Flexibility Marks How and When to Take Abortion Drug

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GENEVA, Switzerland -- The choice of a vaginal or sublingual route for misoprostol, if used alone for early abortion, and the timing of doses gives women several safe and effective options.

GENEVA, Switzerland, June 7 -- The choice of a vaginal or sublingual route for misoprostol, if used alone for early abortion, and the timing of doses leaves women several safe and effective options.

So said Helena von Hertzen, M.D., of the Department of Reproductive Health and Research of the World Health Organization here, and colleagues, adding that sublingual administration is most effective when the medication is taken at three-hour intervals. However, side effects are more unpleasant.

If 12-hour intervals for the three doses are preferred, the vaginal route should be used, they reported in the June 9 issue of The Lancet.

The medical abortion regimen of mifepristone (Mifeprex), known as RU-486, followed by a suitable prostaglandin analogue, usually misoprostol, is available in more than 30 countries, the researchers wrote.

Where mifepristone is not available, various misoprostol-only regimens are used. However, they said, there is no evidence concerning the most effective route of administration or the interval between multiple doses

The effectiveness of vaginal administration is well known, but to determine whether taking the drug orally could be an option, the researchers undertook an equivalence study in 11 teaching hospitals in Armenia, Cuba, Georgia, India, Mongolia, and Vietnam.

The study comprised 2,046 healthy pregnant women requesting medical abortion at 63 days or less of gestation. They were randomly assigned to one of four treatment groups: three 0.8 mg doses of misoprostol given sublingually at three-hour or 12-hour intervals, or vaginally at three-hour or 12-hour intervals. The equivalence trial had a 5% margin of equivalence.

When misoprostol was given at three-hour intervals, complete abortion rates were similar between the two routes. When administration was every 12 hours, complete abortion rates were higher in the vaginal group than in the sublingual group, the researchers reported.

At three-hour intervals, complete abortion rates at two-week follow-up were recorded for 431 women (84%) in the sublingual group and for 434 women (85%) in the vaginal group (difference 0.4%, 95% CI -4.0 to 4.9, P=0.85 equivalence shown).

At 12-hour intervals, complete abortion rates were recorded for 399 (78%) in the sublingual and for 425 (83%) in the vaginal 12-hour groups (4.6%, -0.2 to 9.5, P=0.06, equivalence not shown).

In the three-hour groups, pregnancy continued in 29 women (6%) who'd taken the medication sublingually and in 20 women (4%) after vaginal administration (difference 1.8%, CI -0.8 to 4.4, P=0.19, equivalence shown).

In the 12-hour groups, pregnancy continued in 47 women (9%) after sublingual administration and in 25 (5%) who used the vaginal route (4.4%, 1.2-7.5, P=0.01).

Differences between intervals for complete abortion for sublingual and vaginal routes were 6% (CI 1.0-10.6, P=0.02, three hours better than 12 hours) and 2% (-2.9 to 6.1, P=0.49, equivalence not shown), respectively.

For continuing pregnancies, differences were 4% in the sublingual group versus 1% in the vaginal group (P=0.44, equivalence shown).

Pregnancy-related symptoms, such as nausea and vomiting, increased after the first dose compared with baseline.

Pain was the most common symptom reported after the first dose, the researchers said, and the frequency and intensity of these symptoms increased if the second dose was given after three hours, no matter which route was used.

Chills, fever, pain, and diarrhea were slightly more common among women taking the drug sublingually.

Among women whose pregnancy was between 57 and 63 days, the risk that the drug would not terminate the pregnancy was significantly higher than it was for those with a pregnancy of 49 or fewer days, the researchers found. However, they said, the effect of gestational age was not reflected in the treatment groups.

The researchers acknowledged that the results of the trial might not apply to different populations because of the trial's rather strict eligibility criteria.

Unwillingness to return for follow-up visits was the most common reason for exclusion from the study, but a follow-up visit is important to confirm that pregnancy was terminated, the researchers said.

Their findings show that misoprostol can be used either vaginally or sublingually for termination of early pregnancy, Dr. von Hertzen said.

The study clearly shows the effect of interval on efficacy for sublingual administration, the investigators said, with the three-hour interval between doses significantly better than the 12-hour interval. If the drug is taken sublingually, the intervals between doses need to be short, although side effects are then increased.

For 12-hour administration intervals, the researchers said, the vaginal route should be used, whereas with three-hour intervals, either route could be chosen, the investigators concluded.

In an accompanying comment, Beverly Winikoff, M.D., of Gynuity Health Projects in New York, and Anne R. Davis, M.D., of Columbia University, discussed the ethics involved in the different methods for aborting pregnancies and the difficulties involved in making choices.

To understand the implications of the WHO study, "a major logistical undertaking," they said, it is important to consider all aspects related to the woman-her wishes, hopes, fears, needs, feelings, knowledge, constraints, resources, and so forth-and the society in which she lives."

Therefore, they said, it is important to balance the scientists' wishes to know about all possible combinations of drug regimens, with women's need for a simple uncomplicated approach.

The next step, Drs.Winikoff and Davis said, should include streamlining regimens-fewer doses over a shorter period, a comfortable route of administration, widened inclusion criteria, and reduced costs.

Consideration of personal and societal factors is crucial, they said. Even regimen choices, such as route of administration and number of doses, need to be considered in the context of the abortion procedure.

For example, they said, when women use the medication by themselves and clandestinely, they might be in substantial legal jeopardy if pill fragments remain in the vagina and are visible to an examiner should the woman seek formal medical attention after her procedure. Indeed, this consideration, with the fact that self-administered vaginal medication is not well accepted in some cultures, strongly adds to the need for new regimens that do not rely on the vaginal route.

Although the biology is universal, they noted, the best choices for abortion services cannot be made on the basis of medical considerations alone. "No drug development for abortion makes sense without remembering the centrality of the experience for women themselves," Drs. Winikoff and Davis wrote.

Drs. Winikoff and Davis, the commenters, declared no conflicts of interest.