THE PHARMACOLOGY OF DRUGS USED IN THE MANAGEMENT OF POSTPARTUM HEMORRHAGE: the evidence

Ma. Stephanie Fay S. Cagayan, MD, FPOGS, FPSECP,FPSSTD Associate Professor Department of Pharmacology and Toxicology and Department of Obstetrics and Gynecology UP College of Medicine

Session Objectives
By end of the session, participants will be able to: Identify Uterotonic Drugs Describe pharmacologic aspects related to Selection Storage Use and dosage

Review the evidence on selection of specific agents

She died in childbirth

An estimated 150,000 maternal deaths worldwide result from obstetric hemorrhage each year

More women have probably been killed by

Hemorrhage
than any other complication of pregnancy in the history of mankind.

90% of deaths from postpartum hemorrhage are preventable.

Those caring for pregnant women must be prepared to aggressively treat this complication when it occurs.

GOOD NEWS

WE HAVE THE TOOLS

What can be done?

Preparation for Postpartum Hemorrhage

THE STEPS TO MANAGING PPH: POSTPARTUM HEMORRHAGE:

HANDLE
PREPARE PREDICT
Identify patients at risk

Optimize clinical/medical management

Use a multi-disciplinary approach

80% OF CASES OF POSTPARTUM HEMORRHAGE ARE DUE TO UTERINE ATONY

What about DIC?

Coagulopathy is a relatively uncommon cause of primary PPH Coagulopathy most commonly occurs when another cause of PPH already has produced significant blood loss.

Perhaps the most important

aspect in the management of PPH is the attitude of the attendant in charge. It is critical to maintain equanimity in what can be a chaotic and stressful environment.
Yinka Oyelese, MD, Obstet Gynecol Clin N Am 34 (2007) 421441

Medical Treatment of Postpartum Hemorrhage

TONE
Medications that cause uterine contractions Medications that promote coagulation

Uterotonic drugs used for AMTSL

Oxytocin- posterior pituitary extract
Carbetocin

Ergot alkaloids
Mehtylergonovine maleate

Prostaglandins
Carboprost- prostaglandin F2 nalogue Misoprostol- prostaglandin E1 analogue

Syntometrine- combination of oxytocin and ergometrine May be given IV, IM, orally, vaginally, rectally or bucally

Medications for Uterine Atony

OXYTOCIN The Champ

Cytotec Inexpensive (?) Effective

Factors in the Selection of Appropriate Agent

Efficacy
Response time, stability, adverse effects, contraindications

Cost acquisition, administration, storage Requirements for drug administration

Oxytocin
From posterior pituitary lobe Available as 1 ml ampoule Advantages Acts within 2.5 minutes when given IM Generally does not cause side effects Does not have any contraindications for postpartum use 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

Dose, route, and precautions for oxytocin use for PPH treatment

Uniject device
Oxytocin 10 IU
a prefilled, easy-to-use, non-reusable syringe is an advance in the method of delivering oxytocin and is currently being used in pilot studies ensures the correct dose is given with little preparation and medical waste.

Ergometrine or Methylergonovine maleate

Oral: 125mcg tablet Inj: 200mcg/mL, 1mL ampule Advantages Low price, Effect lasts 24 hours Disadvantages Takes 67 minutes to become effective when given IM; oral form insufficiently effective Increased risk of hypertension, vomiting, headache Contraindicated in women with hypertension or heart disease Dosage for AMTSL

Misoprostol
Prostaglandin E1 analogue directions on its use for AMTSL is included in the International Federation of Gynaecology and Obstetrics (FIGO)/International Confederation of Midwives (ICM) statement, Prevention and

Treatment of Postpartum Haemorrhage: New Advances for Low Resource Settings

Misoprostol
100 and 200 mcg tablets Advantages

Effect lasts 75 minutes

Does not require injection skill or infection prevention measures 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

Dose, route, and precautions for misoprostol use for PPH treatment

Other Uterotonics
Fixed dose combination oxytocin and ergometrine Carbetocin Carboprost

Oxytocin Evidence
In six trials involving 3200 women, oxytocin use was found to halve the risk of PPH with blood loss 500 ml [Relative Risk (RR) 0.50; 95% confidence interval (CI) 0.430.59] In four trials (involving 2243 women), compared with placebo or no uterotonics, oxytocin decreased the risk of severe PPH with blood loss 1000 ml (RR 0.61; 95% CI 0.440.87). A significant reduction in the use of additional uterotonics was also found in five trials involving 2327 women (RR 0.50;

Oxytocin vs. Ergometrine

There was little evidence of differential effects for oxytocin versus ergot alkaloids (six trials, ~2800 women, RR 0.90; 95% CI 0.701.16). However, oxytocin was associated with fewer manual removals of the placenta (RR 0.57; 95% CI 0.410.79). One small trial suggested that there was less raised blood pressure with oxytocin compared with ergot alkaloids. Five trials (~2800 women) had compared oxytocin plus ergometrine versus ergometrine alone. These trials showed little evidence of a synergistic effect of

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.

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

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.

Carbetocin evidence
Carbetocin, an oxytocin agonist, was compared with placebo (one trial) or oxytocin (three trials) for preventing postpartum haemorrhage in recently published systematic review (2007)
Su LL, Chong YS, Samuel M. Oxytocin agonists for preventing postpartum haemorrhage. Cochrane Database of Systematic Reviews 2007;Issue 3. Art. No.: CD005457; DOI: 10.1002/14651858.CD005457.pub2.

Limited evidence suggests that there is little difference in the effectiveness between carbetocin and oxytocin, and adverse effects like headache, nausea and vomiting were also similar. Three of the included trials were known to be have been supported by grants from a

Prostaglandins in the treatment of PPH

Prostaglandins included misoprostol administered via buccal, sublingual, oral, and rectal routes and intramuscular prostaglandins (PGF2alpha [carboprost] and PGE2 [misoprostol]) Results of studies comparing buccal, sublingual, oral, or rectal misoprostol with no uterotonic/placebo are equivocal and come from small trials showing effects in different directions. Across the trials, side-effects were more

 The rate of severe PPH (RR 1.36; 95% CI 1.171.58) and the use of additional uterotonics were statistically significantly higher with 600 g of oral misoprostol compared with conventional injectable uterotonics. These results are dominated by the large WHO trial (Glmezoglu AM, Villar J, Ngoc NN, Piaggio G, Carroli G, Adetoro L, et al., 2001) but other trials showed the same trend. There were no significant differences between the 600 g dose and lower doses (i.e. 500 g or 400 g) in terms of the rate of severe PPH, although trials using the lower doses had smaller sample sizes compared with the trials with the 600 g dose. The use of additional uterotonics was also

 When compared with conventional uterotonics, intramuscular prostaglandins resulted in less blood loss [one trial, 46 women, weighted mean difference (WMD) 224.00 ml; 95% CI -420.35 ml 27.65 ml) and shorter duration of the third stage (WMD 3.60 minutes; 95%CI 7.65 minutes 0.45 minutes). Other outcomes occurred infrequently for any reliable conclusions to be drawn. The concerns related to safety, costs and side-effects are important limitations of intramuscular prostaglandins. Prostaglandin-related side-effects especially shivering, pyrexia, nausea, vomiting and diarrhoea were more frequent and consistent across trials.

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

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.

Response Time

Adverse Effects
Overall, ergometrine alone or in combination with oxytocin is associated with more adverse effects, especially with regard to causing high blood pressure. Misoprostol is associated with an increase in shivering, diarrhea, and temperature higher than 38C.

Stability of Injectable Uterotonics in Tropical Climates

methylergometrine Refrigeration Lost 4-5% active No loss for 12 months ingredient 30oC, dark Lost 25% Lost 14% 2125oC, light Lost 2127% in one Lost 5% month 40oC dark >90% in 12 months Lost > 50% Lost 80%

Simulation condition

Ergometrine/

Oxytocin

Stability of Injectable uterotonics in Tropical Climates

Stability of oxytocin is better than ergometrine/ methylergometrine, especially regarding light Carefully read the manufacturers recommendations for storage of injectable uterotonics where possible, store uterotonics in refrigerator (28C) and away from light Remove injectable uterotonics from box only for immediate use Short periods unrefrigerated are fine (1

Storage of uterotonic drugs In the Pharmacy

adequate stocks of uterotonic drugs, syringes, and injection safety materials 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 28C Protect ergometrine and syntometrine from freezing and light.

Storage of uterotonic drugs In Delivery Rooms

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 30C for up to three months Store ergometrine and syntometrine vials outside the refrigerator in closed boxes and protected from the light for up to one month at 30C

Cost
Acquisition cost
Oxytocin and ergometrine almost same Misoprostol

Administration cost
Higher for injectables

Storage cost
Ergometrine slightly higher

Requirements for Administration

Administering any uterotonic will require
a health worker authorized and trained to provide the drug; a health worker who understands the timing and dose of the drug; a health worked trained to recognize and manage side effects of the drugs; application of manufacturer-specific storage recommendations.

Requirements for Administration

Administering injectable uterotonic will require a health worker authorized and trained to perform injections; a health worked trained to recognize contraindications to ergometrine; consumables and supplies to ensure adequate infection prevention measures; consumables and supplies to ensure injection safety, including disposable needles and syringes;

Summary

BMJ Clinical Evidence

WHO Recommendations Concerning Selection of Uterotonic for AMTSL

Oxytocin is the uterotonic of choice for AMTSL If oxytocin is not available, use syntometrine or ergometrine
Remember: Do not use ergometrine or syntometrine in women with hypertension or heart disease

If injectable uterotonic drugs are not available, use misoprostol 600

References
WHO guidelines for the management of postpartum haemorrhage and retained placenta. Geneva, Switzerland, 2009 Abalos E. Choice of uterotonic agents in the active management of the third stage of labour: RHL commentary (last revised: 2 March 2009). The WHO Reproductive Health Library; Geneva: World Health Organization. POPPHI. Selection of uterotonic drugs in tropical climates. Seattle: PATH; 2008. International Confederation of Midwives (ICM), International Federation of Gynaecology and Obstetrics (FIGO). Prevention and Treatment of Postpartum 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 Nov. 5, 2011.

Cotter A, Ness A, Tolosa J. Prophylactic oxytocin for the third stage of labour. Cochrane Database of Systematic Reviews 2001;Issue 4. Art. No.: CD001808; DOI: 10.1002/14651858.CD001808. McDonald SJ, Abbott JM, Higgins SP. Prophylactic ergometrineoxytocin versus oxytocin for the third stage of labour. Cochrane Database of Systematic Reviews 2004;Issue 1. Art. No.: CD000201; DOI: 10.1002/14651858.CD000201.pub2. Glmezoglu AM, Forna F, Villar J, Hofmeyr GJ. Prostaglandins for preventing postpartum haemorrhage. Cochrane Database of Systematic Reviews 2007;Issue 4. Art. No.: CD000494; DOI: 10.1002/14651858.CD000494.pub3. Su LL, Chong YS, Samuel M. Oxytocin agonists for preventing postpartum haemorrhage. Cochrane Database of Systematic Reviews 2007;Issue 3. Art. No.: CD005457; DOI: 10.1002/14651858.CD005457.pub2. Sackett DL, Haynes RB. Summarising the effects of therapy: a new table and some more terms. Evidence Based Medicine 1997;2:103-104. Glmezoglu AM, Villar J, Ngoc NN, Piaggio G, Carroli G, Adetoro L, et al. for the WHO Collaborative Group to Evaluate Misoprostol in the Management of the Third Stage of Labour. WHO multicentre double-blind randomized controlled trial to evaluate the use of misoprostol in the management of the third stage of labour. The Lancet 2001;358:689-695.

The 4 Ts Recalled
THROMBIN Check labs if suspicious.