Uterine Atony Is Failure of the Uterus to Contract Following Delivery and Is a Common Cause of Postpartum Hemorrhage

Home , Carboprost, Misoprostol, Uterine atony

Uterine atony is failure of the uterus to contract following delivery and is a common cause of postpartum hemorrhage. The options for treating hemorrhage due to this cause are uterotonic agents, including additional oxytocin, carboprost tromethamine, methylergonovine, and misoprostol. Prioritizing the optimal therapy given the circumstances is imperative to maternal safety. ILLUSTRATION: JOE GORMAN FOR OBG MANAGEMENT ILLUSTRATION:

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Stop using rectal misoprostol for the treatment of postpartum hemorrhage caused by uterine atony For women who experience a postpartum hemorrhage, and already have received oxytocin as part of routine obstetric care, prioritize the use of parenteral uterotonics, including oxytocin, methylergonovine, and carboprost tromethamine, and avoid the use of rectal misoprostol

Robert L. Barbieri, MD Editor in Chief, OBG Management Chair, Obstetrics and Gynecology Brigham and Women’s Hospital, Boston, Massachusetts Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology Harvard Medical School, Boston

ost authorities recommend clinical trials and pharmacokinetic 89%, respectively). Fewer women had that, following delivery, studies suggest that rectal misoprostol blood loss of 1,000 mL or greater when Mall women should receive is not an optimal choice if parenteral treated with oxytocin compared with a uterotonic medication to reduce uterotonics are available. Here I pre- misoprostol (1% vs 3%, respectively; the risk of postpartum hemorrhage sent this evidence and urge you to P = .062). In addition, oxytocin was (PPH).1 In the United States, the pre- stop the practice of using rectal miso- associated with fewer temperature ferred uterotonic for this preventive prostol in efforts to manage PPH. elevations of 38°C (100.4°F) or above effort is oxytocin—a low-cost, highly (15% vs 22% for misoprostol, P = .007) effective agent that typically is admin- and fewer temperature elevations of istered as an intravenous (IV) infu- RCTs do not support the 40°C (104°F) or above (0.2% vs 1.2% sion or intramuscular (IM) injection. use of rectal misoprostol for misoprostol, P = .11). Unfortunately, even with the univer- Randomized clinical trials (RCTs) In another trial, women with a sal administration of oxytocin in the have not demonstrated that miso- vaginal delivery who were not treated third stage of labor, PPH occurs in prostol is superior to oxytocin for the with a uterotonic in the third stage about 3% of vaginal deliveries. treatment of PPH caused by uterine were monitored for the develop- A key decision in treating a PPH atony.2 For example, Blum and col- ment of a PPH.4 PPH did develop in due to uterine atony is treatment with leagues studied 31,055 women who 1,422 women, who were then ran- an optimal uterotonic. The options received oxytocin (by IV or IM route) domly assigned to receive oxytocin include: at vaginal delivery and observed (10 U IV or IM) plus a placebo tablet 1. additional oxytocin that 809 (3%) developed a PPH.3 The or oxytocin plus misoprostol (600 µg 2. carboprost tromethamine women who developed PPH were sublingual). (Hemabate) randomly assigned to treatment with Comparing oxytocin alone ver- 3. methylergonovine (Methergine) misoprostol 800 µg sublingual or oxy- sus oxytocin plus misoprostol, there 4. misoprostol. tocin 40 U in 1,000 mL as an IV infu- was no difference in blood loss of Many obstetricians choose rectal sion over 15 minutes. 500 mL or greater after treatment initi- misoprostol alone or in combination Both oxytocin and misoprostol ation (14% vs 14%). However, 90 min- with oxytocin as the preferred treat- had similar efficacy for controlling utes following treatment, temperature ment of PPH. However, evidence from bleeding within 20 minutes (90% and elevations occurred much more often

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serum concentrations, longer time TABLE Peak circulating concentration of misoprostol (pg/mL) following various routes of administration to onset of uterine contraction, and less contractility than buccal admin- Khan Khan Meckstroth istration. The one advantage of rectal 6 7 8 Study (2003) (2004) (2006) administration is that it has a longer Dose of misoprostol 600 µg 400 µg 400 µg duration of action than the oral, buccal, or sublingual routes. In phar- Route of administration macokinetic comparisons of buccal Oral 327 254 − versus sublingual administration of Buccal − − 265 misoprostol, the sublingual route results in greater peak concentra- Vaginal − 211 446 tion, which may cause more adverse 9,10 Rectal 184 87 202 effects. in the women who received oxytocin resulted in higher peak uterine tone Prioritize oxytocin, plus misoprostol compared with the than rectal administration (49 vs methergine, and women who received oxytocin alone 31 mm Hg).8 In addition, time to carboprost tromethamine (temperature ≥38°C: 58% vs 19%; onset of uterine contractility was When treating PPH, administration of temperature ≥40°C: 6.8% vs 0.4%). 41 minutes and 103 minutes, oxytocin, methylergonovine, or carbo- Bottom line: If you have access to respectively, for buccal and rectal prost tromethamine rapidly provides oxytocin, there is no advantage to administration. therapeutic concentration of medica- using misoprostol to treat a PPH due These studies show that rectal tion. For oxytocin, 40 U in 1 L, admin- to uterine atony.5 misoprostol is associated with lower istered at a rate sufficient to control

Rectal misoprostol does Misoprostol is a useful uterotonic if parenteral agents not achieve optimal are not available circulating concentrations of the drug Worldwide, approximately one maternal death occurs every 7 minutes. Post- Misoprostol tablets are formulated partum hemorrhage (PPH) is a common cause of maternal death. Oxytocin, for oral administration, not rectal methylergonovine, and carboprost tromethamine should be stored in a refrig- administration. The studies in the erated environment to ensure the stability and bioavailability of the drug. In settings in which reliable refrigeration is not available, misoprostol, a medica- TABLE show that rectal administration that is heat-stable, is often used to prevent and treat PPH. tion of misoprostol results in lower One approach to preventing PPH is to provide 600 µg of misoprostol to circulating concentration of the women delivering at home without a skilled birth attendant that they can self- medication compared to oral, buc- administer after the delivery.1,2 Another approach is to recommend that skilled cal, or vaginal administration.6−8 After birth attendants administer misoprostol following the delivery.3 rectal administration it takes about Although I am recommending that we not use rectal misoprostol to treat PPH in the United States, it is clear that misoprostol plays an important role in prevent- 60 minutes to reach the peak circulating PPH in countries where parenteral uterotonics are not available. If a clinician in ing concentration of misoprostol.6,7 the United States was involved in a home birth complicated by PPH due to uterine By contrast, parenteral oxytocin, atony, and if misoprostol was the only available uterotonic, it would be wise to methylergonovine, and carboprost administer it promptly. tromethamine reach peak serum References concentration much more quickly 1. Rajbhandari S, Hodgins S, Sanghvi H, McPherson R, Pradhan YV, Baqui AH; Misoprostol Study Group. Expanding uterotonic protection following childbirth through community-based distribution of misopros- after administration. tol: operations research study in Nepal. Int J Gynaecol Obstet. 2010;108(3):282−288. In a study of misoprostol stim- 2. Sanghvi H, Ansari N, Prata NJ, Gibson H, Ehsan AT, Smith JM. Prevention of postpartum hemorrhage at home ulation of uterine contractility as birth in Afghanistan. Int J Gynaecol Obstet. 2010;108(3):276−281. 3. Prata N, Mbaruku G, Campbell M, Potts M, Vahidnia F. Controlling postpartum hemorrhage after home measured by an intrauterine pres- births in Tanzania. Int J Gynaecol Obstet. 2005;90(1):51−55. sure catheter, buccal administration

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10 OBG Management | July 2016 | Vol. 28 No. 7 obgmanagement.com Editorial CONTINUED FROM PAGE 10 atony, or 10 U IM injection are often There is scant evidence that effective in controlling bleeding due misoprostol is more effective than to atony. Carboprost tromethamine oxytocin, and misoprostol clearly 0.25 mg administered intramuscularly causes a higher rate of elevated tem- every 15 minutes up to 8 doses pro- perature than any of the parenteral vides an excellent second-line agent. uterotonic agents. In your practice Carboprost tromethamine is contrain- stop using rectal misoprostol for the dicated for women with asthma. treatment of PPH caused by uterine Could you answer Methylergonovine 0.2 mg atony, and prioritize the use of paren- posttest questions administered intramuscularly only teral uterotonics. can be given every 2 to 4 hours. Con- on this editorial? sequently, because time is of the Find out! To test yourself, visit essence in managing a severe PPH, obgmanagement.com it is unusual to be able to administer /md-iq-quizzes. more than one dose of the agent dur- [email protected] Free registration required. ing the course of treatment. Methy- lergonovine is contraindicated for Dr. Barbieri reports no financial women with hypertension. relationships relevant to this article.

References 1. Westhoff G, Cotter AM, Tolosa JE. Prophylactic as an adjunct to standard uterotonics for treat- 8. Meckstroth KR, Whitaker AK, Bertisch S, Gold- oxytocin for the third stage of labour to prevent ment of post-partum haemorrhage: a multi- berg AB, Darney PD. Misoprostol administered postpartum hemorrhage. Cochrane Database centre, double-blind randomised trial. Lancet. by epithelial routes: drug absorption and uter- Syst Rev. 2013;(10):CD001808. 2010;375(9728):1808−1813. ine response. Obstet Gynecol. 2006;108(3 pt 2. Gibbons KJ, Albright CM, Rouse DJ. Postpar- 5. Weeks A. The prevention and treatment of post- 1):582−590. tum hemorrhage in the developed world: partum hemorrhage: what do we know and where 9. Schaff EA, DiCenzo R, Fielding SL. Comparison whither misoprostol? Am J Obstet Gynecol. do we go to next? BJOG. 2015;122(2):202−210. of misoprostol plasma concentrations following 2013;208(3):181−183. 6. Khan RU, El-Refaey H. Pharmacokinetics and buccal and sublingual administration. Contra- 3. Blum J, Winikoff B, Raghavan S, et al. Treat- adverse-effect profile of rectally administered ception. 2005;71(1):22−25. ment of postpartum hemorrhage with sublin- misoprostol in the third stage of labor. Obstet 10. Frye LJ, Byrne ME, Winikoff B. A crossover phar- gual misoprostol versus oxytocin in women Gynecol. 2003;101(5 pt 1):968−974. macokinetic study of misoprostol by the oral, receiving prophylactic oxytocin: a double- 7. Khan RU, El-Refaey H, Sharma S, Sooranna D, sublingual and buccal routes [published online blind, randomised, non-inferiority trial. Lancet. Stafford M. Oral, rectal and vaginal pharmacoki- ahead of print April 22, 2016]. Eur J Contracept 2010;375(9710):217−223. netics of misoprostol. Obstet Gynecol. 2004;103 Reprod Health Care. doi:10.3109/13625187.2016 4. Widmer M, Blum J, Hofmeyr GJ, et al. Misoprostol (5 pt 1):866−870. .1168799.

Have you read ›› A stitch in time: the B-Lynch, Hayman and Pereira uterine compression sutures. OBG Manag. 2012;23(12):6, 8, 10−11. Dr. Barbieri’s other OBG Management ›› Routine use of oxytocin at birth: just the right amount to prevent postpartum hemorrhage. OBG Manag. 2012;24(7):8, 10−11. editorials on ›› Act fast when confronted by a coagulopathy the treatment postpartum. OBG Manag. 2012;24(3):8, 10−11. of postpartum ›› Have you made the best use of the Bakri balloon in PPH? hemorrhage? OBG Manag. 2011;23(7):6, 8−9.

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