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The European Journal of Contraception & Reproductive
Health Care
ISSN: 1362-5187 (Print) 1473-0782 (Online) Journal homepage: https://www.tandfonline.com/loi/iejc20
Sublingual vs vaginal misoprostol for completion
of first trimester missed abortion: a randomised
controlled trial
Ahmed Abdelshafy, Hassan Awwad, Amgad Abo-Gamra, Ahmed Alanwar,
Ahmed M. Elkotb, Mohamed Shahin, Maya Abd El-Razek & Ahmed M. Abbas
To cite this article: Ahmed Abdelshafy, Hassan Awwad, Amgad Abo-Gamra, Ahmed
Alanwar, Ahmed M. Elkotb, Mohamed Shahin, Maya Abd El-Razek & Ahmed M. Abbas (2019):
Sublingual vs vaginal misoprostol for completion of first trimester missed abortion: a randomised
controlled trial, The European Journal of Contraception & Reproductive Health Care, DOI:
10.1080/13625187.2019.1569224
To link to this article: https://doi.org/10.1080/13625187.2019.1569224
Published online: 12 Feb 2019.
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ORIGINAL RESEARCH ARTICLE
Sublingual vs vaginal misoprostol for completion of first trimester missed
abortion: a randomised controlled trial
Ahmed Abdelshafy
a
, Hassan Awwad
a
, Amgad Abo-Gamra
a
, Ahmed Alanwar
a
, Ahmed M. Elkotb
a
,
Mohamed Shahin
a
, Maya Abd El-Razek
a
and Ahmed M. Abbas
b
a
Ain Shams Maternity Hospital, Faculty of Medicine, Ain Shams University, Cairo, Egypt;
b
Women’s Health Hospital, Faculty of Medicine,
Assiut University, Assiut, Egypt
ABSTRACT
Objective: The study aimed to compare the efficacy and safety of sublingual and vaginal miso-
prostol for termination of pregnancy in women with first trimester missed abortion.
Methods: A single-blind, parallel group, randomised clinical trial (ClinicalTrials.gov NCT02686840)
was conducted in a university hospital between 1 February 2016 and 31 January 2017. All women
who presented with first trimester missed abortion were invited to participate in the study and
were randomised to one of two groups: one group received sublingual misoprostol in three doses
of 800 lg every 4 h, while a second group received vaginal misoprostol in the same dosage regi-
men. The primary outcome of the study was the rate of complete abortion within 7 days after ini-
tiation of treatment.
Results: The study included 200 women (100 in each arm). By day 7, successful complete abortion
was significantly more frequent in the sublingual misoprostol group (71.4%) than in the vaginal
misoprostol group (51.5%) (p¼.006). By day 30, the rate of complete abortion was higher in the
sublingual misoprostol group (90.6%) than in the vaginal misoprostol group (83.9%), but with no
statistically significant difference (p¼.164). The mean length of the induction–expulsion interval in
the sublingual misoprostol group was significantly shorter compared with the vaginal misoprostol
group (12.3 ± 3.1 h vs 16.4 ± 4.2 h, respectively; p¼.001) and the sublingual misoprostol group had
a smaller drop in haemoglobin level (p¼.001). The side effects of misoprostol were significantly
more frequent in the sublingual group compared with the vaginal group.
Conclusion: Sublingual misoprostol is more effective than vaginal misoprostol in completing first
trimester missed abortion, with a shorter induction–expulsion time. Sublingual misoprostol is, how-
ever, associated with more side effects, such as unpleasant taste, gastrointestinal symptoms and
fever, compared with vaginal misoprostol.
ARTICLE HISTORY
Received 22 September 2018
Revised 24 November 2018
Accepted 8 January 2019
KEYWORDS
Misoprostol; missed
abortion; prostaglandins;
sublingual; vaginal
Introduction
Abortion is defined as spontaneous fetal loss before the
age of fetal viability [1]. The rate of abortion is roughly
10–20% among known pregnant women, while rates
among all fertilised zygotes are around 30–50% [2]
.
Women
with ultrasonographically documented first trimester abor-
tion can be managed expectantly, medically or surgically
[3]
.
Traditionally, first trimester abortion has been treated
by surgical uterine evacuation because of the fear of uter-
ine infection and bleeding. It is now clear, however, that
the risk of infection or bleeding is low in spontaneous
abortion, even if no treatment is given [4].
There are various medical treatment options. The chief
pharmacological agent is misoprostol, either alone or com-
bined with the anti-progestogen mifepristone. Current evi-
dence suggests, however, that misoprostol alone has
equivalent efficacy and is more cost-effective than a com-
bination of mifepristone and misoprostol. Numerous stud-
ies have discussed the different routes and dosing of
misoprostol [5].
The systemic bioavailability of vaginal misoprostol has
been observed to be three times higher than that of oral
misoprostol [6]. Some problems, however, have been iden-
tified with vaginal misoprostol tablets, such as inconsistent
absorption (which can be improved by dissolving the tab-
lets in water), incomplete absorption (even several hours
after administration), and discomfort during vaginal admin-
istration in some women [7]. Recent studies suggest that
the sublingual route of misoprostol administration is the
most potent due to its high bioavailability [8].
This study aimed to compare the efficacy and safety of
sublingual and vaginal administration of misoprostol for
completion of first trimester missed abortion.
Methods
The study was a single-blind, parallel group, randomised
clinical trial (RCT). The study protocol was approved by the
ethics review board of Ain Shams University Faculty of
Medicine in December 2015 (IRB00006161). Participants
were recruited from the outpatient clinic of the maternity
hospital of Ain Shams University between 1 February 2016
and 31 January 2017. The trial was designed and reported
according to the revised recommendations of
CONTACT Ahmed Alanwar eladwar@hotmail.com Ain Shams Maternity Hospital, Faculty of Medicine, Ain Shams University, Ramses Street (Ahmed
Lotfy Elsayed Street), Abbassia, 11566 Cairo, Egypt
ß2019 The European Society of Contraception and Reproductive Health
THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE
https://doi.org/10.1080/13625187.2019.1569224
ClinicalTrials.gov for improving the quality of reporting of
RCTs (ClinicalTrials.gov NCT02686840) [9].
Eligibility
All women who presented with first trimester missed abor-
tion were invited to participate in the study. Included were
pregnant women with <12 weeks’gestation and missed
abortion confirmed by ultrasound carried out by two differ-
ent sonographers. Excluded from the study were women
who were haemodynamically unstable; women with fever
or suspected sepsis, severe anaemia or a history of bron-
chial asthma; women receiving anticoagulation for any rea-
son; women with a known allergy to misoprostol; and
women with a history of failed medical or surgical termin-
ation of pregnancy. All recruited women were subjected to
history taking (including age, parity and gestational age)
and to a general and an obstetric examination. Informed
consent was obtained for participation after discussing the
nature of the study including the possible side effects of
misoprostol.
Baseline haemoglobin level was measured in all partici-
pants. Transvaginal ultrasonography was carried out to
confirm the diagnosis of missed abortion according to the
following criteria: mean sac diameter 25 mm in the
absence of a yolk sac; or embryo crown–rump length
7 mm and no heartbeat.
Sample size
Sample size calculation was based on a study by
Prasartsakulchai and Tannirandorn [10] which reported a
72% rate of complete abortions 24 h after administration of
vaginal misoprostol. Using a two-sided v
2
test with a sig-
nificance level of 0.05, the total sample size was calculated
to be at least 200 participants (100 in each study arm),
with 95% power to detect a 20% difference between
groups (odds ratio 4.6) assuming a rate of loss to follow-up
of 10% (Epi Info; Centers for Disease Control and
Prevention, Atlanta, GA).
Randomisation
Randomisation was carried out using a computer-gener-
ated random table prepared by a statistician not otherwise
involved in the study. Eligible women were randomly
assigned to receive either sublingual or vaginal misopros-
tol. Allocation concealment was done using serially num-
bered closed opaque envelopes. Each envelope was
labelled with a serial number and had a card noting the
intervention type. Allocation was never changed after
opening the closed envelopes. Only the study outcomes’
assessor (one of the study investigators [AAb]) was blinded
to the participants’group.
Intervention
Eligible women were randomly allocated to one of two
groups to receive either sublingual or vaginal misoprostol.
The treatment for each group comprised three doses of
misoprostol 800 lg administered sublingually or vaginally
every 4 h. Each dose of misoprostol comprised four 200 lg
tablets (Misotac; Sigma Pharmaceuticals, Cairo, Egypt).
The first dose of misoprostol was administered at the
hospital immediately after admission to the study; the
women were kept under observation for 1 h in case of any
adverse effects. The second and third doses were adminis-
tered by the women themselves at home and they were
asked to document the exact time of each self-medication.
In addition to verbal instructions, each woman was pro-
vided with an information leaflet that explained the pro-
cedure, together with a study kit of the two doses of
misoprostol 800 lg each, four paracetamol 500 mg tablets
as an analgesic or antipyretic if needed, two pairs of dis-
posable gloves, and a pictorial blood loss assessment chart
(PBLAC) to quantify the amount of bleeding.
Patients were instructed to visit the emergency unit if
severe bleeding occurred. An easy reference is the soaking
of two maxi sanitary pads per hour for two consecutive
hours. Moreover, patients were instructed to omit the third
dose of misoprostol if the products of conception were
passed out. A specimen container was given to patients to
collect the products of conception if passed out.
Follow-up
The first follow-up visit on day 7 included measurement of
the haemoglobin level and transvaginal ultrasonography to
determine the endometrial thickness. The following were
also recorded: duration of bleeding; time of passage of
products of conception (using PBLAC); occurrence of side
effects (fever, shivering, nausea, vomiting, diarrhoea,
unpleasant taste). Endometrial thickness was measured as
the distance between the echogenic interfaces of the
endometrium and the myometrium through the central
longitudinal axis of the uterine body, at the junction
between the upper one-third and lower two-thirds of the
endometrial cavity.
Patients with a retained gestational sac were given a
second course of misoprostol treatment at the same dos-
age as before. No further action was taken unless there
was heavy bleeding or signs of pelvic infection.
A second follow-up visit was planned on day 14 after
initiation of the first misoprostol dose. This visit included a
bleeding evaluation and transvaginal ultrasonography to
assess the presence or absence of retained products of
conception. The ultrasonographic appearance is variable
echogenic or heterogeneous material within the endomet-
rial cavity, an intrauterine mass or thickened endometrium
with vascularity by colour flow Doppler.
Surgical evacuation was carried out in patients who had
a retained gestational sac after 14 days. The final judge-
ment for incomplete abortion would be made on day 30. If
no emergency or elective evacuation was necessary during
the period up to day 30, the outcome was classified as
complete abortion.
Failure of treatment was defined as the need for surgical
evacuation either due to method failure (retained gesta-
tional sac on day 14 or endometrial thickness >15 mm on
day 30) or to the occurrence of severe bleeding.
2 A. ABDELSHAFY ET AL.
Study outcomes
The primary outcome measure was the rate of complete abor-
tion within 7 days after the initiation of treatment, defined as
expulsion of the products of conception by visual inspection
and confirmed by ultrasonography as a clear, thin endomet-
rium at day 7. Secondary outcomes included: the rate of com-
plete abortion at day 14 and day 30; the mean length of time
between the initial misoprostol dose and complete abortion
(induction–expulsion interval); the rate of treatment failure; the
need for analgesia; the need for surgical evacuation in cases
of incomplete abortion; the bleeding pattern after misoprostol
intake;andtheoccurrenceofsideeffects.
Statistical analysis
The data were collected and entered into a Microsoft
Access database and analysed per protocol using IBM SPSS,
version 22 (IBM, Armonk, NY). Quantitative variables were
presented in terms of means and standard deviations (SDs)
and were compared using a paired ttest before and after
misoprostol intake; Student’sttest was used for compari-
son between groups. Qualitative variables are presented as
frequencies and percentages. The v
2
test was used for
comparison between groups. A p-value <.05 was consid-
ered significant.
Results
Of 214 eligible women who presented to our hospital with
missed first trimester abortion, 200 consented to partici-
pate. Eleven women did not meet the inclusion criteria and
three refused to participate in the study. Consenting
women were randomly allocated to sublingual misoprostol
(n¼100) or vaginal misoprostol (n¼100). A study flow
chart is presented in Figure 1.
Assessed for eligibility
(n=214)
Included patients
(n=200)
Excluded patients(n=14)
•Did not meet inclusion criteria
(n=11)
•Refused to participate (n=3)
Vaginal misoprostol
group (n=100)
Sublingual
misoprostol group
(
n=100
)
1st visit at 7 days
(n=98)
Complete abortion (n=70)
Incomplete abortion (ET >15 mm) (n=23)
Retained gestational sac (n=5)
Lost to follow-up (n=2)
2nd visit at 14 days
(n=22)
Severe bleeding
requiring evacuation
(n=6)
Complete abortion (n=13)
Incomplete abortion (ET >15 mm) (n=8)
Retained gestational sac requiring evacuation (n=1)
3rd visit at 30 days
(n=6) Lost to follow-up (n=2)
Complete abortion (n=4)
Incomplete abortion (ET >15 mm) requiring
evacuation (n=2)
1st visit at 7 days
(n=97)
Complete abortion (n=50)
Incomplete abortion (ET >15 mm) (n=39)
Retained gestational sac (n=8)
Lost to follow-up (n=3)
2nd visit at 14 days
(n=39) Severe bleeding requiring
evacuation (n=8)
Complete abortion (n=19)
Incomplete abortion (ET >15 mm) (n=19)
Retained gestational sac requiring evacuation (n=1)
3rd visit at 30 days
(n=15) Lost to follow-up (n=4)
Complete abortion (n=9)
Incomplete abortion (ET >15 mm) requiring evacuation
(n=6)
Randomisation
Enrolment
Follow-up and analysis
Figure 1. Flow chart showing the results of all study visits in each group. ET: endometrial thickness.
THE EUROPEAN JOURNAL OF CONTRACEPTION & REPRODUCTIVE HEALTH CARE 3
The baseline characteristics of the study participants are
presented in Table 1. Both groups were similar with regard
to age, body mass index, parity and gestational age. By
day 7, successful complete abortion was significantly more
frequent among the sublingual misoprostol group (71.4%)
than among the vaginal misoprostol group (51.5%)
(p¼.006); the success rate increased with increasing dur-
ation of follow-up (days 14 and 30). By day 30, the rate of
complete abortion was higher among the sublingual miso-
prostol group (90.6%) than among the vaginal misoprostol
group (83.9%); however, the difference was not statistically
significant (p¼.164) (Table 2).
The mean length of the induction–expulsion interval in
the sublingual misoprostol group was significantly shorter
than in the vaginal misoprostol group (12.3 ± 3.1 h vs
16.4 ± 4.2 h, respectively; p¼.001). Duration of bleeding
was shorter in the sublingual misoprostol group than in
the vaginal misoprostol group; however, the difference was
not statistically significant (p¼.113). There was no signifi-
cant difference between the two groups in the number of
women with a retained gestational sac or with retained
products of conception requiring surgical evacuation
(p¼.289). In addition, there was no significant difference in
the failure rate of medical treatment between the two
groups (9.4% vs 16.1%; p¼.198) (Table 2).
The drop in haemoglobin level at day 7 after treatment
was significantly less in the sublingual misoprostol group
compared with the vaginal misoprostol group (p¼.001). On
the other hand, the need for analgesia was significantly
higher in the sublingual misoprostol group compared with
the vaginal misoprostol group (28.6% vs 11.3%; p¼.001)
(Table 2).
Finally, side effects were significantly more frequent in
the sublingual misoprostol group compared with the vagi-
nal misoprostol group. Unpleasant taste was the most com-
mon side effect reported by nearly a third of participants
in that group (Table 3).
Discussion
Findings and interpretation
We found that sublingual misoprostol at a dose of 800 lg
every4hinthreedoseswasmoreeffectivethanvaginalmiso-
prostol at the same dosage for completion of first trimester
missed abortion within 7 days after administration; however, it
was associated with more side effects and need for analgesia.
Medical management of missed abortion has been shown
to reduce the need for surgical evacuation, is less costly and
is associated with a high level of patient satisfaction [11].
Table 1. Baseline characteristics of the study participants.
Characteristic Sublingual misoprostol (n¼100) Vaginal misoprostol (n¼100) pvalue
Age, years 27.6 ± 4.8 28.6 ± 5.5 .169
Parity 2.17 ± 1.61 2.03 ± 1.44 .226
BMI, kg m
2
27.25 ± 3.1 27.11 ± 2.1 .123
Gestational age, weeks 8.6 ± 1.4 8.8 ± 1.3 .418
Primigravida 31 (31) 29 (29) .831
Data are presented as mean ± SD or n(%).
BMI: body mass index.
Table 2. Study outcomes.
Outcome Sublingual misoprostol (n¼100) Vaginal misoprostol (n¼100) pvalue
Complete abortion by day 7
a
70/98 (71.4) 50/97 (51.5) .006
Complete abortion by day 14 83/98 (84.7) 69/97 (71.1) .001
Complete abortion by day 30
b
87/96 (90.6) 78/93 (83.9) .164
Induction–expulsion interval, h 12.3 ± 3.1 16.4 ± 4.2 .001
Duration of bleeding, days 14.6 ± 2.5 15.2 ± 2.9 .113
Failure rate of medical treatment 9/96 (9.4) 15/93 (16.1) .198
Haemoglobin level at baseline, g L
1
111 ± 12 109 ± 13 .816
Haemoglobin level at day 7, g L
1
101 ± 10 95 ± 11 .001
Need for analgesia 28/98 (28.6) 11/97 (11.3) .001
Data are presented as mean ± SD or n(%).
a
Two patients in the sublingual misoprostol group and three in the vaginal misoprostol group were lost to follow-up at
day 7.
b
Two patients in the sublingual misoprostol group and four in the vaginal misoprostol group were lost to follow-up at
day 30.
Statistically significant difference (p<.05).
Table 3. Side effects associated with misoprostol.
Side effect
Sublingual
misoprostol (n¼98)
Vaginal
misoprostol (n¼97)
pvaluen%n%
Nausea 22 22.4 7 7.2 .001
Vomiting 15 15.3 6 6.2 .038
Diarrhoea 24 24.5 8 8.2 .003
Fever 24 24.5 6 6.2 .003
Shivering 22 22.4 4 4.1 .002
Unpleasant taste 31 31.6 3 3.1 .0001
No side effects
a
33 33.7 80 82.5 .0001
a
Women developed more than one side effect, so the sum of values is not equal to the total number of study participants.
Statistically significant difference (p<.05).
4 A. ABDELSHAFY ET AL.
Several studies have investigated the best regimen for med-
ical management of first trimester abortion including dose
(either single or repeated), route and timing of follow-up.
Vaginal administration of misoprostol is associated with
slower absorption, lower peak plasma levels, greater drug
exposure and effect on the cervix, and a lower rate of
gastrointestinal side effects [12,13]. The main disadvantages
of vaginal misoprostol are the possible effects of vaginal
pH and vaginal bleeding on drug bioavailability.
In the current study, the complete abortion rate by day
7 was significantly higher in the sublingual misoprostol
group compared with the vaginal misoprostol group
(p¼.006; relative risk [RR] 0.6; 95% confidence interval [CI]
0.42, 0.86). In addition, 9.4% of patients in the sublingual
misoprostol group and 16.1% in the vaginal misoprostol
group underwent surgical evacuation.
Differences and similarities in relation to other studies
Our results agree with those of Tanha et al. [14], who found
that sublingual misoprostol 400 lgevery6hwassignificantly
more effective than the same dosage of vaginal misoprostol
(84.5% vs 46.4%; RR 0.54; 95% CI 0.442, 0.681). Similar find-
ings were reported by Sharma et al. [15], who described an
overall success rate of 86% with sublingual misoprostol
600 lg every 3 h. Using an assessment of endometrial thick-
ness 15 mm, Ng et al. [16] reported an overall success rate
of 92% with vaginal misoprostol 800 lg every 8 h in three
doses; however, their study included women with incomplete
abortion, which may explain the high success rate.
The point of controversy with many published trials of
medical management of early abortion is the definition of
success. Some studies used an endometrial thickness of
15 mm assessed by transvaginal ultrasonography as a cut-
off for success [17]. Mounting evidence from the literature
on medical termination of missed abortion, however, indi-
cates that this cut-off value is too stringent [18–20].
Strangely, medical abortion studies, which commonly cite
success rates exceeding 95%, do not use endometrial thick-
ness to define success [21].
The unusually wide variation in success rate in different
studies might be due to several factors including patient
selection, concomitant use of mifepristone, and difference
in dosage, route and interval of misoprostol administration.
While some studies included patients with incomplete
abortion, others included missed abortion or a combination
of both [22,23].
In our study, all patients had vaginal bleeding after inser-
tion of misoprostol. In the self-reported PBLAC, patients
recorded the number of pads used and the degree of soak-
ing as well as the number and size of daily blood clots. This
helped us to determine the time of passage of the products
of conception, usually corresponding to peak blood loss, and
the duration of bleeding. Bleeding duration was slightly
shorter in the sublingual misoprostol group compared with
the vaginal misoprostol group, but the difference was not
statistically significant (p¼.113). The mean duration of bleed-
ing was 14.6 days (±2.5 SD) and 15.2 days (±2.9 SD), respect-
ively, in the sublingual misoprostol and vaginal misoprostol
groups. To further aid and support our estimation of blood
loss, haemoglobin levels were obtained before and 7 days
after the procedure. The reduction of haemoglobin was
significantly lower in the sublingual misoprostol group com-
pared with the vaginal misoprostol group (p¼.001).
In the current study, the incidence of side effects includ-
ing pain, shivering, nausea, vomiting, diarrhoea and unpleas-
ant taste was more common in the sublingual than in the
vaginal misoprostol group. This may be explained by the
high bioavailability of sublingual misoprostol. Unpleasant
tastewasthemostfrequentsideeffectofsublingualmiso-
prostol seen in 31.6%, compared with only 3.1% in the vagi-
nal misoprostol group (p¼.0001). Hamoda et al. [24]also
reported unpleasant taste in 63.9% of the sublingual miso-
prostol group compared with 37.5% of the vaginal misopros-
tol group (p¼.02). In our study, other side effects including
shivering, low-grade fever, nausea and diarrhoea were more
frequent in patients receiving sublingual misoprostol; how-
ever, most patients considered the side effects to be toler-
able and transient and found that they decreased gradually
after the first day of treatment.
Strengths and weaknesses of the study
The main strengths of our study are that it was randomised
andincludedalargesamplesizeinwhichtotesttheeffect
of sublingual misoprostol. It does, however, have some limita-
tions. First, all patients self-reported that they administered
the misoprostol on time as instructed. We cannot, however,
rule out the possibility of faulty self-reporting and this may
be the main limitation of the study. Furthermore, we could
not assess patient satisfaction, as participants were not
blinded to the route of administration and treatment out-
come may affect preference and satisfaction with a particu-
lar route.
Conclusion
Sublingual misoprostol may be more effective than vaginal
misoprostol for the completion of first trimester missed
abortion within 7 days after administration, with a shorter
induction–expulsion time, a shorter duration of bleeding
and a lower drop in haemoglobin level. Sublingual miso-
prostol, however, was associated with more side effects,
such as unpleasant taste, gastrointestinal side effects and
fever, compared with vaginal misoprostol. Further RCTs
with larger sample sizes are needed to confirm our results.
Disclosure statement
The authors declare that there are no conflicts of interest associated
with this manuscript.
ORCID
Ahmed Abdelshafy http://orcid.org/0000-0002-1571-2372
Ahmed Alanwar http://orcid.org/0000-0002-7171-1470
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