Two mifepristone doses and two intervals of misoprostol administration for termination of early preg

Two mifepristone doses and two intervals ofmisoprostol administration for termination ofearly pregnancy: a randomised factorialcontrolled equivalence trial*H von Hertzen, G Piaggio, D Wojdyla, L Marions, NT My Huong, OS Tang, AH Fang, SC Wu, L Kalmar,

S Mittal, R Erdenetungalag, M Horga, A Pretnar-Darovec, A Kapamadzija, K Dickson, ND Anh,

NV Tai, HTD Tuyet, A Peregoudov for the WHO Research Group on Post-ovulatory Methods of

Fertility Regulation

See Supporting Information for the full list of author affiliations

Correspondence: Dr H von Hertzen, UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in

Human Reproduction, Department of Reproductive Health and Research, WHO, 1211 Geneva 27, Switzerland. Email [email protected]

Accepted 5 October 2008.

Objective To compare the efficacy of 100 mg and 200 mg of

mifepristone and 24- and 48-hour intervals to administration of

800mg vaginal misoprostol for termination of early pregnancy.

Design Placebo-controlled, randomized, equivalence trial, stratified

by centre.

Setting 13 departments of obstetrics and gynecology in nine

countries.

Population 2181 women with 63 days or less gestation requesting

medical abortion.

Methods Two-sided 95% CI for the risk differences of failure to

complete abortion were calculated and compared with 5%

equivalence margin between two doses of mifepristone and two

intervals to misoprostol administration. Proportions of women

with adverse effects were compared between the regimens using

standard testes for proportions.

Outcome measures Rates of complete abortion without surgical

intervention and adverse effects associated with the regimens.

Results Efficacy outcome was analysed for 2126 women (97.5%)

excluding 55 lost to follow up. Both mifepristone doses were found

to be similar in efficacy. The rate of complete abortion was 92.0%

for women assigned 100 mg of mifepristone and 93.2% for women

assigned 200 mg of mifepristone (difference 1.2%, 95% CI: –1.0 to

3.5). Equivalence was also evident for the two intervals of

administration: the rate of complete abortion was 93.5% for 24-

hour interval and 91.7% for the 48-hour interval (difference –1.8%,

95% CI: –4.0 to 0.5). Interaction between doses and interval to

misoprostol administration was not significant (P = 0.92).

Adverse effects related to treatments did not differ between the

groups.

Conclusions Both the 100 and 200 mg doses of mifepristone and

the 24- and 48-hour intervals have a similar efficacy to achieve

complete abortion in early pregnancy when mifepristone is

followed by 800 micrograms of vaginally administered

misoprostol.

Keywords Medical abortion, mifepristone dose, mifepristone-

misoprostol interval.

Please cite this paper as: von Hertzen H, Piaggio G, Wojdyla D, Marions L, My Huong N, Tang O, Fang A, Wu S, Kalmar L, Mittal S, Erdenetungalag R, Horga M,

Pretnar-Darovec A, Kapamadzija A, Dickson K, Anh N, Tai N, Tuyet H, Peregoudov A, for the WHO Research Group on Post-ovulatory Methods of Fertility

Regulation. Two mifepristone doses and two intervals of misoprostol administration for termination of early pregnancy: a randomised factorial controlled

equivalence trial. BJOG 2009;116:381–389.

Introduction

The antiprogestin mifepristone followed by a suitable prosta-

glandin analogue is registered for termination of early preg-

nancy in more than 35 countries. In Europe and the USA, the

approved regimen consists of 600 mg of mifepristone, fol-

lowed 36–48 hours later by a prostaglandin analogue, most

often misoprostol.

The data from several multicentre trials conducted over

the past 15 years demonstrate that a single dose of 200 mg

of mifepristone has a similar efficacy to achieve complete*ISRCTN24130607; http://www.controlled-trials.com/INRCTN24130607/

ISRCTN24130607

ª 2009 The World Health Organization Journal compilation ª RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology 381

DOI: 10.1111/j.1471-0528.2008.02034.x

www.blackwellpublishing.com/bjogFertility control

abortion as the 600 mg dose.1–3 In addition, administration of

multiple small doses (five doses of 25 mg given at 12-hour

intervals), which is routine in China, was not significantly

different from a single dose of 600 mg.4 On the other hand,

the efficacy decreases when the dose of mifepristone is low-

ered to 50 mg.5 In a study on pharmacokinetics, oral admin-

istration of 100 mg or higher single doses of mifepristone

resulted in similar serum concentrations.6 Similar serum levels

can be explained by saturation of the binding capacity of the

carrier protein as mifepristone binds to the serum transport

protein alfa-1-acid glycoprotein, which limits its availability to

tissues. No previous studies, however, compared the 100 mg

dose with the commonly used dose of 200 mg of mifepristone.

Mifepristone pre-treatment leads to the softening and dila-

tion of the uterine cervix and it increases the sensitivity of the

uterine muscle to prostaglandins. It has been demonstrated

that the maximal sensitivity is achieved when mifepristone is

administered 36–48 hours before the prostaglandin analogue,7

and this is also the time interval to achieve maximal softening

and dilation of the uterine cervix.8 Consequently, the 36- to

48-hour interval was adopted as a standard for the medical

abortion regimen. Also, the data collected on 16 000 women

who had been treated with 600 mg of mifepristone followed by

a prostaglandin analogue 24–72 hours later suggested that the

efficacy was highest if the interval was 48 hours.9

Different time intervals between mifepristone and miso-

prostol have also been tested10 or both drugs have been

administered simultaneously,11 repeating the dose of miso-

prostol if abortion was not complete. When misoprostol

was not repeated, complete abortion rates seem to be signif-

icantly lower with shorter intervals.12 No previous studies had

been undertaken with a 100 mg dose of mifepristone when the

interval to misoprostol is 24 hours.

Based on the pharmacokinetics of mifepristone and the

published reports, we aimed to demonstrate that 100 mg

has a similar efficacy to 200 mg and that the 24- and 48-hour

intervals between mifepristone and misoprostol result in an

equivalent efficacy when using 800 micrograms of misopros-

tol administered vaginally (the null hypothesis being that

there is a difference in efficacy greater than a prestated margin

of 5%). A 24-hour interval would be more practical than 48-

hours and, if found effective, the 100 mg dose could be cheaper

than 200 mg, let alone the registered dose of 600 mg. This is

particularly important as the relatively high price of mifepris-

tone has limited its use in some countries despite its major

advantages as a pre-treatment.

We launched this randomised equivalence trial to test our

hypotheses for pregnancy termination among women with

gestational age of 63 days or less. Our main outcome was

complete abortion. We also studied adverse effects associated

with the use of these four regimens and the timing of expul-

sion. In addition, women were asked questions about their

perceptions of the treatments.

Methods

PatientsThe trial was undertaken in 13 departments of obstetrics and

gynaecology of teaching hospitals in Beijing and Shanghai,

People’s Republic of China; Hong Kong, Special Administra-

tive Region of China, Szeged, Hungary; New Delhi, India;

Ulaanbaatar, Mongolia; Targu Mures, Romania; Ljubljana,

Slovenia; Johannesburg, South Africa; Hanoi (two hospitals)

and Ho Chi Minh City, Viet Nam; and Novi Sad, Serbia.

Institutional review boards at each of the participating hos-

pitals and the WHO Secretariat Committee on Research on

Human Subjects gave ethics approval.

Women requesting early termination of pregnancy were

given information about the study, screened for eligibility

by clinic personnel if willing to participate and included if

they were healthy, older than the age of legal consent, had

haemoglobin level ‡100 g/l, intrauterine pregnancy with

duration £63 days verified by ultrasound, agreed to return

for follow-up visit(s) and agreeable, in principle, to surgical

termination of pregnancy should the treatment fail.

We excluded from this study women who had any indica-

tion of serious past or present illness, those allergic to mife-

pristone or misoprostol, chronic adrenal failure, severe

asthma uncontrolled by corticosteroid therapy, inherited

porphyria, heavy smokers (>20 cigarettes a day) with another

risk factor of cardiovascular disease, a history or evidence

of mitral stenosis, glaucoma, diastolic blood pressure >90

mmHg, systolic blood pressure <90 mmHg, history or evi-

dence of tromboembolism, evidence of liver disease, presence

of an IUD in utero, breastfeeding or haemolytic disorders. All

participants gave written informed consent before entering

the study. Relevant medical, gynaecological and obstetric his-

tories were recorded and bacteriological tests and Rh-typing

performed according to the routine of the centre.

Randomisation and interventionsA computer-generated randomisation sequence was produced

by WHO staff in Geneva to assign participants within each

centre to one of the four dose-interval combinations: 100 mg

of mifepristone and 800 micrograms of misoprostol 24 hours

later, 100 mg of mifepristone and 800 micrograms of misopros-

tol 48 hours later, 200 mg of mifepristone and 800 micrograms

of misoprostol 24 hours later and 200 mg of mifepristone and

800 micrograms of misoprostol 48 hours later. Mifepristone

was administered orally and misoprostol vaginally.

Each centre received assignments by randomly permuted

blocks with a fixed block size of 8. Randomisation was also

stratified by the gestational age (up to 49, 50–56 and 57–63

days). Allocation was concealed by the use of sealed, opaque,

sequentially numbered envelopes, which were filled and

labelled in accordance with the list of randomisation for each

centre by Magistra, Geneva, Switzerland. The 100 mg dose

von Hertzen et al.

382 ª 2009 The World Health Organization Journal compilation ª RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology

of mifepristone consisted of one tablet of 100 mg and one

placebo tablet and the 200 mg dose consisted of two tablets of

100 mg of mifepristone (Hualian Pharmaceuticals Ltd,

Shanghai, China). Placebo tablets were of similar shape and

colour as mifepristone tablets. The interval to misoprostol

(Cytotec; Monsanto, Paris, France) administration was not

blinded.

To establish the equivalent efficacy of the two doses of

mifepristone (100 and 200 mg) within each interval of miso-

prostol administration or of the two intervals between mife-

pristone and misoprostol (24 and 48 hours) within each dose

of mifepristone, we required the 95% CI for the difference in

complete abortion rates to be within the margin of equiva-

lence of 5% with a probability of 80%. This margin was cho-

sen using clinical judgement. If complete abortion rates by the

two doses (or with the two intervals) are both equal to 96%,

about 323 subjects will be required in each group, that is

a total of about 1300 subjects for the whole study. Allowing

for 10% of lost to follow up, at least 1450 subjects would have

to be recruited. In practice, 14 centres wished to participate,

each of them willing to recruit 156 women, that is a total of

2184 women for the whole study.

The primary outcome measure was efficacy of the treat-

ment in inducing complete abortion. Complete abortion

was defined as passing of the products of conception without

surgical intervention during the follow-up period; incomplete

abortion as expulsion of fetus but some products of concep-

tion remaining in uterus needing evacuation; missed abortion

as gestational sac in uterus without cardiac activity on ultra-

sound examination, needing emptying of the uterus; continu-

ing pregnancy as growing gestational sac with fetal heart

activity. If the woman discontinued the treatment and

requested vacuum aspiration before misoprostol administra-

tion or soon after it before the outcome could be known or

she was lost to follow up, the outcome was regarded as

undetermined.

The efficacy was assessed at the follow-up visits 2 and 6

weeks after the start of treatment.

Signs and symptoms were recorded before mifepristone,

before misoprostol and at 1, 2 and 3 hours after misoprostol

administration at the clinic as well as daily until the first

follow-up visit by women. Signs and symptoms were classified

as pregnancy related, treatment related and those related to

the abortion process itself.

ProceduresThe first dose of treatment (two tablets of 100 mg of mife-

pristone or one 100 mg of mifepristone tablet and one placebo

tablet) was administered at the clinic. Women returned either

24 or 48 hours later for vaginal administration of four tablets

of 200 micrograms of misoprostol each, after which they

stayed at the clinic for 3 hours under supervision, during

which period signs and symptoms were recorded hourly.

When leaving the clinic, the women were asked to keep a diary

about adverse effects and bleeding until the follow-up visit.

The initial clinical judgement about the outcome was made

at the first follow-up visit 2 weeks after the treatment. If the

findings at pelvic examination were suggestive of a continuing

pregnancy, an ultrasound examination was performed. In

case of live pregnancy, vacuum aspiration was performed.

If clinical findings were compatible with incomplete abortion,

no further action was taken unless judged necessary by the

investigator. For these women, the final outcome of therapy

was made at the second follow-up visit on day 43 of the study.

Statistical analysisData were analysed with SAS� System statistical software

(version 9.1.3) centrally at WHO. This trial was compliant

with CONSORT guidelines for reporting equivalence trials.13

An independent data monitoring committee reviewed the

data from two interim analyses performed after 509 and

1050 subjects were included in the study. According to the

protocol, a decision to discontinue a treatment regimen due

to low efficacy was based on the comparison with the regimen

of 200 mg of mifepristone followed by 800 micrograms of

misoprostol vaginally 48 hours later.

For the main analysis, women with unknown outcomes

due to lost to follow up were excluded. Additionally, a

per-protocol analysis excluding noncompliant cases was per-

formed. For each treatment regimen, percentages and

two-sided 95% CI were computed for complete abortion

and failure to complete abortion, which included incomplete

abortion, missed abortion, continuing live pregnancy and

undetermined outcomes.

Interaction between mifepristone dose and interval of

misoprostol administration was assessed adding an interac-

tion term to a logistic regression model including dose and

interval effects. Equivalence of mifepristone doses was

assessed within each interval of misoprostol administration

and also combining both intervals. Two-sided 95% CI for the

risk differences of failure to complete abortion were calcu-

lated by standard methods and compared with the equiva-

lence margin (5%). Similarly, equivalence of intervals of

misoprostol administration was assessed within each mife-

pristone dose and combining the doses. Analyses adjusting

by centre and baseline characteristics were carried out using

a logistic regression model. A stratified analysis by gestational

age was carried out together with comparisons of adverse

effect occurrence among the four regimens.

The role of funding sourceThe UNDP/UNFPA/WHO/World Bank Special Programme

of Research, Development and Research Training in Human

Reproduction funded this study including misoprostol tab-

lets. Mifepristone and placebo tablets were donated by

Hualian Pharmaceuticals Ltd. Neither the donors and

Mifepristone dose and interval to misoprostol administration for early abortion


sponsors of the Programme nor Hualian Pharmaceuticals Ltd

had a role in the study design, data collection, data analysis,

data interpretation, writing of the report or the decision to

submit the paper for publication. The corresponding author

had full access to all final data in the study and had the final

responsibility for the decision to submit for publication.

Results

A total of 2181 women were enrolled in the study. Recruit-

ment started in March 2003 and finished in May 2005. Base-

line characteristics were similar among the four treatment

groups (Table 1). The mean age was about 26 years old. For

43% of the women, this was their first pregnancy and 47% of

them were using some form of contraception at the time the

pregnancy started.

All 2181women receivedmifepristone (Figure 1), after which

5 women opted for surgical termination and 1 woman did not

return, so that 2175 women were administered misoprostol. A

total of 2126 women completed the study and the 55 women

considered lost to follow up were distributed evenly across three

of the four treatment regimens. A total of 47 women discon-

tinued their participation before the outcome could be assessed.

The women with undetermined outcome (n = 102) were on

average 25 years old and 34% of them were primigravidas.

The efficacy outcome was analysed for 2126 women includ-

ing the 47 women with undetermined outcome who were

considered as failures to achieve complete abortion. The

numbers and percentages of women in each category are

shown in Table 2. The interaction of mifepristone dose by

interval of misoprostol administration was not significant

for failure to complete abortion (P = 0.92). Both mifepristone

doses produced equivalent rates of failure to achieve complete

abortion within each interval of misoprostol administration

and overall for the two intervals combined (Figure 2). Com-

pared with the 200 mg of mifepristone, the rates of failure to

complete abortion were slightly higher in the 100 mg groups

but the CI for risk difference fell entirely within the equiva-

lence limits (difference 1.2%, 95% CI: –1.0 to 3.5).

When the intervals of misoprostol administration were

compared, combining mifepristone doses, both intervals were

equivalent within a 5% margin. The 24-hour interval tended

to have lower failure rates than the 48-hour interval (differ-

ence –1.8, 95% CI: –4.0 to 0.5). Adjustment for centre and

baseline characteristics (age, weight, haemoglobin level, par-

ity, previous abortion and gestational age) produced almost

the same results (data not shown).

Noncompliance with treatment was 5.3%. Almost all cases

of noncompliance were due to misoprostol administration

more than 2 hours outside the assigned time interval. The

conclusions do not change when noncompliant cases are

excluded (per-protocol analysis) or when all randomised sub-

jects (n = 2181) are included in the analysis considering lost to

follow up as failures.

The stratified analysis of the rate of failure to complete

abortion by gestational age shows that both doses and both

Table 1. Baseline characteristics by treatment group

Mifepristone

100 mg 1 misoprostol

24 hours (n 5 545)

Mifepristone


48 hours (n 5 547)

Mifepristone


24 hours (n 5 544)

Mifepristone


48 hours (n 5 545)

Demographic and physical

Age (years) 26.2 (5.7) 26.2 (5.7) 26.4 (5.7) 26.1 (5.4)

Weight (kg) 55.3 (10.9) 54.7 (10.3) 54.4 (10.1) 55.0 (11.5)

Haemoglobin (g/L) 122.1 (10.6) 122.1 (10.0) 122.6 (10.7) 122.3 (10.5)

Ethnic group

Chinese 156 (29) 156 (29) 155 (28) 155 (28)

Non-Chinese Asian or black 214 (39) 216 (39) 213 (39) 213 (39)

White 175 (32) 175 (32) 176 (33) 177 (33)

Obstetric and gynaecological history

Nulliparity 329 (60) 315 (58) 311 (57) 324 (59)

Previous abortion 187 (34) 205 (37) 224 (41) 216 (40)

Gestational age* (days)

,49 228 (42) 241 (44) 244 (45) 245 (45)

50–56 164 (30) 165 (30) 147 (27) 164 (30)

57–63 152 (28) 141 (26) 151 (28) 136 (25)

.63 1 (,1) 0 (0) 2 (,1) 0 (0)

Median (interquartile range) 51 (44–57) 51 (44–57) 51 (44–57) 51 (44–56)

Data are n (%) or mean (SD), unless otherwise indicated.

*Gestational age assessed by ultrasound.

von Hertzen et al.


administration intervals are equivalent when the gestational

age is 49 days or less (Table 3). The results are inconclusive

when the gestational age is 50 days or more: the trial was not

powered to show equivalence in subgroups.

Among 2051 women with complete and incomplete abor-

tion timing of expulsion was assessed for 1848 women (90%).

The median time to expulsion was 28 hours for regimens with

24-hour interval to misoprostol administration and between

51 and 52 hours in regimens with 48-hour intervals. There-

fore, it would appear that expulsion occurred in all groups

approximately 4 hours after misoprostol administration. No

differences were observed in time from misoprostol adminis-

tration to expulsion between the four regimens.

The percentage of women who reported pregnancy-related

symptoms (nausea and vomiting) and lower abdominal pain

after mifepristone administration and before misoprostol was

higher in the 48 hours of misoprostol administration interval

than in the 24-hour interval (Table 4). After misoprostol

3250 screened for elegibility

2707 eligible

543 not eligible

377 not willing to participate

149 did not participate forother reasons

2181 randomly assigned

545 assigned to100 mg of mifepristone+ 24 hours misoprostol




529 analysed522 had first follow up

498 had second follow up11 VA







4 VA1 VA

545 receivedmisoprostol at 24 hours




16 lost tofollow up

13 lost tofollow up

13 lost tofollow up

12 lost tofollow up

1 lost tofollow-up1 lost to

follow up

Figure 1. Flow chart.

Table 2. Efficacy outcome by treatment group

Outcome Mifepristone


24 hours (n 5 529)

Mifepristone


48 hours (n 5 534)

Mifepristone


24 hours (n 5 531)

Mifepristone


48 hours (n 5 532)

Total

Complete abortion 492 (93.0, 90.5–95.0) 486 (91.0, 88.3–93.3) 499 (94.0, 91.6–95.8) 492 (92.5, 89.9–94.6) 1969 (93)

Failure to complete abortion

Total 37 (7.0, 5.0–9.5) 48 (9.0, 6.7–11.7) 32 (6.0, 4.2–8.4) 40 (7.5, 5.4–10.1) 157 (7)

Incomplete abortion 17 (3.2, 1.9–5.1) 21 (3.9, 2.5–6.0) 17 (3.2, 1.9–5.1) 27 (5.1, 3.4–7.3) 82 (4)

Delayed abortion 3 (0.6, 0.1–1.7) 3 (0.6, 0.1–1.6) 1 (0.2, 0.0–1.0) 0 (0.0) 7 (,1)

Continuing pregnancy 6 (1.1, 0.4–2.5) 7 (1.3, 0.5–2.7) 4 (0.7, 0.2–1.9) 4 (0.7, 0.2–1.9) 21 (1)

Undetermined 11 (2.1, 1.0–3.7) 17 (3.2, 1.9–5.1) 10 (1.9, 0.9–3.4) 9 (1.7, 0.8–3.2) 47 (2)

Data are n (%, 95% CI) in different outcome categories.

Excluding lost to follow up (subjects analysed: 2126, subjects excluded: 55).



administration, the four groups did not differ significantly in

terms of pregnancy-related symptoms.

Lower abdominal pain increased markedly after misopros-

tol administration. About 20% of the women reported pain at

admission, 72% 1 hour after misoprostol, 86% 2 hours after

and 88% 3 hours after, however, no differences were observed

between treatment groups. At the first follow-up visit about

50% of women reported having had some lower abdominal

pain since the last visit. No differences were observed between

the groups for diarrhoea, chills/shivering and headache.

About 61% of the women had experienced less pain and

55% fewer adverse effects than they had expected. When

women were asked after abortion, where they would prefer

to have medical abortion if they need another one, about 77%

said that they would prefer to have it at the clinic rather than

at home.

There were 282 unscheduled visits during the study, 86 of

them (31%) due to lower abdominal pain as the main reason,

while 80 visits (28%) were due to excessive vaginal bleeding.

At admission to the study, 80 women (3.7%) had signs of

abnormal vaginal discharge. Tests for gynaecological infec-

tions were performed for 168 women (7.7%) and found pos-

itive in 16 of them, most having candida or nonspecific

vaginal infection. A total of 176 (8.1%) women received anti-

biotic treatment between admission and first follow-up visit,

149 of them at one site, where women were given antibiotics

routinely after misoprostol visit, and the rest to treat sus-

pected or verified vaginal infection; 43 (2.0%) women

–6 –5 - –3 –2 –1 0 1 2 3 4 5 6

Mifepristone100 versus 200 mg

Mifepristone 100 mg

Mifepristone 200 mg

Overall

Overall

Misprostol at 24 hours

Misprostol at 48 hours

Misoprostol 24 versus 48 hours

100 mg200 mg better100 mg better

24 hours better 48 hours better

Risk difference (%,95%CI)

200 mg

24 hours 48 hours

8.0% 6.8%

7.0% 6.0%

9.0% 7.5%

Failure to achieve

complete abortion

–-4

6.5% 8.3%

7.0% 9.0%

6.0% 7.5%

Figure 2. Risk differences of failure to achieve complete abortion.

Table 3. Failure to achieve complete abortion by treatment group and gestational age

n/N (%) n/N (%) Risk difference

(%, 95% CI)

Comparison: mifepristone 100 versus 200 mg 100 mg 200 mg

Overall 85/1062 (8.0) 72/1061 (6.8) 1.2 (21.0–3.5)

49 days or less 30/459 (6.5) 25/482 (5.2) 1.4 (21.7–4.4)

50–56 days 27/321 (8.4) 28/303 (9.2) 20.8 (25.3–3.6)

57–63 days 28/282 (9.9) 19/276 (6.9) 3.1 (21.6–7.6)

Comparison: misoprostol 24 versus 48 hours 24 hours 48 hours

Overall 69/1057 (6.5) 88/1066 (8.3) 21.8 (24.0–0.5)

49 days or less 30/465 (6.5) 25/476 (5.3) 1.2 (21.8–4.2)

50–56 days 20/300 (6.7) 35/324 (10.8) 24.1 (28.5–0.3)

57–63 days 19/292 (6.5) 28/266 (10.5) 24.0 (28.7–0.6)

Excluding lost to follow up and gestational age more than 63 days (subjects analysed: 2123, subjects excluded: 58 [55 lost to follow up,

3 gestational age .63 days]).

von Hertzen et al.


received antibiotics between the two follow-up visits and two

of them were diagnosed with pelvic inflammatory disease

with retained tissue. Eleven cases of heavy bleeding were

reported as serious adverse events; two women required blood

transfusion and one woman was given plasma expanders. In

all, six women were hospitalised for treatment.

Discussion

Our findings show a similar efficacy for achieving complete

abortion in early pregnancy within a 5% margin, for 100 and

200 mg doses of mifepristone when followed by 800 micro-

grams of vaginal misoprostol and for 24- and 48-hour inter-

vals between these drugs when the gestational length is 63

days or less.

Despite similar pharmacokinetics, no studies have com-

pared the efficacy of 100 and 200 mg doses in medical abor-

tion regimen. The 100 mg dose of mifepristone was used in

a study14 that compared oral and vaginal misoprostol. All 40

women who were randomised to receive 800 micrograms of

misoprostol vaginally 48 hours after mifepristone had com-

plete abortion, while complete abortion rate was 85% among

women who received 400 micrograms of misoprostol orally

and pregnancy continued in four (10%) of these women. This

study suggests that 100 mg dose may not be enough if the dose

of misoprostol is insufficient and/or effective uterine contrac-

tions fail to be produced by the route it is administered.15

When mifepristone dose was lowered to 50 mg in a regimen

with 1 mg of gemeprost, complete abortion rate was 89.8%,

while it was 92.9% in the 200 mg group.5 The rate of con-

tinuing pregnancies was also higher (2.2 versus 0.6%) in the

50 mg group.

Based on available evidence about the time interval to max-

imal effect of mifepristone,7 one would have expected a better

efficacy after 48-hour interval compared with 24 hours. The

effect on uterine contractility is a balance between the degree

of sensitivity and the dose of prostaglandin. If we shorten the

interval, we are likely to need a higher dose of prostaglandin

and a route of administration that leads to effective contrac-

tility, especially when the gestational age increases. We used

one single dose of 800 micrograms of misoprostol vaginally.

This high dose of misoprostol may have masked the effect of

Table 4. Symptoms and adverse effects

Mifepristone

100 mg 1

misoprostol

24 hours

Mifepristone

100 mg 1

misoprostol

48 hours

Mifepristone

200 mg 1

misoprostol

24 hours

Mifepristone

200 mg 1

misoprostol

48 hours

P value

n (%) n (%) n (%) n (%)

Nausea

Between mifepristone and misoprostol 235 (43.1) 289 (52.9) 237 (43.6) 298 (55.2) , 0.0001

Within 3 hours after misoprostol 200 (36.7) 194 (35.5) 204 (37.5) 212 (39.3) 0.6203

After misoprostol up to first follow-up visit 63 (12.1) 58 (11.1) 49 (9.3) 48 (9.2) 0.3519

Vomiting

Between mifepristone and misoprostol 87 (16.0) 126 (23.1) 74 (13.6) 129 (23.9) , 0.0001



Lower abdominal pain

Between mifepristone and misoprostol 159 (29.2) 212 (38.8) 163 (30.0) 197 (36.5) 0.0008



Diarrhoea




Headache




Fever



Chills/shivering




the interval. With lower vaginal doses or with oral adminis-

tration of misoprostol or in later pregnancies, we might not

have obtained similar results. This was demonstrated in a sec-

ond-trimester abortion study16 in which the time until abor-

tion occurred was significantly longer (P < 0.0001) in the 1-

day interval group compared with 2-day interval between 200

mg of mifepristone and the start of administration of vaginal

misoprostol (400 micrograms at 3-hour intervals). Conse-

quently, the total dose of misoprostol given to women was

higher in the 1-day interval group.

A previous study that compared 1-, 2- and 3-day intervals

between 200 mg of mifepristone and 800 micrograms of vag-

inal misoprostol also reported similar rates of complete abor-

tion for both 1- and 2-day intervals.10 However, a second dose

of misoprostol was administered if abortion was not com-

plete, and it is not mentioned whether the need for additional

dose(s) was similar in all groups. Shorter than 24-hour inter-

vals between mifepristone and misoprostol have also been

tested or both drugs have been given at the same time. It

seems common for these studies that additional doses of

misoprostol are given to women who either do not abort or

do not have complete abortion. As abortion can also be

induced by multiple doses of misoprostol without mifepris-

tone,17 one may need to be cautious when drawing conclu-

sions about the efficacy of simultaneous administration when

additional misoprostol doses are given. One could question

whether these studies really compare different intervals if

insufficient success has to be compensated by additional

misoprostol doses to improve the results. When misoprostol

is administered at the same time with mifepristone and the

dose needs to be repeated even in early first trimester, the

benefits of mifepristone are partly lost and it is not clear

whether women abort with the combined regimen or multiple

doses of misoprostol.

The rates of complete abortion in all four arms of our

study were lower than in our previous studies.18 This is

likely to be due to the fact that several of the participating

centres do not provide medical abortion routinely because

mifepristone has not been licensed in their country. Expe-

rienced providers report higher complete abortion rates

than those with less experience.19 The comparison, however,

has internal validity as randomisation was within centres.

Rates of continuing pregnancies were low in all arms.

Whether pregnancies continue or not depends on the effi-

cacy of the regimen and the experience of providers have

little, if any, influence on it.

A higher percentage of women in the 48-hour interval

groups reported pregnancy-related symptoms such as nausea

and vomiting after mifepristone administration than women

in the 24-hour groups. This may be related to the fact that as

the time interval is longer, there is more chance to experience

these symptoms. This was also the case for lower abdominal

pain. As mifepristone sensitises the uterus also for endoge-

nous prostaglandins, uterine contractility is likely to increase

with time and can be experienced as painful. As the 24-hour

interval was associated with lower rates of these symptoms, it

is reasonable to recommend it, given its advantages and its

trend to a better efficacy.

The rate of suspected or verified infections in this study was

low. There has been discussion about whether routine pro-

phylactic antibiotic treatment is necessary when using medi-

cal abortion. The low rate of gynaecological infections after

treatment in this study does not support this practise.

This equivalence trial was designed with a prestated 5%

margin for the difference in percentage of women achieving

complete abortion. This margin was determined using clinical

assessment and it implies that a smaller difference is not clin-

ically relevant. Using a smaller margin would have implied

conducting a larger trial.

This trial has strong internal validity with a clear research

question and clearly defined primary and secondary outcome

measures. The sample size was calculated according to the

prestated hypothesis, randomisation and concealment of the

random allocation were used and both as randomized and

per-protocol analyses were performed (as recommended for

equivalence trials).

This trial also has external validity as it enrolled women of

several different populations and included centres with dif-

ferent levels of experience with medical abortion. Thus, the

results are likely to apply to wider populations.

In conclusion, our results show that for the termination of

early pregnancy (£63 days’ of gestation), mifepristone dose

could be lowered to 100 mg and the administration interval

shortened to 24 hours when using vaginal misoprostol of 800

micrograms.

Contributions to authorshipH.v.H., in collaboration with the members of the Steering Commit-

tee, was responsible for the conception of the trial and selection of

centres. H.v.H.and G.P. prepared the protocol. O.S.T., A.H.F.,

S.C.W., L.K., S.M., R.E., M.H., A.P.-D., A.K., K.D., N.D.A., N.V.T.,

and H.T.D.T. contributed to the final trial protocol and implemented

the trial in their respective countries. H.v.H., G.P. and L.M. super-

vised the trial. G.P. and D.W. were responsible for the statistical

analysis and N.T.M.H. and A.P. for the data management. H.v.H.,

G.P. and D.W. wrote the paper with inputs from the investigators.

WHO Research Group for the trialThe full list can be found in the online supporting information.

Country collaboratorsThe full list can be found in the online supporting information.

Conflict of interest statementOverall responsibility for this paper lies with Dr H.v.H. of the UNDP/

UNFPA/WHO/World Bank Special Programme of Research, Devel-

opment and Research Training in Human Reproduction, WHO.

von Hertzen et al.


Neither she nor the Special Programme or any of its cosponsors have

a conflict of interest.

Ethics approvalInstitutional review boards at each of the participating hospitals and

the WHO Secretariat Committee on Research on Human Subjects

gave ethics approval.

AcknowledgementsThe study was funded by the UNDP/UNFPA/WHO/World Bank

Special Programme of Research, Development and Research Train-

ing in Human Reproduction. We thank the members of the Data and

Safety Monitoring Board for their contribution to interim analyses

and their valuable comments on the manuscript. Grateful thanks are

also due to P Van Look for his critical review of the manuscript.

Supporting information

Additional Supporting Information may be found in the

online version of this article:

List of author affiliations and WHO group and country

collaborator lists.

Please note: Wiley-Blackwell is not responsible for the con-

tent or functionality of any supporting information supplied

by the authors. Any queries (other than missing material)

should be directed to the corresponding author. j

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