Uterotonic drugs and devices

Uterotonic drugs act directly on the smooth muscle of the uterus and increase the tone, rate, and strength of rhythmic contractions. The body produces a natural uterotonic—the hormone oxytocin—that acts to stimulate uterine contractions at the start of labor, throughout the birth process, and in the postpartum period.

Drugs such as oxytocin, ergometrine, and misoprostol have strong uterotonic properties. Uterotonic drugs are unique because they are used for a variety of reasons – prevention of postpartum hemorrhage (PPH), treatment of PPH, induction and augmentation of labor, management of inevitable or incomplete abortion, medical elective abortion, etc. The use of a uterotonic drug immediately after the birth of the newborn is one of the most important actions used to prevent PPH.

Government initiatives to improve maternal outcomes and meet objectives of the Millennium Development Goal 5 (improve maternal health), must quickly increase coverage of uterotonic drugs for prevention and treatment of PPH. This requires the development of a comprehensive PPH strategy that addresses prevention and management in situations both with and without a skilled provider, and in births occurring in and outside the facility. While it is preferable that all women give birth in a facility with skilled attendants, Ministries of Health (MOH) must address the needs of women who live in settings where geographical and socio-economic restrictions do not allow them to reach health centers.

The goal for PPH control initiatives is to increase uterotonic coverage with the most appropriate uterotonic drug. Each country must choose a rational mix of uterotonic drugs for each point of care and by each cadre of birth attendant.

Considerations when selecting a uterotonic drug for prevention and treatment of PPH (POPPHI, 2008)

The decision on which uterotonic drug to use will depend on many factors, including:

Presentation
Cost
Efficacy
Stability
Response time
Adverse effects
Contraindications
Requirements for administering the drug
Presentation

Oxytocin, ergometrine, and Syntometrine are supplied in glass ampoules. Providers must first break openthe ampoules. Ampoulesare sometimes very hard to open and this may result in providers getting cuts from broken glass and/or wastage of ampoules. In addition, users of uterotonic drugs supplied in ampoules must open a sterile needle/syringe and measure out the right dose. Some cadres may find it challenging to load syringes and if they are going to be authorized to practice AMTSL, the chances of their clients receiving AMTSL are much higher if they have access to the Uniject device

Oxytocin is also available in an auto-disable (AD), prefilled, single-dose injection device, called Unijectä*. The Uniject device was designed with the following features:

Single dose—to minimize wastage and facilitate outreach to individual patients
Prefilled—to ensure that the correct dose is given, and to simplify procurement and logistics
Nonreusable—to minimize patient-to-patient transmission of blood borne pathogens
Easy to use—to allow use by health workers who do not normally give injections
Compact size—for easy transport and disposal
Misoprostol is supplied in 25 mcg and 200 mcg tablets.

Cost

The acquisition costs of oxytocin in ampoules and ergometrine are essentially the same (MSH, 2006), while the fixed drug combination of oxytocin and ergometrine and oxytocin in the Uniject device, with or without the time temperature indicator (TTI), are likely to be more expensive in most countries than oxytocin in ampoules or ergometrine alone. The cost of misoprostol tablets varies from country to country, but is generally less than any of the injectable uterotonics.

Administration costs of oxytocin in ampoules, ergometrine, and the fixed drug combination of oxytocin and ergometrine are likely to be generally equivalent. Administration costs of oxytocin in the Uniject device will be less than uterotonic drugs supplied in ampoules because the syringe is pre-loaded and can easily be used by a less skilled birth attendant authorized to give injections. Administration costs of misoprostol will be less because it does not require a syringe and needle, a skilled birth attendant trained and authorized to administer injections, or consumables and supplies to ensure safe injection and infection prevention practices.

Storage costs may be higher for ergometrine (and the fixed drug combination of oxytocin and ergometrine) because it requires temperature-controlled transport and storage and protection from light. Oxytocin is more stable and storage costs may be less than ergometrine (Hogerzeil and Walker, 1996). Oxytocin in the Uniject device takes up more room in the cold chain because of packaging. If the TTI is fixed on the oxytocin-Uniject device, the acquisition cost would be higher, but this difference might be made up by the cold chain flexibility afforded by the TTI. Costs for storage of misoprostol will be minimal as it is the most stable of the three uterotonic drugs and can be stored at room temperature.

Efficacy

The evidence for comparison of oxytocin and ergometrine is based on a systematic review conducted by the WHO (McDonald et al, 2004) of studies that compared ergometrine (or derivatives) and oxytocin, or ergometrine alone versus the fixed dose combination of ergometrine and oxytocin. For the outcomes related to blood loss and transfusion, the results of the trials do not show a difference between lower doses of oxytocin and the recommended dose of ergometrine. The fixed drug combination of oxytocin and ergometrine was associated with less use of additional uterotonics. The available comparisons are limited, but a major difference in the benefits of oxytocin and ergometrine appears unlikely.

The evidence for comparison of oxytocin and misoprostol is based on a systematic review conducted by the WHO (WHO, 2006) of studies that compared use of oxytocin and misoprostol for AMTSL. Blood loss of 1000 ml or more was increased with misoprostol when compared to oxytocin 10 IU IM; there was no statistically significant difference in the use of blood transfusion with misoprostol compared with oxytocin; but there was more use of additional uterotonics with misoprostol.

Stability

The stability of a drug is defined by how well it maintains active ingredient potency (and other measures such as pH) when stored over time. Two factors can influence the effectiveness of injectable uterotonic drugs: temperature and light. Of the injectable drugs, oxytocin is more stable than ergometrine (and the fixed drug combination of oxytocin and ergometrine) when exposed to heat and light (when cold/dark storage is not possible).

Oxytocin in the Uniject™ device is the first uterotonic drug to use time temperature indicators (TTI). TTIs, similar to vaccine vial monitors used in immunization programs, allow precise monitoring of cumulative temperature exposure. They assure quality and potency of the uterotonic drug at the time that the drug is administered. Use of the TTI does not increase stability or negate the need for cold chain, but allows some flexibility in the cold chain as providers will know if the oxytocin has been exposed to heat to a point where potency can no longer be guaranteed.

Misoprostol does not require special transport or storage requirements, though some manufacturers will recommend protecting the product from humidity.

Response time

The following table summarizes response time and length of action for the most commonly used uterotonic drugs. Of the injectable uterotonics, oxytocin acts the most rapidly, while ergometrine has the benefit of sustained action. The fixed drug combination of oxytocin and ergometrine combines the rapid action of oxytocin with the sustained action of ergometrine.

Oral misoprostol acts moderately quickly, within 3-5 minutes, and has a moderately long sustained action of 75 minutes.

Name of drug/preparation

Response time and length of action

Oxytocin

Intramuscular injection:

Acts within 2 to 3 minutes
Effect lasts about 15 to 30 minutes
Misoprostol

Orally:

Acts within 3-5 minutes
Peak serum concentration between 18 and 34 minutes
Effect lasts 75 minutes
Ergometrine

Intramuscular injection:

Acts within 6 to 7 minutes
Effect lasts 2 to 4 hours
Syntometrine

Intramuscular injection:

Combined rapid action of oxytocin and sustained action of ergometrine
Adverse effects

A comparison of oxytocin versus the fixed drug combination (5 IU oxytocin + 0.5 mg ergometrine) showed a higher rate of adverse effects in women treated with the combination drug: nausea, vomiting, and high blood pressure. A lower rate of manual removal of placenta was seen in women treated with oxytocin. 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 38°C.

Contraindications

Misoprostol and oxytocin have no known contraindications for use in the immediate postpartum period.

Doses higher than 1000 mcg of misoprostol are not recommended, which means that misoprostol may not be used for treatment of PPH if a 600 mcg dose was used for prevention.

Ergometrine (and the fixed drug combination of oxytocin and ergometrine) is contraindicated in women with a history of hypertension, heart disease, pre-eclampsia, or eclampsia.

Requirements for administration of an uterotonic drug

Administering injectable uterotonic drugs will require:

a health worker authorized and trained to perform injections
consumables and supplies to ensure adequate infection prevention measures
consumables and supplies to ensure injection safety, including disposable needles and syringes
cold chain
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.
References

Hogerzeil HV, Walker GJ (4) Instability of (methyl)ergometrine in tropical climates: an overview. Eur.J.Obstet.Gynecol.Reprod.Biol. 1996;69:25-9.
Management Sciences for Health & World Health Organization (14) International Drug Price Indicator 2005 Edition. 2006
McDonald S, Abbott JM, Higgins SP. Prophylactic ergometrine-oxytocin versus oxytocin for the third stage of labour. Cochrane Database of Systematic Reviews. 2004;1:CD000201.
POPPHI. Selection of uterotonic drugs in tropical climates. Seattle: PATH; 2008.
World Health Organization (WHO) Department of Making Pregnancy Safer. WHO Recommendations for the prevention of postpartum haemorrhage. WHO: Geneva; 2006.