Management of the third stage of labor: Prophylactic pharmacotherapy to minimize hemorrhage

INTRODUCTION — The third stage of labor refers to the interval from the birth of the newborn to expulsion of the placenta. The major complications of the third stage of labor are:

●Hemorrhage (see "Overview of postpartum hemorrhage" and "Postpartum hemorrhage: Medical and minimally invasive management")

●Retained placenta (see "Retained placenta after vaginal birth")

●Uterine inversion (see "Puerperal uterine inversion")

This topic will discuss prophylactic use of medications to minimize postpartum blood loss and reduce the risk for postpartum hemorrhage (PPH). Available evidence has several limitations, including bias and inaccuracy regarding blood loss, clinical significance of some outcomes (eg, blood loss versus transfusion rate), variability in the timing of hemoglobin determination when hemoglobin was used as an endpoint, and antepartum and intrapartum variability in PPH risk in the study population.

Additional aspects of management of the normal third stage, such as cord clamping and repair of lacerations, are reviewed separately. (See "Repair of perineal lacerations associated with childbirth" and "Labor and delivery: Management of the normal third stage after vaginal birth".)

ACTIVE MANAGEMENT — We recommend active rather than expectant (physiologic) management of the third stage of labor. Active management is a bundle of interventions. We define it as administration of a prophylactic uterotonic medication(s) (table 1) with or without tranexamic acid just after delivery of the anterior shoulder or after birth of the newborn, followed by gentle controlled traction of the umbilical cord until the placenta spontaneously separates and is expelled. Pharmacotherapy is the most important component of this combination of interventions; cord traction has been associated with modest benefits [1-5].

In a meta-analysis of randomized trials comparing active versus expectant management of the third stage of labor, active management reduced the risk for [6]:

●Postpartum hemorrhage (PPH) >1000 mL (8 versus 24 per 1000; relative risk [RR] 0.34, 95% CI 0.14-0.87)

●PPH >500 mL (50 versus 145 per 1000; RR 0.34, 95% CI 0.27-0.44)

●Postpartum maternal hemoglobin <9 g/dL (36 versus 71 per 1000; RR 0.50, 95% CI 0.30-0.83)

●Maternal blood transfusion (1 versus 2.9 percent; RR 0.35, 95% CI 0.22-0.55)

●Use of therapeutic uterotonics during the third stage, within the first 24 hours, or both (3.9 versus 21.1 percent; RR 0.19, 95% CI 0.15-0.23)

It also resulted in a modest reduction in mean maternal blood loss at birth (mean difference -79 mL, 95% CI -96 to -62 mL).

These benefits were most pronounced in patients at high risk of PPH. The overall quality of evidence was low, and the benefit was uncertain in patients at low risk of PPH. Active management did not result in a clinically important reduction in the mean duration of the third stage. Potential adverse maternal effects included increases in manual removal of the placenta, vomiting, afterpains (ie, pain after childbirth caused by contraction of the uterus), and return to the hospital after discharge because of bleeding, each of which occurred in 2 to 7 percent of patients (RR 2.2 to 3.6 compared with expectant management).

An important limitation of the analysis is that there are many possible variations in the package of interventions considered "active management"; for example, the choice/dose/timing of uterotonic medication administration, timing of cord clamping, and timing of initiation of controlled cord traction. While bundles of interventions are now frequently compared in quality improvement efforts, they do not determine which specific intervention works.

Choice of medication — All of the medications listed in the table (table 1) are effective for reducing the risk for PPH ≥500 mL [7]. Medication dosing, effectiveness, and side effects are described below. (See 'Oxytocin' below and 'Misoprostol' below and 'Ergot alkaloids' below and 'Carbetocin' below and 'Tranexamic acid' below.)

This author's preference is:

●Oxytocin 20 units in 500 mL 0.9 percent saline by intravenous (IV) infusion over one hour, followed by an additional 20 units in 1 L of fluid at a rate of 125 mL/hour (2.5 units/hour) until the liter is infused plus

●Either misoprostol 200 to 400 mcg buccally or tranexamic acid 1 g IV over 10 minutes.

This preference is based on evidence from meta-analyses of randomized trials (discussed below) [7-10]. He considers the combination of oxytocin-ergometrine (not available in the United States), oxytocin and methylergometrine, and carbetocin alone (not available in the United States) reasonable alternatives, all of which are similarly effective.

Oxytocin alone is the standard of care for active management of the third stage of labor in the United States [11]. Despite data from randomized trials of prophylactic use of other uterotonic medications with or without the addition of tranexamic acid for prevention of PPH [7-10] (see 'Tranexamic acid' below), the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have not recommended prophylactic use of dual agents instead of oxytocin alone, and the author's approach has not been established as a new standard of care in the United States [12]. Nevertheless, for patients at high risk for PPH, some UpToDate contributors consider administering oxytocin plus another medication (eg, tranexamic acid, misoprostol, methylergometrine) or carbetocin alone (where available) rather than oxytocin alone, given evidence that these regimens appear to be more effective than oxytocin alone for reducing PPH risk, and high-risk patients will derive the largest absolute reduction in PPH.

●Evidence – The benefit of dual therapy or carbetocin alone is supported by a network meta-analysis of randomized trials of the effectiveness and side effects of uterotonic medications for preventing PPH ≥500 or 1000 mL (196 trials, >135,000 participants) [7]. The trials were performed in 53 countries (high-, middle- and low-income), 95 percent were performed in a hospital setting, and 72 percent of the participants were undergoing a vaginal birth.

•For PPH ≥500 mL, risk reductions of 30 percent were noted:

-Oxytocin plus misoprostol versus oxytocin – RR 0.70, 95% CI 0.58-0.86 (low-quality evidence). The absolute risk for PPH ≥500 mL after a vaginal birth was 10.1 versus 14.5 percent and for cesarean birth 42 versus 60 percent.

-Oxytocin-ergometrine versus oxytocin – RR 0.70, 95% CI 0.59-0.84 (moderate-quality evidence). The absolute risk for PPH ≥500 mL after a vaginal birth was 8.5 versus 12.2 percent and for cesarean birth 42 versus 60 percent.

-Carbetocin versus oxytocin – RR 0.72, 95% CI 0.56-0.93 (moderate-quality evidence). The absolute risk for PPH ≥500 mL after a vaginal birth was 8.7 versus 12.2 percent and for cesarean birth 44 versus 60 percent.

•Use of oxytocin plus misoprostol, oxytocin plus ergometrine, or carbetocin alone also reduced the use of additional uterotonic medications and blood transfusion compared with oxytocin alone. Importantly, the risk for transfusion was reduced by approximately 50 percent with oxytocin plus misoprostol, 23 percent with oxytocin plus ergometrine, and 20 percent with carbetocin alone compared with oxytocin alone. The oxytocin plus misoprostol reduction was the only statistically significant result and would lead to 39 fewer blood transfusions per 1000 cesarean births (95% CI 50 to 24 fewer) and 7 fewer transfusions per 1000 vaginal births (95% CI 9 to 5 fewer).

•For PPH ≥1000 mL, oxytocin plus misoprostol, oxytocin plus ergometrine, or carbetocin alone had risk reductions of 12 to 17 percent compared with oxytocin alone, but the differences were not statistically significant.

•Subgroup analyses did not reveal important subgroup differences for patients undergoing vaginal versus cesarean birth or for patients at high versus low risk for PPH.

Although oxytocin alone was associated with a 3 to 4 percentage point higher frequency of PPH ≥500 mL after vaginal birth and a 20 percent higher frequency after cesarean birth compared with the other medications in this analysis, the evidence suggests that use of oxytocin alone is still a reasonable approach, especially for patients at low risk of hemorrhage, because it is effective, less costly, and associated with fewer side effects than dual therapies. For example, compared with oxytocin alone, oxytocin-ergometrine had a higher risk for vomiting (8.2 versus 2.8 percent, RR 2.93, 95% CI 2.08-4.13) and hypertension (20.3 versus 8.2 percent, RR 2.48, 95% CI 0.89-6.88), while oxytocin plus misoprostol had a higher risk for fever (9.1 versus 2.9 percent, RR 3.14, 95% CI 2.20-4.49). (See 'Side effects' below and 'Side effects' below and 'Side effects' below and 'Side effects' below.)

The efficacy of oxytocin plus tranexamic versus oxytocin alone was not evaluated in the network meta-analysis, but some data show similar absolute reductions in PPH ≥500 mL with dual therapy. (See 'Effectiveness' below.)

Timing — Pharmacotherapy is administered immediately after delivery of the anterior shoulder (this author's preference), birth of the newborn, or expulsion of the placenta [13]. Administration of uterotonic medications should not occur before delivery of the anterior shoulder, especially at vaginal birth, since this could exacerbate a shoulder dystocia, if present. Tranexamic acid, which is not a uterotonic medication, can be administered before expulsion of the shoulder.

Role of uterine massage — The author performs uterine massage before and after placental expulsion until the uterus becomes and remains firm, which usually happens within 5 minutes but may take up to 30 minutes. Uterine massage was not clearly beneficial in reducing blood loss in a meta-analysis of randomized trials [2]; however, given the low quality of available data and absence of harm, he continues to perform this procedure.

In this meta-analysis of randomized trials of uterine massage after vaginal birth (three trials, 3842 singleton pregnancies), uterine massage did not reduce PPH in patients who had already received oxytocin prophylaxis and controlled cord traction (blood loss ≥500 mL: 5.9 versus 4.0 percent, RR 1.09, 95% CI 0.33-3.64; low-quality evidence) [2]. All other outcomes (eg, other assessments of blood loss, use of additional uterotonics, and retained placenta) were similar with or without uterine massage. Uterine massage was performed before or after delivery of the placenta, or both.

No randomized trials have analyzed the efficacy of uterine massage after cesarean birth, so its efficacy and safety in this setting are unknown [3].

Identifying patients at high risk for PPH — There is no consensus regarding the precise criteria that distinguish pregnant persons who are at high risk for PPH from those at low risk; labor and delivery units should establish criteria for their unit. The author's labor and delivery unit uses criteria based on the Association of Women's Health, Obstetric and Neonatal Nurse (AWHONN) PPH risk assessment tool [14]. Available risk-factor assessment tools are designed primarily to identify patients who should be crossmatched on admission to the labor unit, and many do not account for risk factors for PPH that develop during the course of labor (eg, prolonged second stage, prolonged oxytocin use, active bleeding, chorioamnionitis, use of magnesium sulfate, unplanned cesarean, vacuum or forceps assisted birth, retained placenta). Risk factors for PPH and risk assessment tools are discussed in detail separately. (See "Overview of postpartum hemorrhage", section on 'Risk factors for PPH' and "Overview of postpartum hemorrhage", section on 'PPH risk assessment tools and risk-based preparation'.)

Active management in resource-limited settings — Resource-limited settings may lack the ability to refrigerate medications that require refrigeration. Options include:

●Nipple stimulation/breastfeeding might reduce the incidence of PPH by promoting the release of endogenous oxytocin [15]. This safe, inexpensive, and easy-to-apply intervention is suggested when medications are not available or are declined by the patient.

●Heat-stable carbetocin does not require refrigeration. It appears to be the preferred uterotonic medication where appropriate refrigeration for medication transport and storage are unavailable. A multicenter, randomized noninferiority trial comparing intramuscular (IM) injections of heat-stable carbetocin (100 mcg) with oxytocin (at a dose of 10 units) immediately after vaginal birth reported the frequency of blood loss ≥500 mL or use of additional uterotonic medications was similar for both groups (14.5 and 14.4 percent, respectively; RR 1.01, 95% CI 0.95-1.06), consistent with noninferiority [16]. The frequency of blood loss ≥1000 mL was also similar (1.51 and 1.45 percent, respectively; RR 1.04, 95% CI 0.87-1.25), but noninferiority was not proven as the upper 95% CI exceeded the noninferiority margin, likely because the trial was underpowered for this outcome. (See 'Carbetocin' below.)

●Misoprostol is another inexpensive uterotonic medication that does not require refrigeration. It can be taken orally or rectally, which is an added advantage over carbetocin, which requires needles for administration. (See 'Misoprostol' below.)

Management of PPH — If excessive uterine bleeding occurs despite prophylaxis, then a management of PPH protocol should be initiated. (See "Overview of postpartum hemorrhage" and "Postpartum hemorrhage: Medical and minimally invasive management".)

MEDICATIONS

Oxytocin — Oxytocin is structurally similar to vasopressin and secreted by the posterior pituitary gland. Stimulation of oxytocin receptors in the myometrium leads to myometrial contractions [17]. The concentration of these receptors increases with gestational age and labor and is higher in the fundus than in the lower uterine segment [18].

Effectiveness — In a network meta-analysis of randomized trials, oxytocin was more effective than placebo/no treatment for reducing postpartum hemorrhage (PPH) ≥500 mL (relative risk [RR] 0.58, 0.49-0.70) [7].

Administration — Intravenous (IV) administration of oxytocin is preferable to intramuscular (IM) administration because it is more effective, dosing is likely more precise, and onset of action is more rapid, but IM injection is an acceptable alternative for patients who do not have IV access. We prefer IV infusion to IV bolus. Hypersensitivity to the medication is the only contraindication to use.

In a meta-analysis of randomized trials of prophylactic IV oxytocin (usually 10 units in one liter of normal saline administered at differing infusion rates) versus IM oxytocin (usually 10 units once) for reducing blood loss in the third stage of labor (7 trials, 7817 participants), IV administration reduced the risk of PPH ≥500 mL (5.6 versus 7.2 percent, average RR 0.78, 95% CI 0.66-0.92) and blood transfusion (0.6 versus 1.3 percent, average RR 0.44, 95% CI 0.26-77) and trended toward reduced serious maternal morbidity (0.3 versus 0.6 percent, average RR 0.47, 95% CI 0.22-1.00) and reduced PPH ≥1000 mL (1.5 versus 2.3 percent, average RR 0.65, 95% CI 0.39-1.08) [19]. The side effect profile was similar in both groups.

Umbilical vein injection is not effective for prevention of PPH [20].

●Intravenous infusion – The dose and duration of IV oxytocin infusion as a prophylactic agent vary widely among institutions because data are insufficient for making definitive recommendations for optimal dosing and duration of therapy [21]. A common dose is 10 to 40 units of oxytocin in 500 to 1000 mL of 0.9 percent saline, with the rate of infusion adjusted according to uterine tone, up to 500 mL/hour [22]. The rate is then decreased (eg, to 1 to 2.5 units/hour) as long as firm uterine tone is maintained and bleeding is not excessive.

•The author's regimen is 30 units in 500 mL 0.9 percent saline by IV infusion over one hour, followed by an additional 30 units in 500 mL infused at 125 mL/hour (2.5 units/hour) until completely infused.

•One expert group (CMQCC) suggests 10 to 30 units in 500 mL crystalloid or 20 to 60 units in 1000 mL crystalloid [23]. A typical infusion is 30 units in 500 mL crystalloid infused at 334 mL/hour to provide 10 units over the first 30 minutes, followed by a maintenance rate of 125 mL/hour to provide 7.5 units over the next 60 minutes [23].

Administration of a standardized concentration as per facility protocol reduces the risk of medication errors [24]. Some facilities prepare the same oxytocin concentration for managing the third stage of labor and for induction of labor to minimize the risk for medication errors.

The IV line is removed at the end of the oxytocin infusion if the patient is stable. Although the total infusion time in patients with normal uterine tone and volume of bleeding varies among protocols, two to four hours after birth is common [25,26]. Some providers extend the infusion for up to eight hours in patients at high risk for hemorrhage.

Doses higher than approximately 40 units over 60 minutes have been studied but did not demonstrate a clear benefit. In a randomized trial comparing two oxytocin doses (80 units/500 mL versus 10 units/500 mL infused over one hour) after vaginal birth, there was no significant difference between the doses in the composite outcome of atony or hemorrhage requiring treatment (uterotonic medications, transfusion, tamponade, embolization, surgery) [27]. High-dose oxytocin was not associated with an increased frequency of side effects requiring a fluid bolus or pressor treatment for hypotension or diuresis for fluid overload. A meta-analysis of intravenous oxytocin dosing regimens for the prevention of postpartum hemorrhage following cesarean birth found no clear evidence of a superior regimen [21]. Infusion of as much as 80 units over 30 minutes was used in one trial with no increase in side effects [28]. Although hypotension, cardiac arrhythmia, and other cardiovascular events can occur secondary to oxytocin administration, even in patients without cardiovascular risk factors, the relationship between these adverse events and specific doses or types of IV administration regimens has not been well-studied.

●Intramuscular administration – IM administration of 10 units oxytocin is an acceptable alternative to IV infusion, especially if there is no IV access, but it is somewhat less effective than IV oxytocin, as described above [19,29,30]. Onset of action is slower (three to seven minutes versus less than one minute with the IV route), but the clinical effect lasts longer (probably ≥1 hour versus three to five minutes with the IV route). Repeated IM dosing has not been studied, but one monograph suggested that the 10 unit IM dose may be repeated in four hours [31].

●Intravenous bolus – Oxytocin given as an IV bolus is effective [32-35], but the safety of this route has been questioned due to case reports of significant hypotension associated with rapid injection, which may lead to myocardial ischemia, cardiovascular collapse, and death [36-39]. These cases were in patients undergoing cesarean birth under neuraxial anesthesia and may have been related, at least in part, to the anesthesia and underlying cardiovascular disease. No instances were reported in a trial of over 1000 patients undergoing vaginal birth [40]. Although bolus injection may be desirable in some patients undergoing treatment of PPH, it is unnecessary for prophylaxis of PPH and should be avoided in patients with risk factors for cardiovascular disease.

If a bolus injection is given, the minimum effective bolus dose of oxytocin is unclear but appears to be ≤3 units over at least one minute and may be as low as 0.3 units [41,42]. If the initial bolus injection is not effective, it may be repeated once or twice before trying a different medication. Slow injection over three minutes has been recommended to attenuate the cardiovascular responses (decrease in blood pressure and systemic vascular resistance index, increase in cardiac and left ventricular work indexes) associated with rapid bolus [43]. A French guideline suggested 5 to 10 units IV over at least one minute, but over at least five minutes in patients with overt cardiovascular risk factors [26].

After the bolus injection, initiation of an oxytocin infusion is common and appears to reduce blood loss and the need for blood transfusion and/or additional uterotonic agents compared with bolus injection alone [44,45]. However, the combination of a bolus injection and an infusion does not appear to reduce the need for additional uterotonic agents compared with use of an infusion alone, despite causing an initially stronger uterine contraction [46]. (See "Anesthesia for cesarean delivery", section on 'Administration of uterotonics'.)

Do delivery characteristics affect oxytocin dosing? — The author administers the same oxytocin dose after vaginal or cesarean birth. Whether dosing should be adjusted based on vaginal versus cesarean birth, scheduled cesarean versus intrapartum cesarean (especially after oxytocin induction or augmentation of labor), and risk factors for PPH has not been studied extensively; protocols vary among institutions [47]. (See "Anesthesia for cesarean delivery", section on 'Administration of uterotonics'.)

The author accounts for higher-risk clinical settings by administering a combination of medications, as described above (see 'Choice of medication' above). In the network meta-analysis of randomized trials discussed above, the combination of oxytocin plus ergometrine or misoprostol resulted in fewer PPHs ≥500 and ≥1000 mLs at cesarean birth compared with oxytocin alone, although the reduction for PPH ≥1000 mLs was not statistically significant (PPH ≥500 mLs: 423 per 1000 with combination prophylaxis versus 604 per 1000 with oxytocin alone; PPH ≥1000 mLs: 124 versus 133 per 1000) [7].

Others have suggested administering higher oxytocin doses for high-risk intrapartum cesareans (eg, 3 to 5 unit bolus over 30 to 60 seconds followed by a maintenance infusion of 8 to 16 units/hour for two to four hours) and lower oxytocin doses for low-risk scheduled cesareans (eg, 1 unit bolus over 30 to 60 seconds followed by a maintenance infusion of 3 to 6 units/hour for two to four hours; after two minutes, an addition bolus of 1 to 3 units may be given if required) [47,48].

Side effects — Most side effects of oxytocin are related to the dose and rate of administration. Relaxation of vascular smooth muscle cells and peripheral vasodilation are associated with flushing. Rapid IV administration (ie, IV bolus) of a high dose of oxytocin can cause serious side effects, such as hypotension and tachycardia, which may lead to chest pain, cardiovascular collapse, and death. Rarely, large doses of oxytocin given for a prolonged period have caused water retention, leading to hyponatremia and its sequelae. Oxytocin can prolong the QT interval, but an electrocardiogram is not needed routinely before use. (See "Induction of labor with oxytocin", section on 'Side effects'.)

Misoprostol — Misoprostol is a synthetic prostaglandin E1 analog that causes uterine contractions. Its heat stability and ease of administration are advantageous compared with oxytocin and ergot alkaloids in those low-resource areas where refrigeration and sterile needles are not available.

Effectiveness — In a network meta-analysis of randomized trials, misoprostol was more effective than placebo/no treatment for reducing PPH ≥500 mL (RR 0.63, 0.52-0.76) [7]. Outcomes compared with oxytocin alone were mixed (eg, PPH ≥500 mL: RR 1.08, 95% CI 0.94-1.24; PPH ≥1000 mL: RR 1.26, 95% CI 1.11-1.43; blood transfusion: RR 0.81, 95% CI 0.65-1.00).

Administration — Misoprostol can be administered orally, sublingually, buccally, or per rectum. Vaginal administration is not practical postpartum because uterine bleeding can interfere with absorption of the medication. The oral, sublingual, and buccal routes have a relatively rapid onset of action (within 10 to 15 minutes) and more rapid onset than rectal administration. The half-life is 20 to 40 minutes. Hypersensitivity to the medication is a contraindication.

The International Federation of Obstetrics and Gynecology and the World Health Organization (WHO) recommend administration of misoprostol 600 mcg orally when injectable uterotonics are not available [49,50].

Side effects — Common side effects include shivering and fever. Misoprostol-related fever is usually preceded by shivering, begins within 20 minutes of administration, peaks at one to two hours, and spontaneously declines over three hours [51]. The incidence of fever varies by dose and route of administration and is most common in patients receiving high doses sublingually [52]. In one small pharmacodynamic study, 8 percent of patients receiving 200 or 400 mcg sublingual misoprostol developed fever over 39°C, while 45 percent of those receiving 600 mcg became febrile [53].

Other side effects include vomiting and diarrhea, which occur in approximately 5 percent of patients [54,55].

Ergot alkaloids — Ergot alkaloids are serotonergic receptor agonists in smooth muscle, weak antagonists of dopaminergic receptors, and partial agonists of alpha-adrenergic receptors. They induce fast rhythmic uterine contractions leading to sustained uterine contraction (spasm, tetany) [56]. The most common ergot alkaloids used for prevention of PPH are ergometrine/ergonovine, methylergometrine/methylergonovine, and the combination ergometrine-oxytocin. Ergometrine-oxytocin takes advantage of the rapid onset of action of oxytocin and the prolonged uterotonic effects of an ergot alkaloid (half-life 30 to 120 minutes).

Effectiveness — In a network meta-analysis of randomized trials, ergometrine alone was more effective than placebo/no treatment for reducing PPH ≥500 mL (RR 0.63, 0.48-0.84) [7]. Compared with oxytocin alone, there was a trend toward lower efficacy (RR 1.31, 95% CI 0.86-1.99).

The combination oxytocin-ergometrine (brand name Syntometrine) is not available in the United States. In the network analysis, ergometrine plus oxytocin was more effective than placebo/no treatment for reducing PPH ≥500 mL (RR 0.37, 95% CI 0.3-0.46).

Administration — Ergot alkaloids are usually given by IM injection. Because of their vasoconstrictive effects, ergot alkaloids are contraindicated in patients with hypertension, Raynaud phenomenon, or known coronary artery disease, as well as hypersensitivity to the medication.

●Methylergonovine (methylergometrine) or ergonovine (ergometrine; not available in the United States) is usually administered at a dose of 0.2 mg IM. Onset of action is two to five minutes. Alternatively, the medication may be injected directly into the myometrium.

Slow intravascular injection is possible but not recommended due to the potential for serious cardiovascular or cerebrovascular adverse events [57]. Oral administration is also possible but not recommended because it takes 20 to 30 minutes before a myometrial effect occurs, and the effect is unpredictable due to variable bioavailability [17,58].

●The combination oxytocin-ergometrine consists of 5 units oxytocin plus 0.5 mg ergometrine and is administered IM.

Side effects — A major disadvantage of ergot alkaloids compared with oxytocin is that they are associated with more side effects, particularly an increased risk of blood pressure elevation and its sequelae [7,59]. Other side effects include headache, an increase in postpartum abdominal pain requiring analgesia, and vomiting.

Carbetocin — Carbetocin, a long-acting synthetic analog of oxytocin, has similar pharmacologic properties to those of natural oxytocin, but the half-life (40 minutes) is 4 to 10 times longer [60]. It binds to smooth muscle receptors of the uterus and has been reported to produce a tetanic uterine contraction within two minutes, lasting approximately six minutes, followed by rhythmic contractions for one hour [61]. It is available in many countries (but not in the United States) for prevention of uterine atony and hemorrhage.

Potential advantages of carbetocin are its long duration of action and availability of a heat-stable formulation. (See 'Active management in resource-limited settings' above.)

Effectiveness — In a network meta-analysis of randomized trials, carbetocin was more effective than placebo/no treatment for reducing PPH ≥500 mL (RR 0.42, 0.31-0.57) [7]. It was also more effective than oxytocin alone (RR 0.75, 95% CI 0.58-0.98).

In a network meta-analysis of randomized trials limited to cesarean births, carbetocin was superior to oxytocin for reducing the estimated blood loss, but by a clinically insignificant volume (55 mL, 95% CI 26–144) and for reducing need for additional uterotonic medications (68 versus 253 times per 1000 cases, 95% CI 130–218) [62].

Administration — Carbetocin 100 mcg is administered IV over 30 to 60 seconds [47,60]. It can also be given by IM injection. The dose is the same after vaginal birth, scheduled cesarean birth, and intrapartum cesarean birth [47]. Lower doses may be sufficient, and repeated if required, up to a total maximum cumulative dose of 100 mcg. The long duration of action eliminates the need for an infusion after the initial dose.

Side effects — Carbetocin has a similar side effect profile as oxytocin (including QT prolongation), but available data are limited [7]. (See 'Side effects' above.)

Tranexamic acid — Tranexamic acid is an antifibrinolytic medication that has been useful for both prevention and treatment of bleeding in various clinical settings. Its mechanisms of action have not been elucidated completely and may extend beyond antifibrinolysis [63] Its use has become a standard of care in the treatment of patients with PPH; the author of this topic uses it prophylactically as well.

Effectiveness

After vaginal birth — In a 2020 meta-analysis of randomized trials of prophylactic use of tranexamic acid after vaginal birth compared with placebo/no tranexamic acid (four trials, 4671 participants), the intervention reduced the incidence of PPH ≥500 mL (8.7 versus 11.4 percent, RR 0.61, 95% CI 0.41-0.91) and modestly reduced total mean blood loss (mean difference -84.74 mL, 95% CI -109.76 to -59.72 mL) without significantly reducing the rate of transfusion (0.8 versus 1.0 percent; RR 0.87, 95% CI 0.46-1.64) or increasing the risk of thrombotic events [8]. The trial participants were mostly nulliparous and at low risk of PPH.

After cesarean birth — In a 2023 meta-analysis of randomized trials comparing prophylactic use of tranexamic acid with placebo, no treatment, standard treatment, or prostaglandin analogs controls at cesarean birth (50 trials; six in only high-risk patients [eg, placenta previa, placenta accreta or percreta, history of PPH, polyhydramnios, chorioamnionitis, and uterine fibroids], one in both high- and low-risk patients, two with prostaglandins as the comparator), prophylactic tranexamic acid was shown to [64]:

●Reduce blood loss >1000 mL (high-risk patients: 11.03 versus 45.5 percent, RR 0.26, 95% CI 0.17-0.42; low-risk patients 11.1 versus 13.8 percent, RR 0.64, 95% CI 0.51-0.81). Administration before making the skin incision resulted in greater benefit for reducing blood loss >1000mL than after birth/cord clamping (before: 3.3 versus 11.2 percent with placebo/no treatment; RR 0.33; 95% CI 0.25−0.44 versus after: 12.9 versus 15.0 percent with placebo/no treatment, RR 0.86, 95% CI 0.79-0.93). The test for before versus after subgroup differences was statistically significant.

●Reduce total blood loss (high-risk patients: mean difference -378 mL, 95% CI -449 to -306; low-risk patients: mean difference -180 mLs, 95% CI -203 to -156). Administration before making the skin incision did not result in a greater benefit than administration after birth/cord clamping and the test for before versus after subgroup differences was not statistically significant.

●Reduce need for blood transfusion (high-risk patients: 6.8 versus 24.5 percent, RR 0.28, 95% CI 0.17-0.44; low-risk patients 2.8 versus 3.9 percent, RR 0.48, 95% CI 0.35-0.68). Administration before making the skin incision reduced the need for blood transfusion (2.4 versus 8.5 percent, RR 0.30, 95% CI 0.22-0.41) but the difference from placebo/no treatment was not statistically significant when given after birth/cord clamping (3.1 versus 3.5 percent, RR 0.87, 95% CI 0.74-1.04). The test for before versus after subgroup differences was statistically significant.

●The number of thromboembolic events was very low and not significantly different for the two groups, but only reported in three trials.

The findings of this meta-analysis should be interpreted with caution. The two largest trials [10,65] reported no substantial benefits of tranexamic acid in reducing the risk for PPH in a largely low-risk population, directly contrasting with the numerous smaller trials that report significant decreases in blood loss. The largest of these randomized trials included 11,000 patients undergoing cesarean birth at 31 hospitals [65]. Administration of tranexamic acid (1 g) intravenously over a period of 10 minutes immediately after umbilical-cord clamping was not significantly more effective than placebo for reducing the following major outcomes:

●Composite of maternal death or blood transfusion (3.6 versus 4.3 percent; aRR 0.89, 95% CI 0.74-1.07)

●Estimated intraoperative blood loss >1000 mL (7.3 versus 8.0 percent; RR 0.91, 95% CI 0.79-1.05)

Patients who received tranexamic acid were less likely to need intervention in response to bleeding complications and had a slightly smaller decrease in hemoglobin levels:

●Interventions for bleeding complications (16.1 versus 18.0 percent; RR 0.90, 95% CI 0.82 to 0.97)

●Change in hemoglobin level (-1.8 g/dL versus -1.9 g/dL; mean difference -0.1 g/dL, 95% CI -0.2 to -0.1)

A limitation of the many small trials in the meta-analysis [64] is that they used different criteria, thresholds, and methods to define and assess PPH, and some used poor randomization procedures and allocation concealment. A possibly important issue with the large trials [10,65] is that they administered tranexamic acid after cord clamping, whereas subgroup analyses in the meta-analysis suggested that it might only be beneficial when administered before skin incision. In general surgery, tranexamic acid is administered before skin incision for reducing surgical bleeding and is effective.

Administration — Tranexamic acid 1 g is administered intravenously (IV) over 10 minutes. When used prophylactically, the author of this topic administers the medication after cord clamping at vaginal birth and before making the skin incision at cesarean birth.

Although it freely crosses the placenta, no fetal harm has been reported in the limited available evidence, and it appears to be more effective if administered at the beginning of the cesarean (before incision) [66,67]. Contraindications include a known thromboembolic event in pregnancy, history of coagulopathy, active intravascular clotting, or known hypersensitivity to the medication [68].

Side effects — Thrombosis and thromboembolism (venous and arterial, including central retinal artery/vein obstruction) are theoretic concerns, but a statistically significant increase in such events compared with controls was not reported in a meta-analysis of randomized trials in patients of all ages, sexes, and medical/surgical disciplines (216 trials, >125,000 patients, thrombotic events 2.1 versus 2.0 percent in the control group, risk difference  0.001; 95% CI -0.001 to 0.002) [69]. As discussed above, there was a trend toward increased thromboembolic events in one randomized trial in which tranexamic acid was administered prophylactically after cesarean birth [10]. (See 'Effectiveness' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Labor" and "Society guideline links: Obstetric hemorrhage".)

SUMMARY AND RECOMMENDATIONS

●Active management of the third stage of labor is routinely utilized because this approach reduces mean blood loss and the rate of postpartum hemorrhage (PPH). It usually consists of pharmaco-prophylaxis (table 1) just before or after birth, typically with controlled traction of the umbilical cord; some protocols include uterine massage. Pharmacotherapy is the more important component; cord traction has been associated with modest benefits, while uterine massage has not been proven to reduce blood loss but is not harmful and commonly performed. (See 'Active management' above.)

•For patients at high risk of PPH, we suggest administering oxytocin plus a second medication (eg, tranexamic acid, misoprostol, methylergometrine) or carbetocin alone (where available) rather than oxytocin alone to reduce risk of PPH (Grade 2C) (algorithm 1). Use of a combination of medications or carbetocin alone results in a lower incidence of PPH than oxytocin alone and appears to reduce the need for additional uterotonic medications or blood transfusion compared with oxytocin alone. The author's preference is to use oxytocin plus either misoprostol or tranexamic acid. (See 'Active management' above.)

There is no consensus regarding the precise criteria that distinguish patients who are at high risk for PPH from those at low risk; labor and delivery units should establish criteria for their unit. (See 'Identifying patients at high risk for PPH' above.)

•For patients at low risk of PPH, either oxytocin alone or oxytocin plus a second medication (eg, tranexamic acid, misoprostol, methylergometrine) or carbetocin alone (where available) is an acceptable approach for reducing the risk of PPH. The absolute risk reduction in low-risk patients is modest. The author's preference is to administer oxytocin plus either misoprostol or tranexamic acid, even in low-risk patients. Combined therapy in low-risk patients is not the routine approach of the other contributors of this topic. (See 'Active management' above.)

•If excessive uterine bleeding occurs despite prophylaxis, then a management of PPH protocol should be initiated. (See "Overview of postpartum hemorrhage" and "Postpartum hemorrhage: Medical and minimally invasive management".)

●Medications

•Oxytocin has a rapid onset of action and short half-life. We prefer intravenous (IV) infusion, but intramuscular (IM) administration is an acceptable alternative and necessary for patients without IV access. Rapid IV administration (ie, bolus injection) is unnecessary for prophylaxis and can cause hypotension, which may lead to myocardial ischemia and cardiovascular collapse. (See 'Oxytocin' above.)

•Misoprostol can be administered orally, buccally, sublingually, or rectally. Because it does not require refrigeration, its use is advantageous in resource-limited areas where medications that must be refrigerated or require needles for IM injection/IV administration may pose a problem. The World Health Organization (WHO) suggests using a single dose of 600 mcg orally. (See 'Misoprostol' above and 'Active management in resource-limited settings' above.)

•Ergot alkaloids induce fast rhythmic uterine contractions leading to sustained uterine contraction. They are contraindicated in patients with hypertension or Raynaud phenomenon. A major disadvantage of these medications is that they are associated with an increased frequency of blood pressure elevation, pain requiring analgesia, and vomiting. (See 'Ergot alkaloids' above.)

•Carbetocin, a long-acting synthetic analog of oxytocin, has similar pharmacologic properties to those of natural oxytocin, but the half-life (40 minutes) is 4 to 10 times longer. It is as (or more) effective than oxytocin for preventing PPH, with a similar toxicity spectrum. (See 'Carbetocin' above.)

Heat-stable carbetocin is advantageous in resource-limited areas where medications requiring refrigeration are not practical; however, it requires parenteral injection. (See 'Active management in resource-limited settings' above.)

•Tranexamic acid is an antifibrinolytic medication that is commonly used for treatment of PPH and also appears to be effective when used prophylactically along with a uterotonic medication. The dose is 1 g administered intravenously over 10 minutes. An increased risk for thrombosis is a theoretic concern. (See 'Tranexamic acid' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Frank Silverman, MD, and Eran Bornstein, MD, who contributed to an earlier version of this topic review.