Misoprostol as an add on to Oxytocin does not further reduce Postpartum hemorrhage in active management or treatment of PPH.

Clinical Pearls:

• Prophylactic misoprostol at a dose of 400 micrograms, added to oxytocin for active management of the third stage of labor, did not reduce the rate of postpartum hemorrhage, severe postpartum hemorrhage, or second-line procedures.
• Misoprostol will produce no further uterotonic effects after a prophylactic infusion of 10 international units of oxytocin.
• Findings of this trial do not support the use of misoprostol in addition to oxytocin for the prevention of postpartum hemorrhage. 
• Misoprostol may be useful in countries with poor health resources where facilities for refrigeration and skilled birth attendants are not freely available.
• Oxytocin should be used as prophylaxis and as the first line of treatment in active management of labor, especially in high income countries or countries with good healthcare facilities.

Postpartum hemorrhage remains the leading cause of maternal morbidity and mortality worldwide with a prevalence of 6% worldwide with Africa topping the list with 10.5% prevalence. It accounts for 30% of maternal deaths in Africa and Asia.[1]

Deaths due to PPH are preventable and considerable variation exist between developed and developing countries. Uterine Atony is the most common cause of PPH and active management of labor is promoted in developing countries to bring down the maternal mortality.

Oxytocin is the agent of choice because of high efficacy and low adverse effects.[2]

Misoprostol is a prostaglandin E1 analog often used off label in active management of labor because of cost, multiple route of administration and storage advantage.[3] An earlier large randomized multicentric trial compared the efficacy of oxytocin and misoprostol and showed that oxytocin was always the first agent of choice.[4]

After that another study suggested that they both could have synergist effect and reduce PPH further.

A large multicentric, double-blind, randomized, placebo-controlled trial recruited women across three French University hospitals from April 2010 to September 2013. The study subjects consist of women 18 years and older,36-42 weeks of pregnancy, in first stage of labor and under epidural anesthesia. The study was published on September 8 in Obstetrics& Gynecology.[5]

Women who met the inclusion criteria were randomized to receive two tablets of 200 micrograms misoprostol (ie, a total dose of 400 micrograms) or two tablets of placebo orally immediately after delivery of the newborn. Women in both the arm had active management of labor and received prophylactic intravenous injection of 10 international units’ oxytocin after delivery of the fetal anterior shoulder, early clamping of the umbilical cord, and controlled cord traction. 

If patient continued hemorrhaging after the treatment, they received treatment according to the standard protocol of PPH, but misoprostol was not repeated.   

There was not significant difference in both the groups in terms of primary outcome of postpartum hemorrhage greater than 500 mL within 2 hours of birth. (8.4% [68/806] in the misoprostol vs 8.3% [66/797] in the placebo group; P = .98).

After the analysis was performed on 1,721 patients enrolled in study, the trial was discontinued because the combination of misoprostol and oxytocin did nothing to reduce the PPH. Misoprostol when added to prophylactic Oxytocin did not further reduced Postpartum hemorrhage, but rather increased incidence of adverse events in mother. Misoprostol was associated with high rates of adverse effects like fever greater than 38°C (P<.001) and shivering (P<.001), diarrhea and vomiting.

"All in all, the findings of this trial do not support the use of misoprostol in addition to oxytocin for the prevention of postpartum hemorrhage," the authors write. "[D]espite misoprostol's ready availability, easy use, and utility for other pregnancy indications, oxytocin should remain the mainstay of prophylaxis of postpartum hemorrhage in high-income countries, and misoprostol should be used infrequently for this indication."

Misoprostol may be useful in countries with poor health resources where facilities for refrigeration and skilled birth attendants are not freely available.

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[1] http://apps.who.int/rhl/archives/guideline_pphprevention_fawoleb/en/

[2] Westhoff G, Cotter AM, Tolosa JE. Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage

[3] Tunçalp Ö, Hofmeyr GJ, Gülmezoglu AM. Prostaglandins for preventing postpartum haemorrhage.

[4] Gülmezoglu AM, Villar J, Ngoc NT, Piaggio G, Carroli G, Adetoro L, et al. WHO multicentre randomised trial of misoprostol in the management of the third stage of labour. Lancet 2001;358:689–95.

[5] http://journals.lww.com/greenjournal/Fulltext/2016/10000/Active_Management_of_the_Third_Stage_of_Labor_With.17.aspx#P70