Comparison of misoprostol only and combi

CLINICAL ARTICLEfor home-based early medical abortion in Tunisia and Vietnam Jennifer Bluma,⁎ , Sheila Raghavana, Rasha Dabasha, Nguyen thi Nhu Ngocb, Héla Chellic, Selma Hajrid, Kathryn

CLINICAL ARTICLE

for home-based early medical abortion in Tunisia and Vietnam

Jennifer Bluma,⁎ , Sheila Raghavana, Rasha Dabasha, Nguyen thi Nhu Ngocb, Héla Chellic, Selma Hajrid, Kathryn Conklinga, Beverly Winikoffa

a

Gynuity Health Projects, New York, USA

b

Center for Research and Consultancy in Reproductive Health, Ho Chi Minh City, Vietnam

c

Maternity and Neonatology Center Rabta El Jaberi, Tunis, Tunisia

d

Medical Consultant, Tunis, Tunisia

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 31 October 2011

Received in revised form 20 March 2012

Accepted 10 May 2012

Keywords:

Medical abortion

Mifepristone

Misoprostol

Objective: To assess the potential advantages of combined mifepristone–misoprostol versus misoprostol-only for early medical abortion Methods: A double-blind randomized placebo controlled study was conducted that enrolled 441 pregnant women (b63 days since last menstrual period) at 2 hospitals in Tunisia and Vietnam The mifepristone–misoprostol group (n=220) received 200 mg of mifepristone on day 1 and 800 μg buccal misoprostol followed by placebo 3 hours later on day 2 The misoprostol-only group (n = 221) received pla-cebo on day 1 and 1600μg of misoprostol (2 doses of 800 μg, given 3 hours apart) on day 2 All medications were self-administered at home with follow-up 1 week later The primary outcome was complete uter-ine evacuation without surgical intervention Results: Successful uteruter-ine evacuation occurred for 78.0% (n = 170) of women with misoprostol only versus 92.9% (n = 195) of women with mifepristone–misoprostol (relative risk 0.84, 95% CI, 0.78–0.91; Pb0.001) Ongoing pregnancy occurred for 13.8% (n=30) of women given misoprostol-only and 1.4% (n = 3) of women given mifepristone–misoprostol (relative risk 9.63, 95%

CI 2.98–31.09; Pb0.001) Conclusion: Mifepristone plus misoprostol is significantly more effective than misoprostol-only for early medical abortion

Clinical trials.gov registration number: NCT00680394

© 2012 International Federation of Gynecology and Obstetrics Published by Elsevier Ireland Ltd All rights reserved

1 Introduction

Medical abortion provides an alternative to surgical evacuation

for women seeking non-invasive pregnancy termination Medical

methods have the potential to reduce system costs, help meet demand

for abortion services, and increase access to care in settings where

skilled providers and supplies are limited

Mifepristone followed by misoprostol is considered the gold

stan-dard regimen for medical abortion[1] However, mifepristone can

be expensive and is not as widely available as misoprostol, which

has led to widespread use of misoprostol-only regimens With the

emergence of more affordable mifepristone and misoprostol products,

the introduction of the combined regimen in new settings is

increas-ingly feasible [2,3] One study hypothesized that the actual cost

differential between misoprostol-only and mifepristone–misoprostol

regimens is small[4] Thus, it is important to better understand the

advantage of adding mifepristone to misoprostol-only regimens

in terms of efficacy, cost, and type of service delivery In resource-limited settings, policymakers and healthcare providers often strug-gle to decide whether adding mifepristone to misoprostol-only regi-mens is likely to be more beneficial than simply expanding access to misoprostol-only services In Tunisia, for instance, the mifepristone-misoprostol regimen is limited to the public sector

The safety and efficacy of mifepristone–misoprostol for medical abortion is well established [5–7] A frequently used regimen is

200 mg of mifepristone followed 1–2 days later by 800 μg of buccal misoprostol[5] Research has documented an efficacy of 64%–92% with misoprostol-only regimens[8–12]; these studies have examined

a number of factors, including the dose, route and intervals of miso-prostol administration

A previous trial compared 200-mg mifepristone followed by 800-μg buccal misoprostol 1 day later or 2 doses of 800-μg buccal misoprostol-only 24 hours apart among women with gestations up to 63 days since last menstrual period in Vietnam and found that mifepristone– misoprostol was associated with a significantly higher success rate (96.5% vs 76.2% for misoprostol-only) The study also revealed 10-fold greater (16.6% vs 1.5%) likelihood of ongoing pregnancy in the misoprostol-only group[12]

⁎ Corresponding author at: Gynuity Health Projects, 15 E 26th Street, Suite 801, New

York, NY 10012, USA Tel.: + 1 212 448 1230.

E-mail address: jblum@gynuity.org (J Blum).

0020-7292/$ – see front matter © 2012 International Federation of Gynecology and Obstetrics Published by Elsevier Ireland Ltd All rights reserved.

Contents lists available atSciVerse ScienceDirect International Journal of Gynecology and Obstetrics

j o u r n a l h o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / i j g o

The aim of the present study was to compare mifepristone plus

buccal misoprostol with repeat doses of buccal misoprostol alone at

3 hour intervals to determine whether this short dosing interval

im-proved the success of treatment with misoprostol alone, thereby

bringing it in line with the gold standard combined mifepristone–

misoprostol regimens

2 Materials and methods

A double-blind randomized placebo-controlled trial was

con-ducted From May 5, 2009, to July 20, 2010, pregnant women

pre-senting for early medical abortion up to 63 days since their last

menstrual period were recruited at two large maternity hospitals:

ei-ther the Centre de Maternite et Neonatologie de la Rabta in Tunisia

(n = 193) or Hung Vuong Hospital, Ho Chi Minh City, Vietnam

(n = 248) Participants had to live or work within a reasonable

dis-tance from the study hospital, have an intrauterine pregnancy, no

known contraindications to mifepristone and/or misoprostol, and

pre-sent in general good health In addition, all participants had to be

will-ing to provide informed consent and return for follow-up at the

hospital Women with known allergy to misoprostol, those with

ges-tations more than 63 days since last menstrual period, and those

who did not give consent were excluded from the trial Treatment

al-location was assigned in blocks of 10 using a computer-generated

ran-dom sequence created by staff at Gynuity Health Projects (New York,

USA) All medication packets were prepared by Gynuity Health

Pro-jects staff; providers and participants were blinded to study

treat-ment Ethics approvals were obtained from the relevant Institutional

Review Boards at the Centre de Maternite et Neonatologie de la

Rabta in Tunisia and at Hung Vuong Hospital, Ho Chi Minh City, Vietnam

Participant flow, randomization, and treatment assignment are presented inFig 1 Eligible participants were randomly allocated to

1 of the 2 treatment groups Women in the combined mifepristone– misoprostol group (n = 220) received 200 mg of mifepristone on day 1 and 800μg of buccal misoprostol followed by placebo 3 hours later on day 2 Women in the mifepristone-only group (n = 221) re-ceived placebo on day 1 and 1600μg of buccal misoprostol, adminis-tered as 2 doses of 800μg given 3 hours apart, on day 2 On study day

1, all participants received an envelope containing 3 packets of pills and were instructed to swallow the tablet in study packet 1 (either

200 mg of mifepristone or matching placebo) Participants were instructed to administer the 4 tablets contained in study packet 2 (800μg of misoprostol as 4×200-μg tablets) after 24 hours and to re-peat 3 hours later with the 4 tablets contained in study packet 3 (ei-ther placebo or 800μg of misoprostol) Women were instructed to administer the pills contained in study packets 2 and 3 buccally (be-tween the cheek and gum) for approximately 20 minutes and to swallow the remainder of the tablets afterwards They were told to take all of the medications even if they believed that the abortion was already complete Women were provided tablets of paracetamol (500 mg, with or without codeine) to manage any pain In addition, they were asked to record use of pain medication and the occurrence

of any adverse effects in a diary card After this counseling, all partic-ipants were scheduled for a follow-up appointment 1 week ± 2 days later at the study hospital Women were instructed that they could return to the hospital or contact their healthcare providers at any time for any reason

ENROLLED AND RANDOMIZED

(n=441)

MIFEPRISTONE–MISOPROSTOL

(n=220)

MISOPROSTOL-ONLY

(n=221)

ALLOCATED (n=220)

Received intervention (n=217) Did not receive intervention or changed mind about taking drugs (n=3)

ALLOCATED (n=221)

Received intervention (n=218) Did not receive intervention or changed mind about taking drugs (n=3)

One week in person or phone follow-up made (n=212)

Did not have 1 week in person or phone follow-up (n=5)

Lost to follow-up after 1 week in person or phone follow-up visit (n=2)

Lost to follow-up after unscheduled visit (n=0)

One week in person or phone follow-up made (n=218)

Did not have 1 week in person or phone follow-up (n=0)

Lost to follow-up after 1 week in person or phone follow-up visit (n=0)

Lost to follow-up after unscheduled visit (n=0)

ANALYZED FOR PRIMARY OUTCOME (n=210)

All available data included in the analysis

ANALYZED FOR PRIMARY OUTCOME (n=218)

All available data included in the analysis

ALLOCATION

FOLLOW-UP

ANALYSIS

flow, randomization, and treatment assignment.

At the follow-up appointment, the study protocol stipulated that

each woman's abortion status would be assessed by clinical

examina-tion and/or transvaginal ultrasonography as the provider deemed

necessary If an ongoing pregnancy was diagnosed, immediate

surgi-cal evacuation was offered (manual vacuum aspiration in Vietnam

and electric vacuum aspiration in Tunisia) Women with a persistent

non-viable pregnancy or gestational sac were given the choice of

ei-ther administering an additional 800μg of misoprostol buccally and

waiting another week to see if the products would evacuate

sponta-neously or immediate surgical completion All women presenting

with retained products of conception at the second follow-up visit

underwent a vacuum aspiration After the abortion was completed,

participants were interviewed about their experience and satisfaction

with the procedure

The primary outcome measure was complete uterine evacuation

without surgical evacuation for any reason The study design assumed

that mifepristone plus buccal misoprostol would be 95% effective and

it was hypothesized that 2 doses of buccal misoprostol administered

3 hours apart would be approximately 88% effective A 7% difference

in efficacy between the 2 treatment regimens was considered to be

clinically meaningful; as a consequence, enrollment of 376

partici-pants was sought to provide for aα value of 0.05, a one-sided test

and 80% power The estimated efficacy of misoprostol-only was

based on results shown with other routes of administration at

3-hour time intervals (approximately 83%)[10] To allow for a

lost-to-follow-up rate of approximately 15%, the intention was to enroll

432 women (216 per treatment arm) Ultimately, 441 women were

enrolled as recruitment was ongoing in 2 countries concurrently

Data entry and analysis were performed using SPSS version 15.0

(IBM, Armonk, NY, USA) Study data were entered separately in

each of the 2 countries and clean datasets merged for analysis by

the investigators in New York The 2 treatment regimens were

com-pared using t tests or the Mann–Whitney U test for continuous

vari-ables andχ2or Fisher exact tests for categoric variables The main

study outcomes were compared using relative risk (RR), 95% con

fi-dence interval (CI), and P value A P value below 0.05 was considered

statistically significant

3 Results

The participants' baseline characteristics are presented inTable 1;

there were no significant differences detected between the 2 groups

In all, 441 women were randomly allocated to treatment with either

misoprostol-only (n = 221) or combined mifepristone–misoprostol

(n = 220) Thefindings of the present study are reported according

to the Consolidated Standards of Reporting Trials (CONSORT) guide-lines[13]

Of the 441 participants, 3 from each group withdrew from the study before administering any study medication and were last seen at their initial visit (Fig 1) No women in the misoprostol group were lost to follow-up; however, treatment outcomes were un-known for 7 women in the mifepristone–misoprostol group The data analysis is presented for 428 women with knownfinal outcomes The outcome measures are presented inTable 2 A significantly higher proportion of women in the mifepristone–misoprostol group (n = 195; 92.9%) experienced complete abortion without surgical evacuation compared with the misoprostol-only group (n = 170; 78.0%) The RR was 0.84 (95% CI, 0.78–0.91; Pb0.001) Women receiv-ing misoprostol-only were significantly more likely to experience on-going pregnancy compared with women treated with mifepristone– misoprostol (13.8% [n = 30] versus 1.4% [n = 3]) The RR was 9.63 (95% CI 2.98–31.09; Pb0.001) The proportion of women with ongo-ing pregnancy in each gestational age group was also significantly higher with misoprostol-only Multivariable logistic regression con-trolling for gestational age revealed that there was a greater likeli-hood of ongoing pregnancy in Vietnam than in Tunisia (odds ratio 2.482; P = 0.042) among women randomized to misoprostol-only Reasons for surgical intervention were also similar in the 2 groups

No serious adverse events were reported (Table 3)

The majority of women in each treatment group indicated that they experienced diarrhea; however, diarrhea was reported more fre-quently in the misoprostol-only group (Pb0.001) No other signifi-cant differences were detected in the adverse effect profiles The participants' experiences of bleeding and pain were not significantly different between the 2 groups, although bleeding was commonly reported to be“less than expected” in misoprostol-only group The

RR was 1.41 (95% CI, 1.09–1.83; P=0.008) The majority of women reported that the adverse effects experienced were“acceptable” or

“very acceptable.”

Reports that the time required for the procedure was“less than expected” was significantly more frequent among the women who received mifepristone–misoprostol (Table 4) The RR was 0.76 (95%

CI, 0.61–0.95; P=0.015) Overall, participants' characterization of the procedure was not different between the 2 groups, and 66.3% (n= 283) characterized the procedure as “not difficult.” Generally, women reported that they were“satisfied” or “very satisfied” with their medical abortion experience Significantly more women reported being“very satisfied” in the mifepristone–misoprostol group than in the misoprostol-only group The RR was 0.75 (95% CI, 0.59–0.96; P=0.020) Satisfaction rates were similar among women with successful uterine evacuations regardless of the medical abortion regimen they received

A characterization of “satisfied or very satisfied” was reported by 94.7% (161/170) in the misoprostol-only group and by 96.4% (187/ 194) in the mifepristone–misoprostol group The RR was 0.98 (95% CI, 0.94–1.03; P=0.613) Although most women said they would opt for medical abortion over surgery if required in the future, significantly more women in the mifepristone–misoprostol group indicated this preference

4 Discussion Medical abortion using mifepristone–misoprostol or misoprostol-only has an important role in safe abortion care for women globally

In some settings, women have access to both mifepristone and miso-prostol, and the results of this study corroborate previous conclusions that, where available, mifepristone regimens should be offered In other settings, due to legal restrictions on abortion and wide avail-ability of misoprostol, the use of misoprostol-only will continue to

be the only medical abortion method available for the foreseeable future

Table 1

Baseline characteristics of the study participants (n = 441) a

Misoprostol-only (n = 221)

Mifepristone–misoprostol (n = 220)

Age, y 29 ± 6.5 (15–45) 29 ± 6.2 (18–46)

Level of education

University or higher 50 (22.6) 45 (20.5)

Gravidity 2.74 ± 1.6 (1–9) 2.98 ± 1.6 (1–9)

Primigravida 60/218 (27.5) 46/217 (21.2)

Number of previous surgical

abortions

Number of previous medical

abortions

a

Values are given as mean ± SD (range) or number (percentage).

b

Table 2

Outcomes following medical abortion a

(n = 221)

Mifepristone–misoprostol (n = 220)

Relative risk (95% confidence interval)

P value

Complete abortion without surgical evacuation b

170/218 (78.0) 195/210 (92.9) 0.84 (0.78–0.91) b0.001 Reasons for surgical intervention b 48/218 (22.0) 15/210 (7.1)

Non-viable pregnancy or gestational sac 9/218 (4.1) 0/210 (0.0)

Complete abortion without surgical evacuation, by gestational age group b,c

Ongoing pregnancy, by gestational age group

Non-viable pregnancy or gestational sac, by gestational age group

Incomplete abortion, by gestational age group

Abbreviation: LMP, last menstrual period.

a

Values are given as number (percentage) unless otherwise indicated.

b Does not include 7 women lost to follow-up in the mifepristone–misoprostol group and 6 women who withdrew from study and did not take any study medication (3 in the mifepristone–misoprostol group; 3 in the misoprostol-only group).

c Breakdown by gestational age does not show interventions for providers' or women's choice, which were evenly distributed across strata.

Table 3

Participants' characterization of adverse effects and experiences of the procedure a,b

Adverse effect or experience Misoprostol-only

(n = 218)

Mifepristone–misoprostol (n = 209)

Relative risk (95% confidence interval)

P value

Experience of bleeding

Experience of pain

Overall experience with adverse effects

a

Values are given as number (percentage) unless otherwise indicated.

b

The present study shows that treatment with 200 mg of

mifepris-tone plus 800μg of buccal misoprostol results in complete abortion

for more than 9 out of 10 women By contrast, repeat doses of

800μg of buccal misoprostol, given 3 hours apart, resulted in

com-plete abortion for 8 out of 10 women These comcom-plete abortion rates

—92.9% for mifepristone–misoprostol and 78.0% for

misoprostol-only—is within the range of previous reports[5,12] Indeed, the

pre-sentfindings closely match those from the largest randomized

con-trolled trial of misoprostol-only, which recorded success rates of

78%–85% with vaginal and sublingual misoprostol administered at

3 hour and 12 hour intervals [10] The ongoing pregnancy rate in

the misoprostol-only arm of the present study (13.8%) is similar to

the 17% rate of ongoing pregnancy reported by Ngoc et al.[12]with

800-μg buccal misoprostol repeated 24 h later Likewise, the observed

outcomes with the mifepristone–misoprostol regimen were not

dis-similar to those previously reported in the USA and in Vietnam[5,12]

The outcomes with the misoprostol-only regimen used in this

study cannot be generalized to all misoprostol-only regimens The

present study tested a regimen of 2 doses of 800μg of buccal

miso-prostol Although pharmacokinetic data show the buccal route this

promising[14,15], it is possible that outcomes may improve slightly

with other routes of administration, possibly with reduced time

inter-vals between doses In our study, if the pregnancy was confirmed as

ongoing at the 1-week follow-up, additional misoprostol doses were

not offered and instead standard surgical termination was provided

In other settings, repeat doses of misoprostol are increasingly

becom-ing the standard of care—an approach that should result in fewer

sur-gical interventions

While the randomization procedure used in the present study was

successful (Table 1), some limitations exist given that the 2 countries

contributed differently to the gestational age groups and that few

women with gestations beyond 57 days of their last menstrual period

were enrolled There was a greater likelihood of ongoing pregnancy

in Vietnam than in Tunisia (odds ratio 2.482; P = 0.042) among

women randomized to misoprostol-only Future research exploring

misoprostol-only regimens might investigate the reasons for these

country-level differences

Looking forward, it is critical to bear in mind that while a need for

medical abortion regimens with and without mifepristone will

con-tinue, service delivery should account for the potential differences

in outcomes In the present study, it was shown that women can

safe-ly and effectivesafe-ly self-administer all of their medical abortion drugs at

home In terms of service delivery, women given misoprostol-only should be counseled and prepared for a higher incidence of ongoing pregnancy and incomplete abortion Service delivery with the inclu-sion of at-home self-checkup mechanisms, such as symptom check-lists and semi-quantitative pregnancy tests, may prove beneficial Future research should address the cost-effectiveness of these 2 methods of medical abortion However, programmatic activities should not curtail global efforts to make mifepristone available to all women in all settings Ensuring that the safest and most efficacious methods are made universally available should continue to be a prior-ity for women's health

Acknowledgments The present study was funded by an anonymous donor

Conflict of interest The authors have no conflicts of interest

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Table 4

Participants' characterization of the procedure and reports of satisfaction a,b

Misoprostol-only (n = 218)

Mifepristone–misoprostol (n = 209)

Relative risk (95% confidence interval)

P value

Time required for procedure

Overall characterization of the procedure

Overall satisfaction

Method of abortion selected in future

a

Values are given as number (percentage) unless otherwise indicated.

b

Some data missing as not all participants responded to all questions.

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