The third stage of labor is the time from the delivery of the infant until delivery of the maternal placenta.¹ The natural course of this final stage of childbirth involves cessation of umbilical cord pulsation, separation of the placenta from the uterine wall, and passage of the placenta through the birth canal. Volume of blood loss depends on how long it takes the placenta to separate from the uterine wall and how effectively the uterine muscle contracts in the immediate postpartum period.

Incidence and Risk Factors

Postpartum hemorrhage occurs in approximately 4 percent of vaginal deliveries, and estimates are that it causes significant morbidity and 25 percent of all maternal childbirth-related deaths.² The World Health Organization defines postpartum hemorrhage as blood loss of 500 mL or more in the first 24 hours postpartum.³ Postpartum blood loss is difficult to evaluate⁴; some healthy women tolerate a 500-mL loss of blood, whereas other women become clinically unstable.

Maternal risk factors for postpartum hemorrhage are summarized in Table 1.⁵ Postpartum hemorrhage often occurs in women with no identifiable risk factors. Uterine atony is the most common cause of postpartum hemorrhage. Uterotonic medications (e.g., oxytocin [Pitocin], ergot alkaloids, and prostaglandins) are widely available in developed countries, are rapidly effective, and have become standard therapy in the treatment of postpartum hemorrhage.

Attempts to prevent postpartum hemorrhage have focused on the prophylactic use of uterotonic agents and the active clinical management of the third stage of labor. This article reviews the evidence supporting these approaches in the prevention of postpartum hemorrhage. Key terms are defined in Table 2.^1,2,6

Expectant vs. Active Management

Expectant management of the third stage of labor also is called the physiologic method and is best described as a “hands off” approach. The umbilical cord is not clamped or cut until cessation of pulsating; separation of the placenta occurs without intervention; and the placenta is delivered spontaneously or aided by gravity.⁶ In active management, the physician facilitates the separation and delivery of the placenta and enhances the effectiveness of the uterine contractions to shorten the duration of the third stage of labor and reduce the risk of postpartum hemorrhage. Active management of labor incorporates three main interventions: administration of a uterotonic medication after delivery of the baby; early cord clamping and cutting; and controlled traction on the umbilical cord while awaiting placental separation and delivery.⁶ The clinical adoption and practice of active management or its individual components varies throughout the world.⁷

A Cochrane systematic review⁶ identified five randomized controlled trials (RCTs) comparing active and expectant management that included more than 6,400 women. Compared with expectant management, active management was associated with: a shorter third stage (mean difference, −9.77 minutes); a reduced risk of postpartum hemorrhage (number needed to treat [NNT] = 12) and severe postpartum hemorrhage (NNT = 57); a reduced risk of anemia (NNT = 27); a decreased need for blood transfusion (NNT = 65); and a decreased need for additional uterotonic medications (NNT = 7).⁶ Active management also was associated with an increased risk of maternal nausea (number needed to harm [NNH] = 15), vomiting (NNH = 19), and elevated blood pressure (NNH = 99), likely caused by the use of an intramuscular ergot alkaloid as the uterotonic medication in four of the five studies in the systematic review. There were no advantages or disadvantages for the baby with either approach.

The uterotonic agents and the route of administration varied, but the outcomes of active and expectant management of the third stage of labor were similar among the five trials. In one trial,⁶ manual removal of the placenta was more common after active management. This trial⁶ was the only one that used an intravenous ergot alkaloid as the uterotonic agent. Ergot alkaloids are thought to promote contraction of the lower uterine segment and may thereby increase the risk of an entrapped placenta and the subsequent need for manual removal of the placenta.⁸ Of the other four trials, one used intramuscular oxytocin, and three used prophylactic ergometrine-oxytocin (a combination of five units of oxytocin and 0.5 mg of ergometrine, which is not available in the United States).

A second analysis⁹ of these data, excluding the trial using intravenous ergonovine and a trial of lesser quality, demonstrated the benefits of active management in preventing postpartum hemorrhage while finding no increased risk of retained placenta or maternal side effects. Together, these two systematic reviews^6,9 provide evidence that active management with uterotonic agents other than an intravenous ergot alkaloid confers important benefits without significant side effects.

Choice of Uterotonic Agent

The evaluation of individual components of the active management of the third stage of labor has focused on the uterotonic medications. A Cochrane systematic review¹⁰ evaluated oxytocin as the prophylactic uterotonic agent in the third stage of labor. In seven RCTs¹⁰ comparing the use of prophylactic oxytocin with no prophylactic uterotonic agent in more than 3,000 women, the use of oxytocin was associated with reduced risk of postpartum hemorrhage (NNT = 8) and reduced need for therapeutic uterotonics (NNT = 15). The trials varied in dose of oxytocin administered, route of administration, and general management (active versus expectant) of the third stage of labor. In the studies using prophylactic oxytocin without the other components of active management (early cord clamping and cutting, controlled cord traction), there was a nonsignificant trend toward increased manual removal of the placenta (4.6 percent of women receiving prophylactic oxytocin versus 3.8 percent of women receiving placebo).The Cochrane review¹⁰ also evaluated six trials that compared the prophylactic use of ergot alkaloids with the use of oxytocin in women in the third stage of labor. The agents were equally effective in preventing postpartum hemorrhage, but the ergot alkaloids were associated with an increased risk of manual removal of the placenta (NNH = 92).

The use of intramuscular ergometrine-oxytocin has been studied in a systematic review including six trials totalling more than 9,000 women.¹¹ The combination uterotonic agent was found to be more effective than oxytocin alone for preventing postpartum hemorrhage (NNT = 61). No difference was seen for the prevention of severe postpartum hemorrhage, and there was significantly more nausea and vomiting (NNH = 61) and hypertension (NNH = 96) in the women receiving ergometrine-oxytocin.¹¹

Overall, the prophylactic use of oxytocin reduces postpartum hemorrhage and the need for therapeutic uterotonics. The ideal dose of oxytocin has not been directly studied. From the available data, the most effective dose appears to be 10 units administered intramuscularly or 20 units diluted in 500 mL of normal saline and given as an intravenous bolus. There seems to be no significant benefit to the prophylactic use of ergot alkaloids alone when compared with oxytocin alone or with the combination of oxytocin and ergometrine-oxytocin.

Carbetocin (not available in the United States) is a synthetic oxytocin analogue with a half-life four to 10 times longer than oxytocin. It can be administered intramuscularly or intravenously as a single injection. An RCT¹² compared 100 mcg of intramuscular carbetocin with 10 units of intravenous oxytocin and found no difference in the number of women requiring additional uterotonic medication.

Misoprostol (Cytotec) is available as a tablet that can be administered by oral, sublingual, rectal, or vaginal route. It is stable at room temperature, inexpensive, and has been studied as prophylactic therapy in the management of the third stage of labor. Neither oral nor rectal administration of misoprostol has been shown to be as effective as injectable uterotonics in preventing postpartum hemorrhage.¹³ In a systematic review including 17 studies, there was an increased need for therapeutic uterotonic medications (NNH = 22) among the women receiving prophylactic misoprostol when compared with women receiving other injectable uterotonic agents. Side effects from misoprostol were common and included shivering (NNH = 7), vomiting (NNH = 225), diarrhea (NNH = 258), and elevated body temperature (NNH = 18). Although prostaglandins are an effective treatment of postpartum hemorrhage because of the balance of risks and benefits, they currently have no role in the prevention of postpartum hemorrhage.

Timing for Administration of the Uterotonic Agent

An area of controversy has been whether to administer the uterotonic agent at the time of the delivery of the anterior shoulder or after the delivery of the placenta. There is concern that administration of these agents before the delivery of the placenta may increase the risk for manual removal of the placenta. Results of a prospective cohort study¹⁴ and an RCT¹⁵ indicated that oxytocin administered before the delivery of the placenta decreased the risk of postpartum hemorrhage; however, the studies were not blinded and did not control for nonpharmacologic interventions (e.g., controlled cord traction). A double-blinded RCT¹⁶ of 1,486 women receiving active management of the third stage of labor was performed to more definitively isolate the effect of the timing of the uterotonic agent. The early administration of prophylactic oxytocin did not increase the risk of manual removal of the placenta, and there was equal effectiveness in preventing postpartum hemorrhage; thus, the uterotonic agent can be administered before or after delivery of the placenta.