in pre- to post-delivery hemoglobin, time to placental delivery, administration of additional oxytocin or other uterotonics, and observed side effects within 1 h postpartum.

The sample size calculation was derived from the expected rate of women with blood loss ≥500 ml in the two comparisons of this three-arm study: IM injection vs. IV infusion and IM injection vs. IV bolus. Based on previous studies, we expected a slightly larger difference of blood loss outcomes for the IV bolus vs. IM injection comparison, thus a smaller sample size was required for that comparison [23, 29]. We augmented sample sizes to compensate for conducting two 80% correlated comparisons (equivalent to requiring a significance level of 0.0435 for each test) and to account for a 2% attrition rate. The resulting sample size requirement was 4900 women, at a 3:3:1 ratio (2100 in each of the IM injection and IV infusion groups and 700 in the IV bolus group), with 80% power for the comparison of IM injection to IV infusion and 85% power for the comparison of IM injection to IV bolus administration. The sample size was also sufficient to detect a 50 ml mean difference in blood loss between study groups.

The simple randomization code was computer-generated in blocks of seven at Gynuity Health Projects in New York, and each assignment was contained in a sequentially numbered, sealed, opaque envelope. Each hospital was independently randomized. Hospital study staff had no access to the randomization code and were instructed to open the next envelope prior to the woman’s delivery, during the second stage of labor.

Analysis was done using the intent to treat approach. P values for baseline characteristics were calculated using the chi-square test of association for categorical variables and one-way analysis of variance (ANOVA) for continuous variables. Differences were considered significant at α = 0.0435, to account for the multiple comparisons made in this three-arm study. Log-binomial regression was used to calculate relative risks (RRs) and associated 95% confidence intervals (CIs) for categorical outcomes. Linear regression was used to calculate regression coefficients and associated 95% CIs for continuous outcomes. We first assessed the assumption of normal distribution all continuous secondary outcomes (including postpartum blood loss, time to placental delivery in minutes, total blood loss, and change in pre-to post-delivery hemoglobin). None were normally distributed, thus transformation (using the natural log ln) was done on all continuous outcomes. To facilitate interpretation of estimates obtained from linear regression of these log-transformed outcomes, we used the following formula to produce an estimate of the percent change in the mean outcome (y) associate with treatment group in question (d): y = 100·[exp(βd) − 1], where β is equal to the regression coefficient for the log-transformed outcome. Analyses were conducted using Stata 12 (StataCorp. 2011. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP).

The findings of this large randomized controlled trial exploring difference in route of prophylactic oxytocin administration in the third stage of labor suggest that route of oxytocin administration affects postpartum blood loss. These results substantiate earlier findings [12, 13, 24] that both IV infusion and IV bolus administration of 10 IU of oxytocin were associated with significantly less average postpartum blood loss when compared to IM injection.

This trial is one of few studies to include the less commonly studied IV bolus administration after vaginal delivery. Our trial found no safety issues with any of the oxytocin administration routes, including IV bolus. Obstetrical practice moved away from IV bolus based upon reports of hemodynamic effects exhibited after oxytocin administration by IV bolus in women undergoing general anesthesia for cesarean section; however, our study corroborates more recent reports that these concerns are unnecessary for vaginal deliveries [22, 23].

Because the total difference in average blood loss (24 ml) was small, the clinical application of these results may be limited; however, our findings have important implications for research on PPH prevention. For example, based on existing data, current World Health Organization guidelines recommend IV and IM administration equally for the prevention of PPH and strongly recommend use of the non-parenteral option, misoprostol, only in settings where use of oxytocin is not possible [1]. However, the key studies underlying international guidelines [30, 31] are based upon data with all routes of oxytocin administration combined. As our study clearly demonstrates the need to disaggregate such findings by route of administration, there is no clear evidence that IM injection of oxytocin is superior to other uterotonics for PPH prevention. If data from key studies that underpin WHO recommendations were disaggregated by oxytocin route, a more robust comparison of IM injection with misoprostol would be possible. As IM oxytocin and misoprostol are the most practical options for PPH prophylaxis in low resource settings, the longer shelf life and greater stability of misoprostol [32–35] could make it a preferable option if the two modalities were found to be equivalent [32].

The large size of this trial ensured that we could detect differences between IV and IM routes. Exclusion of women who had received uterotonics for induction/augmentation of labor made it easier to clearly assess the impact of route of administration on blood loss during the third stage of labor, since pre-delivery oxytocin can desensitize the uterus to the effect of subsequent doses [36], though results may be less generalizable to these women.

Route of oxytocin administration should be standardized and specified in research design and interpretation, and different routes cannot be presumed to be equivalent. Recommendations on drugs for prevention of PPH should consider route of administration when ranking prophylaxis options for future guidelines.

For clinical practice, providers might benefit from knowing 10 IU of IV bolus is a good, safe option for women after vaginal delivery. If an IV line is already in place at delivery, IV infusion or IV bolus administration of oxytocin may be preferable to IM injection in the third stage of labor.