Misoprostol

Misoprostol as Postpartum Hemorrhage Prophylaxis

The leading cause of maternal death and morbidity is postpartum hemorrhage (PPH: >500 mL of blood loss, severe PPH: > 1000 mL blood loss). The failure or delay of the uterus to properly contract after delivery can lead to massive hemorrhage resulting in severe morbidity or death for many mothers. Shortening the third stage of labor through administration of a prophylactic uterotonic agent to assist with uterine contraction decreases postpartum blood loss and the incidence and severity of hemorrhage.

Oxytocin is the drug of choice for PPH prophylaxis; however, it requires skilled attendants, cold storage and sterile equipment. Thus it is not available in many community-based clinical settings. It is typically not available to the many women giving birth at home. The WHO, FIGO, and ICM have endorsed misoprostol use among trained health care workers where oxytocin is unavailable.

Unlike oxytocin, misoprostol can be administered orally, does not require refrigeration, and has a long shelf life. The WHO recommends the administration of 600 µg of oral misoprostol by a health care worker trained in its use immediately after the birth of the baby to produce uterine contractions to reduce the risk of PPH. Research indicates that the administration of 600 µg of oral misoprostol prophylactically is associated with a significant reduction of the rate of PPH, and there is popular support for the distribution of misoprostol at the community level for PPH prevention.

Distribution of misoprostol varies depending upon the community infrastructure and national policies regarding its use, and the availability of community level providers. There are multiple models for the appropriate distribution of misoprostol in community level health care settings. For instance, in settings where the terrain or weather inhibit women’s access to skilled birth attendants, or where birth attendants are barred from providing medication, the direct distribution of misoprostol to pregnant women may be the most feasible option. As of 2010, misoprostol has been registered for use for treatment of PPH in 17 countries in Africa and Asia, but it has not yet been piloted in all community level health care programs.

Misoprostol as Postpartum Hemorrhage Treatment

The evidence base for misoprostol as treatment for postpartum hemorrhage is less developed; however, the WHO recommends misoprostol where oxytocin is not available to treat PPH after a thorough review of 46 randomized control trials (RCTs) of misoprostol’s affect on PPH (Hofmeyr et al., 2009).

An analysis of the distribution of misoprostol as a treatment of 800µg for PPH versus a prophylactic of 600µg for prevention at a home on the community level reported significant reductions in mortality for both methods, of 70% and 81% respectively, and concluded that misoprostol use was more effective at decreasing mortality than standard management of PPH (Sutherland, Meyer, Bishai, Geller, & Miller S., 2010).

Concerns around Misoprostol

Concerns around broad misoprostol recommendation stem from observed side effects such as fever, nausea, shivering, and diarrhea and very few reports of death. Side effects are dose dependent, with 4% – 38% reporting fever at 600 µg, and 32% – 57% reporting shivering. Very rarely malignant high fever has been reported at 800 µg (Hofmeyr et al., 2009). Little clinical information on the contexts of the few severe adverse events is available; thus, while it is generally regarded as safe, monitoring of unexpected adverse events is necessary.

The Continuum of Care

Prophylactic uterotonic administration is an important component to the continuum of care model for postpartum hemorrhage. However, despite prophylaxis, some women will still develop PPH. Identification and quantification of excessive bleeding is critical to preventing mortality and morbidity from PPH and expediting the referral and treatment process. Visit our Continuum of Care (CC) webpage to learn more about how the CC for postpartum hemorrhage can reduce the risk of pregnancy-related mortality and morbidity.

The UCSF Safe Motherhood Program provides technical assistance and consultation to other activities involving misoprostol, including Comprehensive Maternal Health Projects in Timor Leste and Tanzania.

Safe Motherhood Program Misoprostol Research 

Misoprostol for Secondary Prevention of OH at Homebirths and Sub-Center Births Attended by Rural Auxiliary Midwives: A Randomized Cluster Trial of Two Methods of Service Delivery

Project Background 

In India, 125,000 girls and women are lost every year.

In India, fewer than 50% of women have a skilled attendant at birth; the maternal mortality ratio is 254 (254 women die for every 100,000 live births), and a lifetime risk of maternal death of 1 in 70 (UNICEF, 2009).

Project Description

Treatment options for post-partum haemorrhage are needed at the community level as universal prophylaxis with uterotonics is not 100% effective. A new approach, secondary prevention, may eliminate prioritization of prevention or treatment strategies, as it preemptively treats women with above-average post-partum bleeding. This trial assessed whether secondary prevention is non-inferior to universal prophylaxis.

In collaboration with the BDLEA, Bijapur, Karnataka, India; KLE University’s JN Medical College, Belgaum, Karnataka, India; University of Illinois at Chicago; and Gynuity Health Projects, UCSF’s Safe Motherhood Program is conducting a cluster randomized trial of two service delivery methods of prevention of obstetric hemorrhage.

In the control arm of the study, auxiliary nurse midwives (ANMs) give all women they attend, whether birthing at home or at the Sub-Center, 600 µg oral misoprostol for universal prophylaxis. In the experimental arm, ANMs only give 800 µg sublingual misoprostol to women who lose more than 350 mL blood after delivery. We call the experimental arm a hybrid approach, as 500 mL is the definition of hemorrhage. Our goal is to investigate whether a secondary prevention approach is as effective as universal prophylaxis in preventing hemorrhage. This will reduce the need for transport to referral facilities and overall costs. We also intend to assess acceptability to families and ANMs.

September 2013

As of September 2013, more than 2000 of the estimated 3000 women have been enrolled in the study.

March 2014 

All 3000 women have been enrolled and study entry has been stopped.

December 2014

The analysis of the primary outcome included 1064 women enrolled by 18 ANMs offering primary prevention and 1937 women enrolled by 20 ANMs offering secondary prevention. Misoprostol was administered to 99·7% of women in primary prevention. In secondary prevention, 92 (4·7%) women had post-partum bleeding ≥350 mL and should have received misoprostol per protocol; 90 (97·8%) received misoprostol. The proportion of women with post-partum hemoglobin ≤7·8 g/dL was 5·9% and 8·8% in secondary and primary prevention clusters, respectively (difference = -2·9%, one-sided 95% CI <1·3%). Post-partum transfer and haemorrhage rates were low (<1%) in both groups. Shivering was more common in primary prevention clusters (p=0·013). The majority of ANMs and mothers found both strategies of misoprostol administration acceptable.

We found secondary prevention of post-partum hemorrhage with 800 µg sublingual misoprostol to be a good alternative to universal prophylaxis with 600 µg oral misoprostol. Using a secondary prevention approach medicates fewer women and is an acceptable and feasible strategy at the community level.

We disseminated this information at two meetings in India, one in Goa and one in Belgaum, we will also present this at FIGO 2015, in Canada. A paper is in preparation for submission to BJOG.

Misoprostol as Abortifacient

Misoprostol is an E1 prostaglandin analog originally produced for the prevention of gastrointestinal ulceration. Its uterotonic properties make it effective for a variety of off-label obstetric uses including medical abortion, medical management of miscarriage, and the prevention and treatment of postpartum hemorrhage (PPH).

In the European Union and the United States, misoprostol is used for medical abortion either alone or in combination with mifepristone (RU486). Oral or vaginal administration of misoprostol during pregnancy results in cervical dilation, uterine contractions, uterine bleeding and, depending upon the dose and duration of the pregnancy, complete abortion.

Safe Motherhood Research on How Misoprostol Availability Reduced Abortion-Related Maternal Mortality in the Dominican Republic            

In 2005, the Safe Motherhood Program published research indicating a decline in abortion-related complications in the Dominican Republic after the introduction of misoprostol into the country in 1986 (Miller et al., 2005). Abortion is illegal in the Dominican Republic, forcing many women to turn to clandestine procedures and/or black-market drugs to terminate a pregnancy. The social and legal barriers to abortion access increase morbidity and mortality risk due to abortion-related complications.

Pharmacies in Santo Domingo carried misoprostol. Two-thirds of the women surveyed who were familiar with the drug knew how to obtain it and 60% of those surveyed say they know it is available without a prescription (Miller et al., 2005). Based on qualitative interviews, focus groups, and retrospective record review, Miller et al reported that one-third of informants felt that misoprostol helped improve women’s health. In 1986 (the year misoprostol was introduced in the country) there were 596 abortion-related admissions, and 11.7% of these abortions had serious complications. By 1994, the number of abortion-related admissions had increased to 777, but the proportion of abortions with serious complications decreased to 4.6%. By 2001, there were 648 abortion-related admissions with only 1.7% resulting in serious complications. While there may have been other factors influencing these results, this suggests that the greater availability of misoprostol resulted in both greater care seeking for abortion-related issues and reduced complication rates.

Today, misoprostol is included in the WHO List of Essential Medicines and is approved for the management of medical abortion and miscarriage and the prevention of postpartum hemorrhage when oxytocin is unavailable or cannot be used safely.

References

Hofmeyr, G. J., Gülmezoglu, A. M., Novikova, N., Linder, V., Ferreira, S., & Piaggio, G. (2009). Misoprostol to prevent and treat postpartum haemorrhage: a systematic review and meta-analysis of maternal deaths and dose-related effects. Bulletin of the World Health Organization. Retrieved from http://www.who.int/bulletin/volumes/87/9/08-055715/en/

Miller et al. (2005). Misoprostol and declining abortion-related morbidity in Santo Domingo, Dominican Republic: a temporal association. BJOG, 112(9), 1291-6. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16101610

Sutherland, T., Meyer, C., Bishai, D. M., Geller, S., & Miller, S. (2010). Community-based distribution of misoprostol for treatment or prevention of postpartum hemorrhage: cost-effectiveness, mortality, and morbidity reduction analysis. IJGO, 108(3), 289-94. doi: 10.1016/j.ijgo.2009.11.007