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RESEARCH ARTICLE Open Access
Medical termination for pregnancy in earlyfirst trimester (≤ 63 days) usingcombination of mifepristone andmisoprostol or misoprostol alone: asystematic reviewFerid A. Abubeker1* , Antonella Lavelanet1, Maria I. Rodriguez2 and Caron Kim1
Abstract
Background: A wide range of drugs have been studied for first trimester medical abortion. Studies evaluatingdifferent regimens, including combination mifepristone and misoprostol and misoprostol alone regimens, showvarying results related to safety, efficacy and other outcomes. Thus, the objectives of this systematic review were tocompare the safety, effectiveness and acceptability of medical abortion and to compare medical with surgicalmethods of abortion ≤63 days of gestation.
Methods: Pubmed and EMBASE were systematically searched from database inception through January 2019 usinga combination of MeSH, keywords and text words.Randomized controlled trials on induced abortion at ≤63 days that compared different regimens of medicalabortion using mifepristone and/or misoprostol and trials that compared medical with surgical methods of abortionwere included.We extracted data into a pre-designed form, calculated effect estimates, and performed meta-analyses wherepossible. The primary outcomes were ongoing pregnancy and successful abortion.
Results: Thirty-three studies composed of 22,275 participants were included in this review. Combined regimensusing mifepristone and misoprostol had lower rates of ongoing pregnancy, higher rates of successful abortion andsatisfaction compared to misoprostol only regimens. In combined regimens, misoprostol 800 μg was more effectivethan 400 μg. There was no significant difference in dosing intervals between mifepristone and misoprostol androutes of misoprostol administration in combination or misoprostol alone regimens. The rate of serious adverseevents was generally low.
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© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.
* Correspondence: [email protected]/UNFPA/UNICEF/WHO/World Bank Special Programme of Research,Development and Research Training in Human Reproduction (HRP),Department of Reproductive Health and Research, World HealthOrganization, Geneva, SwitzerlandFull list of author information is available at the end of the article
Abubeker et al. BMC Women's Health (2020) 20:142 https://doi.org/10.1186/s12905-020-01003-8
(Continued from previous page)
Conclusion: In this systematic review, we find that medical methods of abortion utilizing combination mifepristoneand misoprostol or misoprostol alone are effective, safe and acceptable. More robust studies evaluating both thedifferent combination and misoprostol alone regimens are needed to strengthen existing evidence as well as assesspatient perspectives towards a particular regimen.
Keywords: Medical abortion, First trimester, Mifepristone, Misoprostol, Systematic review
BackgroundMedical methods emerged as an alternative to surgicalabortion with the discovery of prostaglandins in the early1970s [1–3]. Their use has evolved in the last two de-cades and various drugs have been used for first trimes-ter medical abortion. Several studies have exploredutilization of mifepristone, methotrexate and variousprostaglandins with different doses, routes and intervalsof administration [4]. A Cochrane review compared dif-ferent medical methods for first trimester abortion in2011 and since that time, there has been growing evi-dence assessing the effectiveness and safety of medicalmethods using two specific regimens: the combinationregimen (mifepristone and misoprostol) and misoprostolalone [5].However, individual studies evaluating medical man-
agement of abortion at ≤63 days have not demonstratedsuperiority of one of these regimens. Not only have stud-ies compared combination of mifepristone and miso-prostol (combination mifepristone misoprostol) withmisoprostol alone [6–8], other studies have looked atdifferent routes and doses of misoprostol in combinedregimens [9, 10], besides comparing different intervalsbetween mifepristone and misoprostol doses [11–13].Similarly, different misoprostol only regimens have beenevaluated [14].The 2012 World Health Organization (WHO) safe
abortion guideline had varying regimens for inducedabortion at < 12 weeks. With the emergence of new evi-dence, this systematic review was done as part of the evi-dence synthesis for the WHO guidance on medicalabortion. Options for medical abortion vary globally, andevidence-based guidance is needed to inform clinicalcare in selecting a regimen. The objectives of this reviewwere to compare the effectiveness, safety and acceptabil-ity of different regimens of medical abortion containingmifepristone and/or misoprostol and to compare med-ical with surgical methods of abortion at ≤63 days of ges-tational age.
MethodsSearch strategyWe searched Pubmed and EMBASE for randomizedcontrolled trials on induced abortion at ≤63 days. Oursearch was from database inception through January
2019 using a combination of MeSH, keywords and textwords (Additional file 1).
Selection criteriaInclusion criteria comprised randomized controlled trials(RCTs) that compared different medication regimens forinduced abortion at ≤63 days using mifepristone and/ormisoprostol; different frequencies of administration ofmisoprostol in combination regimens; different dosesand dosing intervals of misoprostol in combination regi-mens; different routes of misoprostol in combinationregimens; and different dosing regimens and routes inmisoprostol only regimens. We also included trials thatcompared surgical and medical abortion using combin-ation or misoprostol alone regimens. We excluded stud-ies that included induced abortion > 63 days, missedabortion, miscarriage, fetal demise and those that didnot report on the primary outcomes. We also excludedstudies comparing medical regimens beyond mifepris-tone and/or misoprostol, such as those using methotrex-ate or gemeprost. In addition, we excluded studies thatcompared various mifepristone dosages beyond theWHO recommended 200 mg dose, as a previously con-ducted Cochrane review showed effectiveness of mife-pristone at this lower dose (5).All search results (titles, abstracts and when neces-
sary, full articles) were screened using the Covidencetool [15].
Data extraction and analysisData extraction was performed using a standardizeddata-abstraction form.The primary outcomes were ongoing pregnancy and
successful abortion (defined as uterine evacuation with-out need for surgical intervention). Secondary outcomeswere: safety (defined as serious adverse events and com-plications; such as hospitalization; blood transfusion;need for surgical interventions beyond uterine evacu-ation; or death), expulsion time from initiation of treat-ment, side effects (including bleeding; pain; andvomiting) and satisfaction.For dichotomous data (e.g., complete abortion rate),
we used the number of events in the control and inter-vention groups of each study to calculate Risk Ratios(RRs) with 95% confidence intervals for our primary
Abubeker et al. BMC Women's Health (2020) 20:142 Page 2 of 17
outcome, and secondary outcomes as available. Analyseswere conducted using RevMan version 5.3 (Copenhagen,Denmark: The Nordic Cochrane Centre, The CochraneCollaboration, 2014).We used GRADEpro software and Cochrane methods
to evaluate the overall quality of the body of evidencefor the main review outcomes. We relied on GRADE(Grading of Recommendations, Assessment, Develop-ment and Evaluations) criteria (e.g., risk of bias,consistency of effect, imprecision, indirectness, and pub-lication bias) to assess the quality of the evidence. TheCochrane Risk of Bias Assessment tool was used to as-sess risk of bias across studies [16]. We specificallyassessed: selection (random sequence generation and al-location concealment); performance (blinding of partici-pants and personnel); detection (blinding of outcomeassessors); attrition (incomplete outcome data); report-ing (selective reporting); and other biases. Studies wereranked as low risk, high risk, or unclear risk using thecriteria outlined by the Cochrane Handbook for System-atic Reviews of Interventions [16].Two review authors (FAA and CK) independently per-
formed study selection, data extraction, assessment of
risk of bias and quality of evidence. Discrepancies wereresolved by discussion with the third author (MIR).
ResultsThe initial search yielded 1506 articles, of which 33articles fit our inclusion criteria (Fig. 1). Studies in-cluded for this review were conducted across 19countries with a total of 22,275 participants. Usingthe World Bank’s 2018 classification of economies,the articles represent data from six high incomeeconomies, six upper-middle income economies, sixlower-middle income economies and one low incomeeconomy [17]. The year of publication ranged from1994 to 2017. The characteristics of the includedstudies are shown in Table 1. Approximately 85% ofthe included studies had a low risk of selection biasbased on random sequence generation and 78% hada high risk of performance bias (Additional file 2).
Medical regimensDifferent regimens of medical abortion managementcontaining combination mifepristone misoprostol, or mi-soprostol alone were reviewed. Six studies compared
Fig. 1 PRISMA flow diagram
Abubeker et al. BMC Women's Health (2020) 20:142 Page 3 of 17
Table
1Characteristicsof
includ
edstud
ies
S.No
Autho
r,year
Metho
dsSetting
Participants
Interven
tions
1.Blanchard
etal.
2005
[14]
Rand
omized
controlled
trial
KEM
HospitalinPu
ne,Ind
ia,and
Hun
gvuo
ngHospitalinHo
Chi
MinhCity,Vietnam
.Wom
enseekingpreg
nancyterm
inationat
56days
orless
ofam
enorrhea.A
lleligiblewom
enhadatransvaginalultrasou
ndscan
toconfirm
duratio
nof
preg
nancy.
Misop
rostol
oral400μg
every3hfor4do
ses
(N=36)
vs.
Misop
rostol
oral800μg
every6hfor2do
ses
(N=24)
vs.
Misop
rostol
vaginal600
μgfor1do
se(N
=40)
2.Blum
etal.
2012
[6]
Rand
omized
controlled
trial
Twolargematernity
hospitals:the
Cen
trede
Maternite
etNeo
natologiede
laRabtain
Tunisia(n=193)
andHun
gVu
ong
Hospital,HoChi
MinhCity,Vietnam
(n=248).
Preg
nant
wom
enpresen
tingforearly
med
icalabortio
nup
to63
days
sincetheirlastmen
strualpe
riod.
Mifepristone
+misop
rostol
combine
dMifepristone
200mgon
day1and800μg
buccalmisop
rostol
followed
byplaceb
o3h
lateron
day2(N
=220)
vs.
Misop
rostol
alon
ePlaceb
oon
day1and1600
μgof
misop
rostol
(2do
sesof
800μg
,given
3hapart)on
day2
(N=221)
3.Chaietal.
2013
[18]
Rand
omized
controlled
trial
Con
ducted
attheFamily
Planning
Associatio
nin
Hon
gKo
ng.
Health
ywom
enaged
18yearsor
olde
rwho
requ
ested
term
inationof
preg
nancyof
upto
63days’g
estatio
n.A
transvaginalultrasou
ndexam
inationwas
perfo
rmed
toverify
thedu
ratio
nof
preg
nancyandto
determ
inethege
stational
age.
Misop
rostol
buccal
Misop
rostol
buccal800μg
(four
200μg
misop
rostol
buccalandfour
sublingu
alplaceb
o)48
hafterreceivingmifepristone
(N=45)
vs.
Misop
rostol
sublingu
alMisop
rostol
sublingu
al800μg
(four
200μg
misop
rostol
sublingu
alandfour
buccal
placeb
o)48
hafterreceivingmifepristone
(N=45)
4.Chawdh
ary
etal.
2009
[19]
Rand
omized
controlled
trial
Dep
artm
entof
ObstetricsandGynecolog
y,Tribhu
van
University
Teaching
Hospital,Kathmandu
,Nep
al.
Transvaginalu
ltrasou
ndde
mon
stratin
gan
intact
sing
leintrauterin
epreg
nancyup
toa63-day
perio
dof
gestation.
Mifepristone
+misop
rostol
combine
dMifepristone
200mgon
day1andvaginal
misop
rostol
800μg
onday3(N
=50)
vs.
Misop
rostol
alon
eMisop
rostol
vaginal(800μg
)on
day1and3
(totaldo
se1600
μg)(N
=50)
5.Cho
nget
al.
2012
[9]
Rand
omized
controlled
trial
Threeclinicsin
theRepu
blicof
Geo
rgiaandat
Hoc
Mon
HospitalinVietnam.
Wom
enwho
presen
tedforterm
inationof
preg
nancywith
gestations
upto
63days
sincelastmen
strualpe
riod(LMP).
Misop
rostol
buccal400μg
Misop
rostol
buccal400μg
(two200μg
misop
rostol
andtw
oplaceb
opills)36–48h
aftermifepristone
(N=559)
vs.
Misop
rostol
buccal800μg
Misop
rostol
buccal800μg
(four
200μg
misop
rostol
pills)36–48haftermifepristone
(N=563)
6.Coyajietal.
2007
[20]
Rand
omized
controlled
trial
K.E.M.H
ospitalinPu
ne(n=150)
andtheHealth
Cen
tre,Larsen
andToub
roLimited,
Mum
bai,India(n=150).
Wom
enseekingterm
inationof
preg
nanciescouldparticipate
ifthey
hadam
enorrhoe
aof
8weeks
orless.
Twodo
sesof
misop
rostol
Twodo
sesof
400μg
oralmisop
rostol
takenin
3hinterval48
haftermifepristone
(N=150)
vs.
Sing
ledo
seof
misop
rostol
Sing
ledo
seof
400μg
oralmisop
rostol
and2
Abubeker et al. BMC Women's Health (2020) 20:142 Page 4 of 17
Table
1Characteristicsof
includ
edstud
ies(Con
tinued)
S.No
Autho
r,year
Metho
dsSetting
Participants
Interven
tions
placeb
otablets3hlater48
hafter
mifepristone
(N=150)
7.Creinin
etal.
2007
[12]
Rand
omized
controlled
trial
Four
centers:TheUniversity
ofPittsburgh
,Orego
nHealth
and
ScienceUniversity,N
orthwestern
University,and
theUniversity
ofSouthe
rnCalifornia.The
University
ofPittsburgh
served
asthespon
sorin
ginstitu
tion.
Health
ywom
enrequ
estin
gan
electiveabortio
n,hadan
intrauterin
epreg
nancyless
than
oreq
ualto63
days
ofge
stationon
thedayof
mifepristone
administrationas
confirm
edby
vaginalu
ltrasou
nd.
Misop
rostol
800μg
vaginalimmed
iatelyafter
taking
mifepristone
(N=567)
vs.
Misop
rostol
800μg
vaginalm
isop
rostol
24h
aftertaking
mifepristone
(N=561)
8.Dahiya
etal.
2011
[21]
Rand
omized
controlled
trial
Postpartum
center
atPG
IMSRo
htak,Ind
ia.
Health
ywom
enwith
intrauterin
epreg
nancy<56
days
based
onmen
strualhistoryandclinicalexam
ination.
Misop
rostol
oral400μg
24hafter
mifepristone
(N=48)
vs.
Misop
rostol
sublingu
al400μg
24hafter
mifepristone
(N=45)
9.Dahiya
etal.
2012
[7]
Rand
omized
controlled
trial
Outpatient
departmen
tof
ObstetricsandGynecolog
yof
PtBD
SharmaPG
IMS,Ro
htak,Ind
ia.
Wom
enwith
amen
orrhea
<56
days,age
>18
years,requ
est
forelectiveabortio
nwith
theindicatio
nas
perthegu
idelines
ofthe1971
MTP
act.
Mifepristone
+misop
rostol
combine
dMifepristone
200mgoraland800μg
buccal
misop
rostol
after24
h(N
=50)
vs.
Misop
rostol
alon
eMisop
rostol
buccal800μg
(N=50)
10.
El-Refaey
etal.
1994
[22]
Rand
omized
controlled
trial
Dep
artm
entof
ObstetricsandGynaecology,U
niversity
ofAbe
rdeen
Wom
enrequ
estin
gterm
inationof
preg
nancyof
less
than
56days
amen
orrhea
confirm
edby
ultrasou
ndscan
exam
ination
andfulfilling
thecriteria
ofthe1967
Abo
rtionAct.
Misop
rostol
oral800μg
sing
ledo
se36–48h
aftermifepristone
(N=75)
vs.
Misop
rostol
oral400μg
repe
ated
2hlater36–
48haftermifepristone
(N=75)
11.
El-Refaey
etal.
1995
[23]
Rand
omized
controlled
trial
Fertility-con
trol
clinic,A
berdeenRo
yalH
ospitals,A
berdeen,
Scotland
.Wom
enrequ
estin
gterm
inationof
preg
nancywith
in63
days
from
theon
setof
amen
orrhea
andfulfilling
thecriteria
ofthe
1967
Abo
rtionAct.
Misop
rostol
oral800μg
36–48hafter
mifepristone
(N=130)
vs.
Misop
rostol
vaginal800
μg36–48hafter
mifepristone
(N=133)
12.
Fekihet
al.
2010
[24]
Rand
omized
controlled
trial
Dep
artm
entof
ObstetricsandGynecolog
yin
Farhat
Hache
dTeaching
Hospital,Sousse,Tun
isia.
Wom
enrequ
estin
g1sttrim
esterabortio
nof
less
than
oreq
ual
to56
days
from
theirlastmen
strualpe
riod,
determ
ined
byvaginalp
robe
ultrasou
ndandamaxim
umem
bryonicleng
thof
17mm.
Mifepristone
+misop
rostol
combine
dMifepristone
200mgfollowed
by400μg
oforalmisop
rostol
after48
h(N
=126)
vs.
Misop
rostol
alon
eMisop
rostol
sublingu
al800μg
(repe
ated
every
4hforup
toamaxim
umof
3do
ses)(N
=126)
13.
Goe
letal.
2011
[25]
Rand
omized
controlled
trial
ObstetricsandGynaecology
Dep
artm
ent,MMIMSR,M
ullana
(Ambala),Haryana,Ind
ia.
Health
ypreg
nant
wom
en,w
howererequ
estin
gan
elective
abortio
nandhadasing
leintrauterin
epreg
nancyof
<7weeks
(49days)of
gestationas
confirm
edby
transvaginal
ultrason
ograph
y.
Misop
rostol
vaginal400
μgsimultane
ously
with
mifepristone
(N=40)
vs.
Misop
rostol
vaginal400
μg24
hafter
mifepristone
(N=40)
14.
Guestet
al.
2007
[11]
Rand
omized
controlled
trial
Ninew
ellsHospital,Dun
dee,Scotland
.Anintrauterin
epreg
nancyconfirm
edon
pelvicultrasou
ndscan,g
estatio
nno
texceed
ing63
days
attheadministrationof
mifepristone
andparticipantsmustbe
aged
16yearsor
olde
r,seekingaterm
inationof
preg
nancy.
Misop
rostol
vaginal800
μgafter6hof
mifepristone
(N=225)
vs.
Misop
rostol
vaginal800
μgafter36–48hof
mifepristone
(N=225)
15.
Ham
oda
Rand
omized
Abe
rdeenRo
yalInfirm
ary,UnitedKing
dom.
Wom
enwith
aviablesing
letonintrauterin
epreg
nancy
Misop
rostol
sublingu
al600μg
followed
3h
Abubeker et al. BMC Women's Health (2020) 20:142 Page 5 of 17
Table
1Characteristicsof
includ
edstud
ies(Con
tinued)
S.No
Autho
r,year
Metho
dsSetting
Participants
Interven
tions
etal.
2005
[26]
controlled
trial
(con
firmed
bytransvaginalultrasou
ndscan)requ
estin
gmed
icalabortio
nup
to13
weeks
ofge
station.
Data
aggreg
ated
byge
stationalage
.
laterby
afurthe
rdo
seof
400μg
sublingu
almisop
rostol
(N=57)
vs.
Misop
rostol
vaginal800
μgfollowed
3hlater
byafurthe
rdo
seof
400μg
vaginal
misop
rostol
(N=72)
16.
Jain
etal.
2002
[27]
Rand
omized
controlled
trial
Wom
en’sandChildren’sHospitaland
affiliatedclinics,Los
Ang
eles
Cou
nty-University
ofSouthe
rnCaliforniaMed
icalCen
-terandSanFranciscoGen
eralHospital,University
ofCalifornia,
SanFrancisco,
UnitedStates.
Atotalo
f250he
althywom
ende
sirin
gterm
inationof
preg
nancies<56
days
gestationwereen
rolled.
Mifepristone
+misop
rostol
combine
dMifepristone
200mgfollowed
after48
hby
800μg
ofvaginalm
isop
rostol
(repe
ated
every
24hforup
toamaxim
umof
3do
ses)(N
=125)
vs.
Misop
rostol
alon
ePlaceb
oon
day1andmisop
rostol
vaginal
800μg
repe
ated
every24
hforup
toa
maxim
umof
3do
ses(N
=125)
17.
Middleton
etal.
2005
[28]
Rand
omized
controlled
trial
Twositesin
Rochester,NY,UnitedStates.
Wom
enseekingabortio
nwith
preg
nanciesthroug
h56
days
LMP.
Misop
rostol
buccal800μg
1–2days
after
mifepristone
(N=223)
vs.
Misop
rostol
vaginal800
μg1–2days
after
mifepristone
(N=219)
18.
Ngo
cet
al.
2011
[8]
Rand
omized
controlled
trial
Tertiary
hospitalinHoChi
MinhCity,Vietnam
.Wom
enwith
gestationalage
upto
63days
byLM
P,livingand
working
with
inan
hour
from
theho
spitald
esiring
med
ical
abortio
n.
Mifepristone
+misop
rostol
combine
dMifepristone
200mgfollowed
24hlaterby
800μg
buccalmisop
rostol
followed
byplaceb
o24
hlateraftermisop
rostol
(N=202)
vs.
Misop
rostol
alon
ePlaceb
ofollowed
by800μg
buccal
misop
rostol
repe
ated
24and48
hlater
(1600μg
total)(N
=198)
19.
Prasad
etal.
2009
[29]
Rand
omized
controlled
trial
Dep
artm
entof
ObstetricsandGynecolog
y,Maulana
Azad
Med
icalCollege
,New
Delhi,Ind
ia.
Wom
enwith
gestationalage
upto
49days
confirm
edby
clinicalexam
inationandpe
lvicultrasou
ndseekingabortio
n.Med
icalabortio
n-misop
rostol
vaginal800
μg(N
=70)
vs.
Surgicalinterven
tion(N
=70)
20.
Ragh
avan
etal.
2009
[30]
Rand
omized
controlled
trial
University
Clinic,M
unicipalClinicalHospitalN
o.1,Chisinau,the
Repu
blicof
Moldo
va.
Thedate
ofon
setof
lastmen
sesplus
pelvicexam
inationwere
used
tocalculatege
stationalage
,with
ultrasou
ndconfirm
ationas
need
ed.
Misop
rostol
sublingu
al400μg
24hafter
mifepristone
(N=240)
vs.
Misop
rostol
oral400μg
24hafter
mifepristone
(N=240)
21.
Ragh
avan
etal.
2010
[31]
Rand
omized
controlled
trial
University
Clinic,M
unicipalClinicalHospitalN
o.1,Chisinau,the
Repu
blicof
Moldo
va.
Wom
enwith
gestationalage
throug
h63
days
byLM
Ppresen
tingforabortio
n.Gestatio
nalage
was
determ
ined
byon
eor
moreassessmen
tmetho
d:lastmen
sesmetho
d,pe
lvic
exam
inationandultrasou
nd.
Misop
rostol
buccal400μg
24hafter
mifepristone
(N=277)
vs.
Misop
rostol
sublingu
al400μg
24hafter
mifepristone
(N=273)
22.
Schaffet
al.
2000
[32]
Rand
omized
controlled
trial
SixteenUSprim
arycare
andreferralabortio
nfacilities.
Participantswereat
least18
yearsold,
nomorethan
56days
preg
nant,h
ealth
yandde
siredan
abortio
n.1)
Misop
rostol
vaginal800
μg1daylaterafter
mifepristone
(N=745)
vs.
2)Misop
rostol
vaginal800
μg2days
laterafter
Abubeker et al. BMC Women's Health (2020) 20:142 Page 6 of 17
Table
1Characteristicsof
includ
edstud
ies(Con
tinued)
S.No
Autho
r,year
Metho
dsSetting
Participants
Interven
tions
mifepristone
(N=778)
vs.
3)Misop
rostol
vaginal800
μg3days
laterafter
mifepristone
(N=772)
23.
Schaffet
al.
2001
[33]
Rand
omized
controlled
trial
Multicen
terstud
yat
15sitesin
UnitedStates.
Wom
enno
morethan
63days
preg
nant,con
firmed
bysono
gram
,desiring
anabortio
n.Misop
rostol
oral800μg
24hafter
mifepristone
and400μg
,the
nanothe
r400μg
misop
rostol
2hlater,lastdo
seno
laterthan
midnigh
ton
day2(N
=548)
vs.
Misop
rostol
vaginal800
μg24
hafter
mifepristone
(N=596)
24.
Schaffet
al.
2002
[34]
Rand
omized
controlled
trial
Multicen
terstud
yat
14sitesin
UnitedStates
Wom
enno
morethan
63days
preg
nant,con
firmed
bysono
gram
,desiring
anabortio
n.1)
Misop
rostol
oral400μg
48hafter
mifepristone
(N=220)
vs.
2)Misop
rostol
oral800μg
48hafter
mifepristone
(N=269)
vs.
3)Misop
rostol
vaginal800
μg48
hafter
mifepristone
(N=522)
25.
Shanno
net
al.
2006
[35]
Rand
omized
controlled
trial
Threeclinicsassociated
with
major
research
universitiesin
Canada;tw
oin
major
urbanareasandon
ein
ape
riurban
area.
Wom
enaged
16yearsor
olde
r,seekingelectiveabortio
nof
preg
nanciesless
than
56days
sincelastmen
strualpe
riodor
onvaginalu
ltrasou
nd.
1)Misop
rostol
oral400μg
24–48hafter
mifepristone
(N=319)
vs.
2)Misop
rostol
oral600μg
24–48hafter
mifepristone
(N=319)
vs.
3)Misop
rostol
vaginal800
μg24–48hafter
mifepristone
(N=318)
26.
Tang
etal.
2003
[36]
Rand
omized
controlled
trial
Dep
artm
entof
ObstetricsandGynaecology,The
University
ofHon
gKo
ng,Q
ueen
MaryHospital,Hon
gKo
ngSA
R,China.
Wom
enwith
gestationalage
ofless
than
9weeks,con
firmed
byUS,requ
estin
glegalterminationof
preg
nancy.
Misop
rostol
sublingu
alMisop
rostol
sublingu
al800μg
(and
four
tabletsof
vaginalp
lacebo
)48
hafterreceiving
mifepristone
(N=112)
vs.
Misop
rostol
vaginal
Misop
rostol
vaginal800
μg(and
four
tablets
ofsublingu
alplaceb
o)48
hafterreceiving
mifepristone
(N=112)
27.
Tend
ler
etal.
2015
[37]
Rand
omized
controlled
trial
Dep
artm
entof
ObstetricsandGynecolog
y,GalileeMed
ical
Cen
ter,Nahariya,Israel.
Wom
enno
morethan
55days
gestationalage
desirin
gmed
icalabortio
n.Misop
rostol
oral400μg
2haftermifepristone
(N=50)
vs.
Misop
rostol
oral400μg
48hafter
mifepristone
(N=50)
28.
Verm
aet
al.
2011
[13]
Rand
omized
controlled
trial
Dep
artm
entof
ObstetricsandGynaecology,H
indInstitu
teof
Med
icalSciences,Ind
ia.
Wom
enless
than
63days
ofge
stationchoo
sing
med
ical
abortio
n.Misop
rostol
vaginal400
μg24
hafter
mifepristone
(N=100)
vs.
Misop
rostol
vaginal400
μg48
hafter
mifepristone
(N=100)
29.
Verm
aet
al.
2017
[38]
Rand
omized
controlled
Dep
artm
entof
ObstetricsandGynaecology,H
indInstitu
teof
Med
icalSciences,Ind
ia.
Wom
enup
to63
days
ofge
stationchoo
sing
med
icalabortio
n.Misop
rostol
vaginal400
μgsimultane
ously
with
mifepristone
(N=100)
Abubeker et al. BMC Women's Health (2020) 20:142 Page 7 of 17
Table
1Characteristicsof
includ
edstud
ies(Con
tinued)
S.No
Autho
r,year
Metho
dsSetting
Participants
Interven
tions
trial
vs.
Misop
rostol
vaginal400
μg48
hafter
mifepristone
(N=100)
30.
Von
Hertzen
etal.
2007
[39]
Rand
omized
controlled
trial
Eleven
gyne
cologicalcen
tersin
sixcoun
tries.
Wom
enwith
sing
leintra-uterinepreg
nancyless
than
oreq
ual
to63
days
verifiedby
US,requ
estin
gterm
inationof
preg
nancy.
1)Misop
rostol
800μg
sublingu
alevery3h×3
doses(N
=517)
vs.
2)Misop
rostol
800μg
sublingu
alevery12
h×
3do
ses(N
=516)
vs.
3)Misop
rostol
800μg
vaginalevery
3h×3
doses(N
=516)
vs.
4)Misop
rostol
800μg
vaginalevery
12h×3
doses(N
=517)
31.
Von
Hertzen
etal.
2009
[40]
Rand
omized
controlled
trial
Thirteende
partmen
tsof
obstetricsandgyne
cology
innine
coun
tries.
Wom
enwith
63days
orless
gestationverifiedby
ultrasou
nd,
requ
estin
gterm
inationof
preg
nancy.
1)Mifepristone
100mg+misop
rostol
800μg
vaginal24hlater(N
=545)
vs.
2)Mifepristone
100mg+misop
rostol
800μg
vaginal48hlater(N
=547)
vs.
3)Mifepristone
200mg+misop
rostol
800μg
vaginal24hlater(N
=544)
vs.
4)Mifepristone
200mg+misop
rostol
800μg
vaginal48hlater(N
=545)
32.
Von
Hertzen
etal.
2010
[10]
Rand
omized
controlled
trial
Fifteenob
stetrics/gyne
cology
departmen
tsin
tencoun
tries.
Wom
enrequ
estin
glegalterminationof
preg
nancyat
age
stationof
upto
63days.
1)Mifepristone
200mg+misop
rostol
400μg
sublingu
al24
hlater(N
=751)
vs.
2)Mifepristone
200mg+misop
rostol
800μg
sublingu
al24
hlater(N
=752)
vs.
3)Mifepristone
200mg+misop
rostol
400μg
vaginal24hlater(N
=751)
vs.
4)Mifepristone
200mg+misop
rostol
800μg
vaginal24hlater(N
=751)
33.
Winikoff
etal.
2008
[41]
Rand
omized
controlled
trial
Sevenfacilitiesin
theUnitedStates.
Wom
enseekingmed
icalabortio
nwith
preg
nanciesno
texceed
ing63
days
sincetheLM
Pon
thedayof
themed
ical
abortio
n.Gestatio
nalage
was
determ
ined
byLM
P,clinical
exam
ination,
and/or
ultrason
ograph
y,as
need
ed.
Misop
rostol
oral800μg
24–36hafter
mifepristone
(N=482)
vs.
Misop
rostol
buccal800μg
24–36hafter
mifepristone
(N=484)
Abubeker et al. BMC Women's Health (2020) 20:142 Page 8 of 17
combined mifepristone misoprostol vs. misoprostolalone, 6 studies compared different doses of misoprostolin combined regimens, 8 studies compared the timinginterval between mifepristone and misoprostol in com-bined regimens, 13 compared routes of misoprostol incombined regimens, 2 compared various misoprostolalone regimens, and 1 study compared medical with suc-tion evacuation.
1. Combination mifepristone misoprostolcompared with misoprostol alone
Three studies compared combined with misoprostolalone regimens [6–8] (Table 2).Women treated with a combined regimen had lower
rates of ongoing pregnancy (RR 0.16 CI 95% 0.08–0.31,low certainty of evidence) and higher rates of successfulabortion (RR 1.23 CI 95% 1.16–1.30, very low certaintyof evidence) compared to women treated with a miso-prostol only regimen. The combined regimen resulted ina higher rate of satisfaction compared with misoprostolonly regimen (RR 1.13 CI 95% 1.00–1.26, low certaintyof evidence) (Table S1, Additional file 3).
2. Comparisons of different regimens of misoprostolwhen combined with mifepristone2.1.Comparison of misoprostol doses in
combined regimen
Six studies assessed different doses of misoprostol, usingthe same routes, in combined regimens. These includedcomparisons of 400 μg buccal vs. 800 μg buccal [9], 400 μgoral twice vs. 400 μg oral once [20], 800 μg oral once vs.400 μg oral twice [22, 34], 400 μg sublingual vs. 800 μgsublingual [10], 400 μg vaginal vs. 800 μg vaginal [10] and400 μg oral versus 600 μg oral [35] (Table 2).Women treated with misoprostol 400 μg buccal had lower
rates of ongoing pregnancy (RR 0.16 CI 95% 0.08–0.31,moderate certainty of evidence) and higher rates of success-ful abortion (RR 1.23 CI 95% 1.16–1.30, moderate certaintyof evidence) compared to women taking 800 μg buccal [9].For women taking a total of 800 μg oral misoprostol,
there were lower rates of ongoing pregnancy (RR 0.10 CI95% 0.01–0.80, low certainty of evidence) compared towomen taking oral 400 μg [20]. Other studies that inves-tigated 800 μg dosage of misoprostol showed comparablerates of successful abortion between 800 μg oral onceand 400 μg oral twice (RR 0.94 CI 95% 0.89–0.99, mod-erate certainty of evidence) [22, 34].Another significant finding was that women taking
400 μg sublingual misoprostol were more likely to ex-perience ongoing pregnancy compared to the group whotook 800 μg misoprostol (RR 3.44 CI 95% 1.14–10.40,moderate certainty of evidence) [10].
Although the remaining comparisons did not providestatistically significant findings, there was moderate cer-tainty on the higher rates of ongoing pregnancy in the400 μg vaginal misoprostol compared to the 800 μg vagi-nal misoprostol (Table 2). Safety and satisfaction ap-peared to be comparable throughout the groups (TableS2, Additional file 3).
2.2.Comparison of dosing intervals betweenmifepristone and misoprostol in combinedregimen
Eight studies assessed different time intervals betweenmifepristone and misoprostol dosing in the combinedregimen. These include comparisons between < 8 h vs. >24 h [11, 12], 24 h vs. 48 h [13, 32, 40], concurrent ad-ministration vs. 24 h [25, 38] and < 8 h vs. 48 h [37](Table 2).Administration of misoprostol within 8 h of mifepris-
tone was found to have similar rates of successful abortioncompared to 24-h (RR 0.98 CI 95% 0.91–1.06, moderatecertainty of evidence) and 48-h intervals (RR 0.91 CI 95%0.66–1.25, very low certainty of evidence) [11, 12, 37].There may be little to no difference in rates of success-
ful abortion between concurrent administration of miso-prostol and a 24-h interval (RR 1.01 CI 95% 0.84–1.21,very low certainty of evidence) [25, 38]. There was nosignificant difference between 24-h and 48-h interval interms of ongoing pregnancy and successful abortion [13,32, 40]. All dosing interval comparisons showed similarsafety and satisfaction rates (Table S3, Additional file 3).
3. Comparisons of misoprostol routes in combinedmifepristone misoprostol regimen
Thirteen studies assessed different routes of misopros-tol in the combined regimen (Table 2).Treatment with 800 μg oral misoprostol showed higher
rates of ongoing pregnancy compared with vaginal (RR6.70 CI 95% 1.88–23.86, moderate certainty of evidence)and buccal routes (RR 3.61 CI 95% 1.20–10.80, low cer-tainty of evidence) [23, 33, 34, 41].Women treated through sublingual route were found
to have similar rates of successful abortion compared tothose treated through vaginal route (RR 0.99 CI 95%0.92–1.07, moderate certainty of evidence) [10].There may be little to no difference in successful abor-
tion rates among women treated through buccal routecompared to those treated through sublingual (RR 0.98 CI95% 0.73–1.33, very low certainty of evidence) or vaginalroutes (RR 1.00 CI 95% 0.87–1.15, low certainty of evi-dence) [18, 28].Safety and satisfaction rates of tested routes appears to
be similar (Table S4, Additional file 3).
Abubeker et al. BMC Women's Health (2020) 20:142 Page 9 of 17
Table
2Summaryof
finding
sof
efficacy,safety
andsatisfactionof
different
regimen
sof
med
icalabortio
n
Outcomes
Risk
Ratio
n(RR)
Con
fiden
ceInterval(CI)
Num
berof
participants(Studies)
GRA
DE
1.Co
mbina
tionmife
pristone
/misop
rostol
compa
redwith
misop
rostol
alon
e
A.C
ombinationmife
priston
e-misop
rostol
compared
withmisop
rostol
alon
e(Tab
leS1
A)
Efficacy:on
goingpreg
nancy
RR0.16
(0.08to
0.31)
922(3
RCTs)
LOW
Efficacy:success
RR1.23
(1.16to
1.30)
922(2
RCTs)
VERY
LOW
Safety
notestim
able
(1RC
T)VERY
LOW
Satisfaction
RR1.13
(1.00to
1.26)
820(2
RCTs)
LOW
2.Co
mpa
risons
ofdifferen
tregimen
sof
misop
rostol
whe
ncombine
dwith
mife
pristone
2.1.
Compa
risonof
misop
rostol
dosesin
combine
dregimen
A.M
isop
rostol
buc
cal4
00μg
compared
with80
0μg
inco
mbined
regim
en(Tab
leS2
A)
Efficacy:on
goingpreg
nancy
RR0.16
(0.08to
0.31)
1115
(1RC
T)MODERATE
Efficacy:success
RR1.23
(1.16to
1.30)
1115
(1RC
T)MODERATE
Safety
RR1.00
(0.02to
50.76)
1115
(1RC
T)MODERATE
Satisfaction
RR0.99
(0.97to
1.02)
1106
(1RC
T)VERY
LOW
B.M
isop
rostol
oral
400μg
twiceco
mpared
with40
0μg
inco
mbined
regim
en(Tab
leS2
B)
Efficacy:on
goingpreg
nancy
RR0.10
(0.01to
0.80)
297(1
RCT)
LOW
Efficacy:success
RR1.03
(0.86to
1.23)
297(1
RCT)
LOW
Safety
notestim
able
(0stud
ies)
–
Satisfaction
RR1.03
(0.87to
1.23)
293(1
RCT)
LOW
C.M
isop
rostol
oral
800μg
sing
ledoseco
mpared
with40
0μg
twicein
combined
regim
en(Tab
leS2
C)
Efficacy:on
goingpreg
nancy
RR0.88
(0.24to
3.19)
637(2
RCTs)
MODERATE
Efficacy:success
RR0.94
(0.89to
0.99)
637(2
RCTs)
MODERATE
Safety
notestim
able
(0stud
ies)
–
Satisfaction
notestim
able
(0stud
ies)
–
D.M
isop
rostol
sublin
gua
l400
μgco
mpared
with80
0μg
inco
mbined
regim
en(Tab
leS2
D)
Efficacy:on
goingpreg
nancy
RR3.44
(1.14to
10.40)
1480
(1RC
T)MODERATE
Efficacy:success
RR0.99
(0.92to
1.07)
1480
(1RC
T)MODERATE
Safety
notestim
able
(0stud
ies)
–
Satisfaction
RR0.99
(0.92to
1.07)
1475
(1RC
T)LO
W
E.Misop
rostol
vaginal
400μg
compared
with80
0μg
inco
mbined
regim
en(Tab
leS2
E)
Efficacy:on
goingpreg
nancy
RR2.23
(0.98to
5.11)
1482
(1RC
T)MODERATE
Efficacy:success
RR0.97
(0.90to
1.05)
1482
(1RC
T)MODERATE
Safety
notestim
able
(0stud
ies)
–
Satisfaction
RR0.99
(0.92to
1.07)
1479
(1RC
T)LO
W
Abubeker et al. BMC Women's Health (2020) 20:142 Page 10 of 17
Table
2Summaryof
finding
sof
efficacy,safety
andsatisfactionof
different
regimen
sof
med
icalabortio
n(Con
tinued)
Outcomes
Risk
Ratio
n(RR)
Con
fiden
ceInterval(CI)
Num
berof
participants(Studies)
GRA
DE
F.Misop
rostol
oral
400μg
compared
with60
0μg
inco
mbined
regim
en(Tab
leS2
F)
Efficacy:on
goingpreg
nancy
RR0.33
(0.01to
8.10)
638(1
RCT)
LOW
Efficacy:success
RR1.01
(0.91to
1.13)
638(1
RCT)
LOW
Safety
RR0.33
(0.01to
8.10)
638(1
RCT)
LOW
Satisfaction
RR1.02
(0.91to
1.16)
599(1
RCT)
LOW
2.2.
Compa
risonof
dosing
intervalsbe
tweenmife
pristone
andmisop
rostol
incombine
dregimen
A.M
isop
rostol
800μg
vaginal
given
<8hco
mpared
with>24
haftermife
priston
e(Tab
leS3
A)
Efficacy:on
goingpreg
nancy
RR2.23
(0.69to
7.20)
1525
(4RC
Ts)
MODERATE
Efficacy:success
RR0.98
(0.91to
1.06)
1525
(2RC
Ts)
MODERATE
Safety
RR0.99
(0.02to
49.60)
1100
(1RC
T)MODERATE
Satisfaction
RR1.02
(0.87to
1.18)
357(1
RCT)
LOW
B.M
isop
rostol
400–
800μg
vaginal
given
24hco
mpared
with48
haftermife
priston
e(Tab
leS3
B)
Efficacy:on
goingpreg
nancy
RR0.92
(0.40to
2.12)
3301
(3RC
Ts)
VERY
LOW
Efficacy:success
RR0.99
(0.80to
1.23)
192(3
RCTs)
VERY
LOW
Safety
notestim
able
(0stud
ies)
–
Satisfaction
notestim
able
(0stud
ies)
–
C.M
isop
rostol
400μg
vaginal
given
conc
urrently
compared
with24
haftermife
priston
e(Tab
leS3
C)
Efficacy:on
goingpreg
nancy
RR0.98
(0.02to
49.25)
258(2
RCTs)
VERY
LOW
Efficacy:success
RR1.01
(0.84to
1.21)
280(2
RCTs)
VERY
LOW
Safety
RR1.00
(0.02to
50.01)
178(2
RCTs)
VERY
LOW
Satisfaction
RR1.02
(0.74to
1.39)
80(1
RCT)
VERY
LOW
D.M
isop
rostol
400μg
oral
given
<8hco
mpared
with48
haftermife
priston
e(Tab
leS3
D)
Efficacy:on
goingpreg
nancy
RR8.34
(0.46to
151.20)
100(1
RCT)
VERY
LOW
Efficacy:success
RR0.91
(0.66to
1.25)
100(1
RCT)
VERY
LOW
Safety
RR1.96
(0.18to
20.90)
100(1
RCT)
VERY
LOW
Satisfaction
notestim
able
(0stud
ies)
–
3.Co
mpa
risons
ofmisop
rostol
routes
incombine
dmife
pristone
-misop
rostol
regimen
A.M
isop
rostol
400μg
sublin
gua
lcom
pared
withvaginal
inco
mbined
regim
en(Tab
leS4
A)
Efficacy:on
goingpreg
nancy
RR0.79
(0.39to
1.55)
1479
(1RC
T)MODERATE
Efficacy:success
RR1.01
(0.94to
1.09)
1479
(1RC
T)MODERATE
Safety
notestim
able
(0stud
ies)
–
Satisfaction
RR1.00
(0.94to
1.07)
1473
(1RC
T)MODERATE
B.M
isop
rostol
800μg
vaginal
compared
withsublin
gua
linco
mbined
regim
en(Tab
leS4
B)
Abubeker et al. BMC Women's Health (2020) 20:142 Page 11 of 17
Table
2Summaryof
finding
sof
efficacy,safety
andsatisfactionof
different
regimen
sof
med
icalabortio
n(Con
tinued)
Outcomes
Risk
Ratio
n(RR)
Con
fiden
ceInterval(CI)
Num
berof
participants(Studies)
GRA
DE
Efficacy:on
goingpreg
nancy
RR0.50
(0.15to
1.67)
1483
(1RC
T)MODERATE
Efficacy:success
RR0.99
(0.92to
1.07)
1483
(1RC
T)MODERATE
Safety
notestim
able
(0stud
ies)
–
Satisfaction
RR0.99
(0.92to
1.07)
1481
(1RC
T)VERY
LOW
C.M
isop
rostol
600/80
0μg
sublin
gua
lcom
pared
with80
0μg
vaginal
inco
mbined
regim
en(Tab
leS4
C)
Efficacy:on
goingpreg
nancy
RR0.15
(0.08to
3.05)
346(2
RCTs)
LOW
Efficacy:success
RR1.01
(0.87to
1.18)
346(2
RCTs)
LOW
Safety
RR1.00
(0.02to
49.96)
224(1
RCT)
LOW
Satisfaction
notestim
able
(0stud
ies)
–
D.M
isop
rostol
800μg
oral
compared
withvaginal
inco
mbined
regim
en(Tab
leS4
D)
Efficacy:on
goingpreg
nancy
RR6.70
(1.88to
23.86)
1287
(3RC
Ts)
MODERATE
Efficacy:success
RR0.94
(0.85to
1.04)
1455
(3RC
Ts)
MODERATE
Safety
RR0.35
(0.01to
8.35)
263(1
RCT)
VERY
LOW
Satisfaction
notestim
able
(0stud
ies)
–
E.Misop
rostol
400μg
oral
compared
with80
0μg
vaginal
inco
mbined
regim
en(Tab
leS4
E)
Efficacy:on
goingpreg
nancy
RR2.38
(0.34to
16.81)
1378
(2RC
Ts)
MODERATE
Efficacy:success
RR0.98
(0.91to
1.04)
2025
(2RC
Ts)
MODERATE
Safety
RR0.33
(0.01to
8.15)
637(1
RCT)
LOW
Satisfaction
RR1.02
(0.91to
1.16)
599(1
RCT)
LOW
F.Misop
rostol
800μg
buc
calcom
pared
withsublin
gua
linco
mbined
regim
en(Tab
leS4
F)
Efficacy:on
goingpreg
nancy
RR0.98
(0.02to
49.25)
90(1
RCT)
VERY
LOW
Efficacy:success
RR0.98
(0.73to
1.33)
90(1
RCT)
VERY
LOW
Safety
RR0.98
(0.02to
48.70)
178(1
RCT)
VERY
LOW
Satisfaction
notestim
able
(0stud
ies)
–
G.M
isop
rostol
400μg
buc
calcom
pared
withsublin
gua
linco
mbined
regim
en(Tab
leS4
G)
Efficacy:on
goingpreg
nancy
RR1.55
(0.22to
11.03)
539(1
RCT)
LOW
Efficacy:success
RR0.98
(0.91to
1.04)
539(1
RCT)
LOW
Safety
RR0.33
(0.01to
8.15)
539(1
RCT)
LOW
Satisfaction
RR1.02
(0.91to
1.16)
533(1
RCT)
LOW
H.M
isop
rostol
800μg
buc
calcom
pared
withvaginal
inco
mbined
regim
en(Tab
leS4
H)
Efficacy:on
goingpreg
nancy
RR0.49
(0.09to
2.68)
429(1
RCT)
LOW
Efficacy:success
RR1.00
(0.87to
1.15)
429(1
RCT)
LOW
Safety
RR2.94
(0.12to
71.80)
429(1
RCT)
LOW
Abubeker et al. BMC Women's Health (2020) 20:142 Page 12 of 17
Table
2Summaryof
finding
sof
efficacy,safety
andsatisfactionof
different
regimen
sof
med
icalabortio
n(Con
tinued)
Outcomes
Risk
Ratio
n(RR)
Con
fiden
ceInterval(CI)
Num
berof
participants(Studies)
GRA
DE
Satisfaction
RR0.98
(0.85to
1.13)
423(1
RCT)
LOW
I.Misop
rostol
800μg
oral
compared
withbuc
calinco
mbined
regim
en(Tab
leS4
I)
Efficacy:on
goingpreg
nancy
RR3.61
(1.20to
10.80)
847(1
RCT)
LOW
Efficacy:success
RR0.97
(0.88to
1.07)
847(1
RCT)
LOW
Safety
RR0.33
(0.01to
8.08)
847(1
RCT)
LOW
Satisfaction
RR1.02
(0.91to
1.12)
835(1
RCT)
LOW
J.Misop
rostol
400μg
oral
compared
withsublin
gua
linco
mbined
regim
en(Tab
leS4
J)
Efficacy:on
goingpreg
nancy
RR0.44
(0.10to
1.96)
564(2
RCTs)
LOW
Efficacy:success
RR1.03
(0.99to
1.07
564(2
RCTs)
LOW
Safety
RR0.98
(0.01to
49.14)
471(1
RCT)
LOW
Satisfaction
RR1.02
(0.89to
1.18)
470(1
RCT)
LOW
4.Co
mpa
risons
ofdifferen
tmisop
rostol
only
regimen
s
A.M
isop
rostol
400μg
oral
every3hfor4doses
compared
with60
0μg
vaginal
misop
rostol
once
(Tab
leS5
A)
Efficacy:on
goingpreg
nancy
RR1.50
(0.67to
3.30)
76(1
RCT)
VERY
LOW
Efficacy:success
RR0.94
(0.52to
1.70)
76(1
RCT)
VERY
LOW
Safety
notestim
able
(0stud
ies)
–
Satisfaction
RR0.9(0.5to
1.6)
76(1
RCT)
VERY
LOW
B.M
isop
rostol
800μg
oral
every6hfor2doses
compared
with60
0μg
vaginal
misop
rostol
once
(Tab
leS5
B)
Efficacy:on
goingpreg
nancy
RR0.86
(0.28to
2.59)
64(1
RCT)
VERY
LOW
Efficacy:success
RR1.12
(0.61to
2.05)
64(1
RCT)
VERY
LOW
Safety
notestim
able
(0stud
ies)
–
Satisfaction
RR1.01
(0.54to
1.88)
64(1
RCT)
VERY
LOW
C.M
isop
rostol
400μg
oral
every3hfor4doses
compared
with80
0μg
oral
misop
rostol
every6hfor2doses
(Tab
leS5
C)
Efficacy:on
goingpreg
nancy
RR1.75
(0.62to
4.90)
60(1
RCT)
VERY
LOW
Efficacy:success
RR0.84
(0.44to
1.59)
60(1
RCT)
VERY
LOW
Safety
notestim
able
(0stud
ies)
–
Satisfaction
RR0.89
(0.46to
1.72)
60(1
RCT)
VERY
LOW
5.Com
parison
ofmed
ical
andsurgical
man
agem
ent-Med
ical
man
agem
entwith80
0μg
vaginal
misop
rostol
compared
withsurgical
man
agem
ent(Tab
leS6
)
Efficacy:on
goingpreg
nancy
RR6.70
(1.88to
23.86)
137(1
RCT)
VERY
LOW
Efficacy:success
RR1.02
(0.89to
1.17)
137(1
RCT)
VERY
LOW
Safety
RR0.33
(0.01to
8.04)
137(1
RCT)
VERY
LOW
Satisfaction
notestim
able
(0stud
ies)
–
Abubeker et al. BMC Women's Health (2020) 20:142 Page 13 of 17
4. Comparisons of different misoprostol onlyregimens
One study compared 7 different misoprostol only regi-mens [14] (Table 2). In this study, oral misoprostol400 μg every 3 h administered for 4 doses was comparedto vaginal misoprostol 600 μg once and oral misoprostol800 μg administered every 6 h for 2 doses. In anotherarm, vaginal misoprostol 600 μg once was compared tooral misoprostol 800 μg administered every 6 h for 2doses.None of the study arms was more effective than the
other. In addition, we were not able to compare thesafety outcomes of these regimens (Table S5, Add-itional file 3).
5. Comparisons of medical versus surgicalmanagement
One study compared surgical with medical manage-ment using a single dose of 800 μg vaginal misoprostol[29] (Table 2). Women treated with medical methodshowed higher rates of ongoing pregnancy than thosereceiving surgical management (RR 6.70 CI 95% 1.88–23.8). There was little to no difference in rates of suc-cessful abortion between the two methods (RR 1.02 CI95% 0.89–1.17). There was a lower rate of serious ad-verse events and complications among women who re-ceived medical compared with those who receivedsurgical management (RR 0.33 CI 95% 0.01–8.04). Thecertainty of evidence is very low for all reported out-comes (Table S6, Additional file 3).
DiscussionIn this review we identified 33 trials conducted acrossdifferent settings with a total of 22,275 participants. Wecompared effectiveness, safety and acceptability of differ-ent combination and misoprostol only regimens. Accept-ability was not explicitly reported; thus, we usedsatisfaction, which was reported in 25 of the includedstudies, as a proxy indicator.The results of this review demonstrate that the major-
ity of the studies compared different combination andmisoprostol alone regimens in terms of dosing, routeand frequency of administration. This reflects the factthat mifepristone has replaced older medications, suchas methotrexate and gemeprost, when used in combin-ation with misoprostol.A combined regimen of mifepristone and misoprostol
was found to be more effective in terms of lower rates ofongoing pregnancy and higher rates of successful abor-tion compared to the misoprostol alone regimen [6–8].There have been multiple studies that focus on the
combination regimen, comparing various misoprostol
doses and routes and the interval between mifepristoneand misoprostol.When comparing different doses of misoprostol in the
combined mifepristone misoprostol regimen, the in-cluded studies focused on the dosages of 400 μg and800 μg. Comparing 400 μg to 800 μg buccal misoprostol[9], treatment with 400 μg misoprostol was found to bemore effective (moderate certainty of evidence). On theother hand, administration of 800 μg oral misoprostoldemonstrated more effectiveness than 400 μg oral miso-prostol. Moreover, there is moderate certainty of evi-dence that 800 μg sublingual misoprostol is 3 timesmore effective than 400 μg [10]. Although there weremultiple comparisons, it appears that the dosage of800 μg of misoprostol in the combined mifepristone mi-soprostol regimen showed higher effectiveness withlower rates of ongoing pregnancy and higher rates ofsuccessful abortion. In addition, 800 μg were associatedwith higher rates of satisfaction [9, 10].Review of studies that compared different dosing inter-
val between mifepristone and misoprostol in combinedregimen showed inconclusive results. Individual studiesshowed a 24-h interval to be more effective compared toeither 8- or 48-h intervals [5, 9, 10, 32, 40]. However, wewere not able to replicate these findings in the pooledanalysis. We found similar rates of effectiveness between24-h and 48-h intervals. In addition, the safety profileand satisfaction rates were not significantly differentacross intervals.Comparing 8-h interval to 24-h and 48-h intervals
showed that a shorter interval of misoprostol administra-tion did not significantly compromise effectiveness [11,12]. Furthermore, a 24-h interval was no more effectivethan concurrent administration. Our results align withexisting evidence that demonstrates that concurrent ad-ministration can lead to higher satisfaction rates [5, 25,38], while also impacting the number of visits requiredand time needed to complete the procedure [5]. Nonethe-less, satisfaction rate was not consistently reported acrossstudies. Thus, further research is needed to assess the im-pact of dosing interval on this outcome and how it relatesto the acceptability of the procedure to women.When comparing studies to determine optimal
routes of misoprostol in combined mifepristone miso-prostol regimen, there were mixed results. There ismoderate certainty of evidence that oral misoprostolis significantly less effective than vaginal misoprostol[23, 33, 34]. Similarly, oral route was less effectivethan buccal route (low certainty of evidence) [41].However, individual studies show that oral adminis-tration of misoprostol in the combined regimen leadsto better overall satisfaction [18, 23, 33, 34].Buccal route was as effective as sublingual and vaginal
route and there was no significant difference between
Abubeker et al. BMC Women's Health (2020) 20:142 Page 14 of 17
sublingual and vaginal routes [18, 28, 31]. Given thefindings of the non-significant differences between theroutes, women should be given the full range optionsfactoring in their satisfaction towards a particular treat-ment regimen.A review of one study with 7 different arms com-
paring misoprostol only regimens failed to demon-strate superiority of one regimen over the others.This potentially means that the compared regimensare equally effective and at this time no conclusionscan be made without additional studies evaluating mi-soprostol only regimens. This is important in order toaddress the needs of those who cannot afford or ac-cess mifepristone [14].Compared to surgical method, medical management
had significantly higher rates of ongoing pregnancy.Lower rates of serious adverse events and complicationswere observed with medical compared to surgicalmethods [29]. However, interpretation of this finding re-quires caution as it was based on only one trial and cer-tainty of evidence was very low.One study comparing oral versus vaginal misoprostol
reported one woman in the vaginal arm who died from asystemic Clostridium sordellii infection [35]. However, ingeneral, the rates of serious adverse events reported inour review are very low, thus we cannot draw definitiveconclusions related to adverse events.
Strengths and limitationsThis review has several strengths. We used a compre-hensive and replicable search strategy to identify relevantarticles. In addition, the included studies were conductedacross different settings. We employed the GRADE sys-tem that can assist health care providers, program man-agers and policy makers to design and implement bestpractice recommendations and guidelines.Limitations of this review include the inclusion of only
RCTs and using satisfaction as a proxy for acceptability.Specifically, inclusion of observational studies could bemore informative about client satisfaction and accept-ability of treatment regimens. We were not able to dem-onstrate statistically significant differences for variousdosing intervals and routes of misoprostol administra-tion in combination or in misoprostol alone regimens.There are only a limited number of studies for some ofthe comparisons (medical vs. surgical, misoprostol onlyregimens). In addition, some of the included studieshave a high risk of performance and detection bias.Thus, we recommend future research studies to considerblinding of outcome assessor as it is feasible to blind theindividual who is assessing the success of the abortion(whether by history, physical exam or ultrasound) andthis in turn can improve the quality of data.
ConclusionIn this systematic review, we establish that medicalmethods of abortion are effective, safe and acceptablefor termination of pregnancy of ≤63 days of gestation.The combined regimen of mifepristone and misoprostolwas more effective than the misoprostol alone regimen.In the combined regimen, the dosage of 800 μg miso-prostol was more effective than 400 μg. Although therewere no significant differences in the dosing interval andthe routes of misoprostol, the additive information onthe certainty of evidence and consideration of women’ssatisfaction, suggest that a 24-h interval and offering dif-ferent routes of administration are effective, safe and ac-ceptable options for medical abortion. This furtherhighlights the fact that in many cases, demonstratingthat one option does not lead to statistically significantbetter outcomes than the other allows for making clin-ical decisions based on an individual’s preference. Morerobust studies evaluating both the different combinationand misoprostol alone regimens are needed tostrengthen existing evidence as well as assess patientperspectives towards a particular regimen.
Supplementary informationSupplementary information accompanies this paper at https://doi.org/10.1186/s12905-020-01003-8.
Additional file 1. Search strategies from electronic databases.
Additional file 2. Risk of bias.
Additional file 3 Table S1. Regimens for medical abortion ≤63 days.Table S2. Comparison of misoprostol doses in combined regimen.Table S3. Comparison of dosing intervals between mifepristone andmisoprostol in combined regimen. Table S4. Comparison of misoprostolroutes in combined mifepristone-misoprostol regimen. Table S5. Com-parison of different misoprostol only regimens. Table S6. Comparison ofmedical and surgical management- Medical management with 800 μgvaginal misoprostol compared with surgical management.
AbbreviationsCI: Confidence Interval; GRADE: Grading of Recommendations, Assessment,Development and Evaluations; LMP: Last Menstrual Period; MeSH: MedicalSubject Headings; PRISMA: Preferred Reporting Items for Systematic Reviewsand Meta-Analyses; RCTs: Randomized Controlled Trials; RR: Risk Ratio;WHO: World Health Organization
AcknowledgementsThe authors would like to thank Tomas Allen from World HealthOrganization, Geneva, Switzerland and Kavita Kothari for formulating oursearch strategy and organizing results of the electronic searches.
Authors’ contributionsThe initial review was conducted as part of the evidence synthesis for theWHO guidance on medical abortion. AL had overall responsibility of theguideline development and coordinated the work. FAA and CK conceivedthe idea and conducted the search, screening, data extraction and qualityassessments. MIR carried out the analysis and assessed the overall qualityand validity of the evidence with the GRADE (grading of recommendationsassessment, development and evaluation) system. FAA and CK wrote the firstdraft of the manuscript. All authors participated in the revision and writing ofthe final manuscript.
Abubeker et al. BMC Women's Health (2020) 20:142 Page 15 of 17
FundingThis work was funded by the UNDP-UNFPA-UNICEF-WHO-World Bank SpecialProgramme of Research, Development and Research Training in HumanReproduction (HRP), a cosponsored programme implemented by the WorldHealth Organization (WHO). Extraction of the data, analysis, and compositionof this manuscript was performed by WHO staff members (FAA, CK, AL) anda WHO consultant (MIR).
Availability of data and materialsThe datasets supporting the conclusions of this article are included withinthe article and its additional files.
Ethics approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Competing interestsThe authors declare that they have no competing interests.
Author details1UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research,Development and Research Training in Human Reproduction (HRP),Department of Reproductive Health and Research, World HealthOrganization, Geneva, Switzerland. 2Department of Obstetrics & Gynecology,Oregon Health & Science University, Oregon, Portland, USA.
Received: 27 September 2019 Accepted: 26 June 2020
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