Tuesday, August 31, 2010

The Miscarriage Study: 400 vs 800 mcg misoprostol

Mater Mother’s Hospital in Queensland has been conducting a randomized controlled trial comparing two doses of misoprostol (800 mcg versus 400 mcg) for the medical management of miscarriage. More information can be found in the brochure for The Miscarriage Study on their website:


Medical management is only available to women participating in the Miscarriage Study. Surgery or expectant management is offered as standard care options to women who choose not to participate.

The web brochure explains that the study is being carried out because currently there is no agreement on the most effective dose for misoprostol use in miscarriage. However it points out that 800mcg is the most common dose used in studies. While it is true that researchers have not determined a dosage/regimen which is as effective as D&C i.e. the ‘optimum’ protocol for medical management using misoprostol, preliminary guidelines based on hundreds of studies have been produced by the expert group convened by WHO in Bellagio in February 2007. They are published in a supplement to the International Journal of Gynecology and Obstetrics (2007, vol. 99) and can be read here. According to these guidelines, 600-800 mcg misoprostol is the recommended dose for first trimester miscarriage. The guidelines for misoprostol use according to indication and gestational age are also available at: http://www.misoprostol.org/ This website also provides excellent resources to clinicians interested in information about misoprostol use and the misoprostol debate.

The researchers have chosen to study quite a low dosage of misoprostol to reduce side effects. However, it has already been established that even 600-800 mcg is not as effective for first trimester miscarriage as the standard care D&C (it remains questionable as to why it is imperative for medical management to be equally as effective as D&C for it to be used when medical management offers the advantages of being non-invasive, cheap, free of anesthetics and safer for future fertility than D&C).The drug is inexpensive, so cost is evidently not an issue. Furthermore, the optimum dose for use in termination up to 7 weeks is 800 mcg (in combination with mifepristone). A recent study found that this dose should not be lowered (link). Apparently misoprostol side effects for termination are not a concern for women. One would imagine the same for women who miscarry.

Misoprostol is listed in the Standard Drug List of Queensland Hospitals for use in miscarriage and is currently used in this hospital for the treatment of other pregnancy complications. The Therapeutic Goods Administration (TGA), which is the Australian equivalent of the FDA in the US, has not approved of its use in pregnancy in Australia.

However, the Queensland Health and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists support its use in the treatment of miscarriage. Despite this, misoprostol use for first trimester miscarriage remains uncommon in Australia. The drug is quite commonly used for miscarriage management in European countries. In contrast, a combined misoprostol/mifepristone regimen is offered by most if not all services in Australia specializing in pregnancy termination. It has also become common practice for labour induction despite the fact that there is not more evidence to support its use for this indication than for miscarriage. Interestingly, expectant management is considered acceptable although it is not more effective than for miscarriage management in clinical trials. Health professionals excuse the restricted access to misoprostol for miscarriage management with the pretext that misoprostol is not TGA approved, yet misoprostol use in ALL obstetric/gynecologic indications is not approved (misoprostol was developed for the treatment and prevention of ulcers). The unlicensed use of misoprostol for terminations is cunningly circumvented by a legal loophole which allows its use in combination with mifepristone which is only TGA approved for use in pregnancy termination. Unlicensed use of misoprostol in labour induction, curiously, does not seem to hinder clinicians from using it for labour induction even though substantially less is known about the short and long term effects it may have on infants exposed to it. Misoprostol is also used in the treatment of osteoarthritis and marketed under the name Arthrotec. Curiously, there is no debate over the unlicensed use of misoprostol for arthritis. Yet none of the above has lead to questioning the objective validity behind the selective use of misoprostol for some unlicensed obstetric (or other) indications but not for miscarriage management. Why is it that the only people who seem to be prevented from using misoprostol are women who miscarry?

Most women who miscarry have no choice but to undergo a costly D&C, potentially leading to long term adverse effects on fertility (Asherman’s syndrome) and a host of possible future obstetric complications (placenta accreta, percreta, previa, IUGR, pre eclampsia, preterm birth, cervical insufficiency leading to second trimester loss, and uterine rupture). It is ironic that the very women who desire a pregnancy most are also those who are exposed to iatrogenic infertility and/or pregnancy complications arising from surgical management. Disappointing overall reproductive outcomes (40%) and associated healthcare costs (not to mention patient discontent) do not make the approach of relying on treatment of Asherman’s syndrome a paradigm. The restriction of a safe, inexpensive and non-invasive alternative such as misoprostol for miscarriage management can be considered unethical and perhaps even discriminatory as it is available to other populations of women for unlicensed obstetric/gynecological indications.

The Mater Mother’s Hospital webpage mentions potential complications from surgical management (D&C) without specifically naming Asherman’s syndrome (intrauterine adhesions and/or fibrosis) or cervical insufficiency (from cervical dilation). It also quotes the risk of complications from D&C as 1:200-500 surgeries, a greatly underestimated frequency (see Frequency of intrauterine adhesions after curettage).

It is encouraging to see local studies on misoprostol for miscarriage management. Even if 400 ug will turn out to have a significantly lower success rate than 800 ug, exposure to women and clinicians could help promote awareness about it and increase its demand/use. Perhaps it is a sign that Australia is finally ready to implement medical management as a routine care option.