Uterotonic drugs used for active management of the third stage of labor (AMTSL) Name of presenter Prevention of Postpartum Hemorrhage Initiative (POPPHI) Project Adapted from JHPIEGO. Active Management of the Third Stage of Labor: Advances in Maternal and Neonatal Health. Available at: http://www.reproline.jhu.edu/english/2mnh/2ppts/3rdstage/3rdstagepg.htm. Accessed March 12, 2008.

By end of the session, participants will be able to: Session Objectives By end of the session, participants will be able to: Identify Uterotonic Drugs used for AMTSL Advantages and disadvantages Stability in Tropical Climates Describe aspects related to Selection Storage Use and dosage

Uterotonic drugs used for AMTSL Oxytocin- posterior pituitary extract Ergometrine- preparation of ergot Syntometrine- combination of oxytocin and ergometrine Misoprostol- prostaglandin E1 analogue Misoprostol holds promise for use as an uterotonic. It is effective, practical and inexpensive. In contrast to the other three uterotonics, misoprostol is stable (heat, light) and does not have to be given by injection. It can be given orally or rectally.

Oxytocin Advantages Acts within 2.5 minutes when given IM Generally does not cause side effects Does not have any contraindications for postpartum use Is more stable than ergometrine when exposed to heat and light Disadvantages More expensive than ergometrine IM or IV preparations only Not heat stable Dosage for AMTSL 10 IU IM or 5 IU IV slow push

Ergometrine Advantages Low price Effect lasts 2–4 hours Disadvantages Takes 6–7 minutes to become effective when given IM; oral form insufficiently effective Causes tonic uterine contraction Increased risk of hypertension, vomiting, headache Contraindicated in women with hypertension or heart disease Not stable when exposed to heat, light, or freezing Dosage for AMTSL 0.2 mg IM

Oxytocin vs Ergometrine Results of trials do not show a difference in outcomes related to blood loss and transfusion between lower doses of oxytocin and the recommended dose of ergometrine A lower rate of manual removal of placenta was seen in women treated with oxytocin Ergometrine is associated with more adverse effects, especially with regard to causing high blood pressure

Recommendation: Oxytocin vs Ergometrine In the context of active management of the third stage of labor, if all injectable uterotonic drugs are available: Skilled attendants should offer oxytocin to all women for prevention of PPH in preference to ergometrine/methylergometrine to women without hypertension or heart disease for prevention of PPH.

Uterotonic Drugs: Syntometrine Advantages Combined effect of rapid action of oxytocin and sustained action of ergometrine Disadvantages More expensive than oxytocin or ergometrine alone Same disadvantages as ergometrine: Causes tonic uterine contraction Increased risk of hypertension, vomiting, headache Contraindicated in women with hypertension or heart disease Not stable when exposed to heat, light, or freezing Dosage for AMTSL 1 mL IM (ergometrine 0.5 mg + oxytocin 5 IU)

Oxytocin vs. Syntometrine: Results Syntometrine was associated with a small reduction in risk of PPH < 1000 mL (OR 0.74, 95% CI 0.65-0.85) Adverse effects of vomiting and hypertension were associated with the use of syntometrine There were no differences in other maternal or neonatal outcomes Conclusion Need to weigh benefit of reduction in risk of PPH with risk of other adverse effects associated with syntometrine McDonald, Prendiville and Elbourne 2000.

Recommendation: Oxytocin vs Syntometrine In the context of active management of the third stage of labor, if all injectable uterotonic drugs are available: Skilled attendants should offer oxytocin to all women for prevention of PPH in preference to the fixed drug combination of oxytocin and ergometrine to women without hypertension or heart disease for prevention of PPH.

Uterotonic Drugs: Misoprostol Advantages Effect lasts 75 minutes Can be stored at room temperature but should be protected from humidity Does not require injection skill or infection prevention measures required for giving an injection Can be distributed at the community level Disadvantages Acts within 6 minutes. Common side effects: shivering and elevated temperature Dosage for AMTSL 600 mcg po

Oxytocin vs. Misoprostol: Conclusion Oral misoprostol is not as effective as oxytocin when used for prevention of PPH HOWEVER Oral misoprostol: is easy to administer has no known contraindications for use in the postpartum can be stored easily at room temperature (it is thermostable and light stable) does not require specific conditions for transfer has a shelf life of several years

Oxytocin vs. Misoprostol: Recommendations In the context of active management of the third stage of labor: Skilled attendants should offer oxytocin for prevention of PPH in preference to oral misoprostol (600 mcg). In situations where oxytocin is not available or birth attendants’ skills are limited: administer misoprostol 600 mcg by mouth soon after the birth of the baby to reduce the occurrence of hemorrhage In the absence of active management of the third stage of labor, a uterotonic drug (oxytocin or misoprostol) should be offered by a health worker trained in its use for prevention of PPH.

Nipple Stimulation Nipple stimulation has not been shown to reduce risk of PPH Randomized controlled trial of suckling immediately after birth with over 4,000 subjects in Malawi showed no significant difference in frequency of PPH, mean blood loss or retained placenta Advantages of early breastfeeding and nipple stimulation: Stimulates natural production of oxytocin May maintain tone of contracted uterus Benefits baby Conclusions: When uterotonics are not available, use nipple stimulation and perform fundal massage after delivery of the placenta When uterotonics are not available, CCT should NOT be performed even with nipple stimulation Need uterotonics; efforts should be made to make it available at all levels of care. Getting the uterus to contract probably requires some “surge” of oxytocin, such as that delivered by an injection of oxytocin. When uterotonics are not available, CCT and fundal massage should be performed. Natural oxytocin produced by suckling of baby at breast may be useful for helping to maintain the tone of an already contracted uterus. Bullough, Msuku and Karonde 1989.

Stability of Injectable Uterotonics in Tropical Climates: Objective and Design To determine pattern of stability in long term dark storage, short term exposure to high temperature and light To develop guidelines Methods: Tested field samples of ergometrine and methylergometrine and also simulated field storage conditions at different temperature/light exposure WHO 1993.

Stability of Injectable Uterotonics in Tropical Climates: Results Field: Ergometrine: only 31% of samples had compliant level of active ingredient Oxytocin: one expired, 5 samples had 104–142% of stated amount of active ingredient WHO 1993.

Stability of Injectable Uterotonics in Tropical Climates: Results (continued) Simulation condition Ergometrine/ methylergometrine Oxytocin Refrigeration for 12 months Lost 4-5% active ingredient No loss 30oC, dark Lost 25% Lost 14% 21–25oC, light Lost 21–27% in one month >90% in 12 months Lost 5% 40oC dark Lost > 50% Lost 80% WHO 1993.

Stability of Injectable uterotonics in Tropical Climates: Conclusions Stability of oxytocin is better than ergometrine/ methylergometrine, especially regarding light Carefully read the manufacturer’s recommendations for storage of injectable uterotonics – where possible, store uterotonics in refrigerator (2–8ºC) and away from light Remove injectable uterotonics from box only for immediate use Short periods unrefrigerated are fine (1 month at 30°C) uterotonics are not heat stable, but oxytocin is better than ergometrine/methyl-ergometrine. WHO 1993.

Storage of uterotonic drugs - In the Pharmacy Make sure that there are adequate stocks of uterotonic drugs, syringes, and injection safety materials Check manufacturer’s label for storage recommendations Follow the rule of first expired – first out (or first in – first out) to reduce wastage of uterotonic drugs If possible, keep injectable uterotonics refrigerated at 2–8°C Store misoprostol at room temperature and away from excess heat and moisture Protect ergometrine and syntometrine from freezing and light. Make sure that there is a system in place to monitor the temperature of the refrigerator / cold box

Storage of uterotonic drugs In Delivery Rooms Check manufacturer’s label for storage recommendations Periodically remove ample amount of injectable uterotonics needed for expected client load from refrigerator Avoid storage of injectable uterotonics in open kidney dishes, trays, or coat pockets Store oxytocin outside the refrigerator at a maximum of 30°C (warm, ambient climate) for up to three months Store misoprostol at room temperature away from excess heat and moisture Store ergometrine and syntometrine vials outside the refrigerator in closed boxes and protected from the light for up to one month at 30°C

Recommendations Concerning Selection of Uterotonic for AMTSL Oxytocin is the uterotonic of choice for AMTSL If oxytocin is not available, use syntometrine or ergometrine If injectable uterotonic drugs are not available, use misoprostol 600 mcg by mouth Remember: Do not use ergometrine or syntometrine in women with hypertension or heart disease

Recommendations concerning management of the third stage of labor in the absence of an SBA In situations where birth attendants’ skills are limited: administer misoprostol 600 mcg by mouth soon after the birth of the baby to reduce the occurrence of hemorrhage use nipple stimulation do not perform CCT perform uterine massage after delivery of the placenta

Summary Oxytocin is the uterotonic of choice for AMTSL If oxytocin is not available, give ergometrine or syntometrine for AMTSL If injectable uterotonics are not available, give oral misoprostol for AMTSL If birth is not attended by an SBA, give oral misoprostol soon after birth of the baby to reduce PPH Ensure the adequate storage and supply of uterotonic drugs

References Bamigboye A et al. 1998. Randomized comparison of rectal misoprostol with syntometrine for management of third stage of labor. Acta Obstet Gynecol Scand 77: 178–181. Bullough CH, RS Msuku and I Karonde. 1989. Early suckling and postpartum haemorrhage: Controlled trial in deliveries by traditional birth attendants. Lancet 2(8662): 522–525. Carpenter JP. Misoprostol for Prevention of Postpartum Hemorrhage: An Evidence-Based Review by the US Pharmacopeia, Rockville, Maryland: United States Pharmacopeia, 2001. International Confederation of Midwives (ICM), International Federation of Gynaecology and Obstetrics (FIGO). Prevention and Treatment of Post-partum Haemorrhage: New Advances for Low Resource Settings Joint Statement. The Hague: ICM; London: FIGO; 2006. Available at: www.figo.org/docs/PPH%20Joint%20Statement%202%20English.pdf. Accessed April 2, 2007.

References (continued) Irons DW, P Sriskandabalan and CHW Bullough. 1994. A simple alternative to parenteral uterotonics for the third stage of labor. Int J Obstet Gynecol 46:15–18. McDonald S, W Prendiville and D Elbourne. 2000. Prophylactic syntometrine versus oxytocin for delivery of the placenta (Cochrane Review), in The Cochrane Library. Issue 4. Update Software: Oxford. McDonald et al. 1993. Randomized controlled trial of oxytocin alone versus oxytocin and ergometrine in active management of third stage of labor. BMJ 307(6913):1167–1171. World Health Organization (WHO). 1993. Stability of injectable uterotonics in tropical climates: Results of field surveys and simulation studies on ergometrine, methylergometrine, and oxytocin. WHO: Geneva.