Uterotonic Agents: An Update

US Pharm. 2011;36(5):HS-36-HS-40.  

Generally, the third stage of labor starts with the delivery of the fetus and ends with the delivery of the placenta and its attached membranes. If there is any sign of complications during or after labor, the clinician will determine the risks and assess the situation. As a result, many authorities have named a fourth stage of labor that begins with the delivery of the placenta and lasts for several hours. The most common complication in the third and fourth stages of labor is postpartum hemorrhage (PPH). Although maternal mortality rates are coming down, PPH remains a leading cause of maternal mortality.¹

In the United States, the maternal mortality rate is approximately seven to 10 women per 100,000 live births. National statistics suggest that approximately 8% of these deaths are caused by PPH. However, the World Health Organization (WHO) statistics suggest that worldwide, 25% of maternal deaths are due to PPH, accounting for more than 100,000 maternal deaths per year. The death of these mothers has serious implications for the newborn and any other members of the family.²  

If a complication arises during or after labor, the right choice and proper use of one or two uterotonic agents can control PPH and reduce maternal mortality up to 40%.  For many years, the uterotonic agent of choice has been oxytocin with or without supplemental methylergonovine. Methylergonovine ampules are unstable at room temperature and thus require special temperature and light storage conditions to remain effective. On the other hand, misoprostol, an oral preparation of a prostaglandin (PGE₁) analogue, is a prime candidate due to its uterotonic properties; ease of use as an oral (vaginal usually not used for PPH) or rectal preparation; relatively low cost in some areas; and stability at high temperature. A fourth agent that is used is carboprost, another prostaglandin analogue with other features. This article will briefly review these four drugs and look at their pros and cons as the first line of therapy in the treatment of PPH.³

Oxytocin (Pitocin)

Oxytocin is a synthetic form of the nanopeptide produced in the posterior pituitary. It stimulates the (upper) active segment of the myometrium to contract rhythmically, which constricts spiral arteries and decreases blood flow through the uterus.

Dosing: Synthetic oxytocin is available in a number of different concentrations and forms: 10 USP U/mL vial (1 mL), 20 U/1,000 mL LR/5% dextrose, and 30 U/500 mL LR. All can be stored at room temperature.

For the third stage of labor, oxytocin is dosed at 10 to 40 U/L of IV fluid and given as an IV infusion at a rate of 0.5 to 1 mU/min. The 30-U/500-mL concentration is used for the induction and augmentation of labor with a slow infusion. The rate of infusion should be sufficient to maintain uterine contractility. The plasma half-life of oxytocin is 1 to 6 minutes, and the clinical response is rapid after IV infusion. Administration of IV infusion requires the use of an infusion pump. Oxytocin can be given as an intramuscular (IM) injection (total dose of 10 U) for postpartum bleeding, and the clinical response occurs within 3 to 5 minutes. For adjunctive treatment of abortion, 10 to 20 mU/min is given up to a total dose of 30 U/12 h.¹

Oxytocin is compatible with heparin, hydrocortisone sodium succinate, insulin (regular), meperidine, morphine, potassium chloride, vitamin B complex with C, and warfarin if used as Y-site administration.

Oxytocin side effects are very rare, but occasional nausea and vomiting have been reported. The only serious side effect is dilutional hyponatremia, which may happen with prolonged use. Rapid IV infusion is associated with hypotension and tachycardia. This drug should not be given as an IV bolus. Dinoprostone and misoprostol may enhance the therapeutic effect of oxytocin, and therapy must be modified accordingly. The only contraindication to use of oxytocin would be hypersensitivity to the drug. This drug is probably the safest uterotonic agent.³

Methylergonovine Maleate (Methergine)

Methylergonovine is a semisynthetic ergot alkaloid that is FDA approved for prevention and treatment of postpartum and postabortion hemorrhage caused by uterine atony or subinvolution. Methylergonovine causes generalized smooth-muscle contraction in which the upper and lower segments of the uterus contract tetanically.

It is available as 0.2-mg tablets and is used 0.2 mg 3 to 4 times/day in the puerperium for 2 to 7 days. (Puerperium is the time period following childbirth when the mother's uterus shrinks and the other functional and anatomic changes of pregnancy are resolved.) Methylergonovine's onset of action is within 5 to 10 minutes with a bioavailability of 60%. The IM dose is 0.2 mg after delivery in the anterior shoulder, after delivery of the placenta, or during the puerperium; the dose may be repeated as required at intervals of 2 to 4 hours. The onset of the IM dose is 2 to 5 minutes, with a bioavailability of 78%. This drug should not be given by IV administration routinely, and it must be refrigerated when stored.⁴

Ergot alkaloids are contraindicated with potent inhibitors of CYP450 3A4 (includes protease inhibitors, azole antifungals, and some macrolide antibiotics); with hypertension; with toxemia; and in pregnancy.

Caution: Prolonged constriction of the uterine vessels and/or increased myometrial tone may lead to reduced placental blood flow. This has contributed to fetal growth retardation in animals.  Methylergonovine is intended for use after delivery of the infant, and it enters breast milk. This drug should be used with extreme caution in patients with hypertension or preeclampsia, especially if ephedrine (a vasoconstrictive agent) is already given.⁵

The combination product oxytocin and ergometrine (Syntometrine) is not used in the U.S.

Misoprostol (Cytotec)

This drug is a synthetic prostaglandin E1 analogue available as 100- and 200-mcg tablets. Misoprostol increases uterine tone and decreases postpartum bleeding. It is used in four different cases, as follows. The first application is not a labor and delivery unit concern.

Prevention of NSAID-induced ulcers: Oral: 200 mcg 4 times/day with food; if not tolerated, may decrease dose to 100 mcg 4 times/day with food. Last dose of the day should be taken at bedtime.

Postpartum hemorrhage: Prevention or treatment of serious PPH in the presence of uterine atony.

Medical termination of pregnancy: Oral: Use as an adjunct to mifepristone for medical termination of an intrauterine pregnancy. For this purpose, misoprostol 400 mcg is administered orally on Day 3 (2 days after mifepristone administration) unless abortion has occurred and has been confirmed by clinical examination or ultrasonographic scan.

Labor induction or cervical ripening (unlabeled uses): Intravaginal: 25 mcg (1/4 of 100-mcg tablet); may repeat at intervals no more frequent than every 3 to 6 hours. Should not use in patients with previous cesarean delivery or prior major uterine surgery.⁴    

Misoprostol is a water-soluble drug and is quickly absorbed after sublingual, oral, vaginal, and rectal use. The most common method of administering misoprostol for PPH is rectally. The dose usually ranges from 800 to 1,000 mcg. After rectal administration, plasma levels are maintained for longer than sublingual administration. When used orally, the drug undergoes a series of chemical reactions, converting it to a prostaglandin F analogue, very similar to Hemabate (carboprost). Therefore, if Hemabate has failed, the use of misoprostol would be irrational. This drug does not exacerbate bronchospasm in patients with asthma, which is an advantage over Hemabate. One major advantage of this drug is that it is not heat sensitive and can be stored on labor and delivery hospital units.⁶ Some reported side effects include diarrhea, shivering, pyrexia, and headaches.

Carboprost (Hemabate)

Prostaglandins enhance uterine contractility and cause vasoconstriction. The prostaglandin most commonly used is 15-methyl prostaglandin F 2a (Hemabate). Carboprost is used for three different indications.

Refractory postpartum uterine bleeding: IM dosing, initial: 250 mcg; if needed, may repeat at 15- to 90-minute intervals; maximum total dose, 2 mg (8 doses). 

Abortion: IM dosing: 250 mcg, then 250 mcg at 1.5- to 3.5-hour intervals, depending on uterine response; a 500-mcg dose may be given if uterine response is not adequate after several 250-mcg doses; do not exceed 12 mg total dose or continuous administration for >2 days.⁶

Hemorrhagic cystitis (unlabeled/investigational use): Bladder irrigation: 50 mL (0.1-1.0 mg/dL as solution) instilled into bladder 4 times/day for 1 hour.

The drug is supplied in 250-mcg and tromethamine 83-mcg/mL ampules and is given as one ampule for IM injection. In 75% of cases, a successful clinical response is reached within 30 minutes. The clinical response may be enhanced with concomitant use of oxytocin. This drug and other uterotonic agents are less effective in chorioaminonitis. For IM administration, the injection is given deep, and the site is rotated if repeated injections are needed. This drug should not be given IV as it may result in bronchospasm, hypertension, vomiting, or anaphylaxis. Carboprost must be refrigerated when stored.⁷

The reported side effects include nausea, vomiting, diarrhea, bronchospasm, and hypertension. The recommendation is that the drug be given with caution to patients with hepatic or cardiovascular disease, asthma, or hypersensitivity to the drug.

Conclusions

In labor and delivery units, the standard of care for treating PPH is oxytocin, and there should not be a change to this practice. The cost of oxytocin is relatively low, and it is easily available. Recent WHO guidelines on the prevention of PPH recommend that oxytocin be used by skilled clinical staff, but this should not prevent staff who are skilled in administering uterotonics (but not skilled in active management) from administering the drug. In units with active management of the third stage of labor, the staff need to be trained to ensure that they have the skills to use injectable uterotonics and to implement the protocols. In units where this level of proficiency is not available, misoprostol could be considered as the drug of choice, and it is recommended to start with the lowest effective dose to avoid this drug's side effects.⁸

Although the prophylactic IV and IM use of ergot alkaloids during the third stage of labor is effective in reducing blood loss and preventing PPH, the adverse effects of these agents (vomiting, elevation of blood pressure, and pain after birth requiring analgesia), in particular via the IV route of administration, are not very favorable.

The use of methylergonovine plus oxytocin was associated with a small but significant reduction in the incidence of PPH (blood loss ≥500 mL) compared with oxytocin alone irrespective of the dose (5 U or 10 U). Other studies indicate no difference in severe PPH (blood loss ≥1,000 mL) with the methylergonovine-plus-oxytocin combination. However, the addition of methylergonovine to oxytocin increased the incidence of high blood pressure and vomiting, and these harmful effects should be taken into account in determining the best therapy.¹

Oxytocin is the drug of choice for preventing PPH because it is at least as effective as ergot alkaloids or prostaglandins and has fewer side effects. Misoprostol has a role in the prevention of PPH. This drug has more side effects, but is inexpensive, heat and light resistant, and requires no syringes and parenteral skills.

REFERENCES

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2. Jongkolsiri P, Manotaya S. Placental cord drainage and the effect on the duration of third stage labor, a randomized controlled trial. J Med Assoc Thai. 2009;92(4):457-460.
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4. Parsons SM, Walley RL, Crane JM, et al. Rectal misoprostol versus oxytocin in the management of the third stage of labor. J Obstet Gynaecol Can. 2007;29(9):711-718.
5. Derman RJ, Kodkany BS, Goudar SS, et al. Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomized controlled trial. Lancet. 2006;368:1248-1253.
6. Magann EF, Evans S, Chauhan SP, et al. The length of the third stage of labor and the  risk of postpartum hemorrhage. Obstet Gynecol. 2005;105:290-293.
7. Hofmeyr GJ, Walraven G, Gulmezoglu AM, et al. Misoprostol to treat postpartum hemorrhage: a systematic review. BJOG. 2005;112:547-553.
8. Magann EF, Lanneau GS. Third stage of labor. Obstet Gynecol Clin North Am. 2005;32:323-332.

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