Arch Gynecol Obstet
DOI 10.1007/s00404-017-4297-9
MATERNAL-FETAL MEDICINE
Comparison betweenvaginal andsublingual misoprostol 50g
forcervical ripening prior toinduction oflabor: randomized
clinical trial
AndrsConde1,2 SebastinBen1 JosefinaTarigo1 SantiagoArtucio1
VirginiaVarela1 PamelaGrimaldi1 ClaudioSosa1 JustoAlonso1
Received: 14 October 2016 / Accepted: 12 January 2017
Springer-Verlag Berlin Heidelberg 2017
Abstract
Objective To compare the effectiveness and safety of sub-
lingual versus vaginal misoprostol on improving the Bishop
score after 6h of administration.
Methods Randomized clinical trial which includes preg-
nant women in gestational ages from 32/0 to 41/6, with
indication of induction of labor with misoprostol. Bishop
score was assessed at the time of induction and 6 h after
administration of 50 g misoprostol. Analysis was made
over difference in mean Bishop score of 2 points, using a
standard deviation of 2, with 90% power, reaching a 95%
confidence interval.
Results 102 patients were studied, 51 received sublingual
misoprostol, and 51 received vaginal misoprostol. There
was a statistically significant difference in cervical modi-
fications in global terms regardless of the administration
route at 6 h (P<0.05). When analyzing each group, there
was no significant difference for the mean and standard
deviation for Bishop score for sublingual and vaginal route
(P=0.761). There was no significant difference in terms of
mode of delivery, Apgar score, cord pH, nor in the pres-
ence of complications.
Conclusion There is no statistically significant difference
in terms of administration route for cervical ripening using
misoprostol 50g, whether it was sublingual or vaginal.
Trial registration numberNCT02732522.
Registry website: https://clinicaltrials.gov/.
* Andrs Conde
acmaine@hotmail.com
1
Department ofObstetrics andGinecology, Hospital Pereira
Rossell, University ofUruguay, Bulevar Gral, Artigas 1550,
Montevideo11600, Uruguay
2
Gabriel Pereira 2845, CP11300Montevideo, Uruguay
Keywords Cervical ripening Misoprostol Sublingual
Introduction
The characteristics of the uterine cervix prior to induc-
tion of labor are of utmost importance to predict its result.
Any method of induction is effective if the uterine cervix
presents favorable characteristics, and on the contrary, no
method will be highly successful if the cervix has non-
favorable characteristics for induction. This is why, in a
non-favorable uterine cervix, the use of cervical ripening
methods is fundamental.
Cervical ripening is a complex process that results in
softening and distension of the uterine cervix, which in the
last stages of labor ends with effacement and partial dila-
tion [13]. These changes are hormone-induced (estrogen,
progesterone, and relaxin), as well as induced by cytokines,
prostaglandins, and nitric oxide.
Among the most common techniques, cervical ripening
is the use of prostaglandins. These cause the dissolution
of collagen threads and increase the water content of the
uterine cervical submucosa [4]. Aside from this, prosta-
glandins also cause uterine contractions, and may initiate
labor. They present a good safety profile in women with-
out uterine scars, since low Apgar scores need for admis-
sion of newborn in intensive care, presence of meconium
staining of the amniotic fluid, and cesarean delivery that
are similar to the ones found when using other methods for
cervical ripening [5]. The American College of Obstetri-
cians and Gynecologists (ACOG) has indicated that the use
of misoprostol is safe and effective when used for cervical
ripening and/or as an agent for labor induction [6]. Drug,
optimal route, frequency, and dose have not been deter-
mined yet. Originally, they were administered intravenous
13
Vol.:(0123456789)

or orally, and later, local administration was preferred, with
intravaginal route, maintaining acceptable clinical response
[7, 8]. Optimal dose and intervals are still unknown. A
50g dose is more effective than 25g, with higher rates of the administration route assigned to the patient assessed
vaginal delivery after a single dose within the first 24h of
its administration and lower rates of oxytocin use [9]. Side
effects of prostaglandins include tachysystole, fever, shiver-
ing, emesis, and diarrhea. Their frequency depends on the
type of prostaglandin, route, and dose. As for the route of
administration, most studies are not conclusive between
oral and vaginal routes as the most effective [10]. However,
new trends analyze benefits of the sublingual administra-
tion [11]; this route avoids hepatic first step in its metab-
olism as opposed to oral administration. Pharmacokinetic
data support the hypothesis that sublingual route is associ-
ated with a more rapid beginning of action and higher bioa-
vailability [12]. Nowadays, there are 50g pills (Partum, new doses were needed to continue with induction of labor
Servimedic S.A) with which exact dosing can be ensured.
Objectives
The aim of this study is to compare the effectiveness and
safety of sublingual versus vaginal misoprostol on improv-
ing the Bishop score after 6 h of administration. In addi-
tion, different effects at the maternal, fetal, and neonatal
levels will be assessed, such as evolution of uterine con-
tractions, presence of adverse effects and complications,
need of medication to continue induction of labor, time-to-
birth, and mode of delivery, clinical evolution after admin-
istration of misoprostol, newborn umbilical cord pH, and
Apgar score.
Methods
A randomized, single blind clinical trial, was performed.
Inclusion criteria were all pregnant women admitted at
Pereira Rossell Hospital Center with gestational ages
between 32/0 and 41/6 according to first trimester sono-
gram, with a viable fetus in cephalic presentation, with esti-
mated fetal weight lower than 4000g, without contraindi-
cations for vaginal birth, to whom induction of labor with
misoprostol had been previously indicated, from 8 to 20h
7days a week. Protocol counted with approval of the Eth-
ics Commission of the Pereira Rossell Hospital. All par-
ticipants gave written informed consent before the study
began. Once there was confirmation that the patient met the
inclusion criteria, information was given and consent form
was signed, the patient entered the study, and the interven-
tion was randomized. Randomization was computer gener-
ated in permuted blocks of 2 by an epidemiologist from the
Service, and the result was in a sealed and opaque envelope
13
Arch Gynecol Obstet
which was opened at the time of administering the medica-
tion. Prior to administration of the medication, an Obste-
trician or Obstetrics resident who was not familiar with
through vaginal examination the characteristics of the cer-
vix in terms of Bishop score. Afterwards, a technician from
the investigation team administered the misoprostol accord-
ing to the assigned route (50 g misoprostol vaginal or
sublingual).
Tachysystole was defined as the presence of at least six
uterine contractions in 10min.
Primary result was defined as the clinically significant
variation (of at least 2 points) of the Bishop score at 6 h
after administration of 50g misoprostol. Secondary results
were defined as the presence of tachysystole, frequency of
vaginal birth and cesarean section, and frequency in which
and frequency with which labor was diagnosed at 6 h of
administration of misoprostol. Neonatal results included
Apgar score at 1 and 5min and pH value in umbilical cord
gasometry. Final analysis was made according to intention
to treat.
To detect a difference in the mean of Bishop score of 2
points, using a standard deviation of 2, with a 90% power,
reaching a confidence interval of 95%, a population of 49
patients was required for each group.
Randomization was done in permuted blocks of 2, using
a table of randomized numbers. Group 1 included those
patients who received sublingual misoprostol and group 2
those patients who received vaginal misoprostol. Analy-
sis was done in statistical package SPSS (reg) V16. For
continuous variables, a mean and standard deviation were
described; for categorical variables, absolute frequency and
percentage were described. For statistical analysis, a two-
tailed independent t test was used, to compare the mean of
the two groups. In addition, to compare proportions among
the two groups, Chi-squared test and Fishers exact test
were used.
Results
Recruitment was carried out over a period of 6 months,
with a total of 102 women who gave consent to enroll in
the study. Fifty-one women were randomly assigned to
receive misoprostol through vaginal route, and 51 were
randomly assigned to receive misoprostol through sublin-
gual route. Analysis was done through the previously stated
groups. Data loss was only registered for the umbilical
cord gasometry registry (Fig. 1). Neither group presented
statistical differences in terms of age, gestational age at
the moment of interruption of pregnancy, number of pre-
vious vaginal deliveries, nor initial Bishop score (Table1),
Arch Gynecol Obstet

Fig.1Flow diagram of the progress through the phases of this RCT (enrollment, intervention, follow-up, and data analysis) based on the CON-
SORT statement 2010

as well as with respect to previous medical history. Once
misoprostol was administered for labor induction, there was
a significant difference in terms of cervical modifications
6h after its administration regardless of the administration
route. When we analyzed the two groups separately, there
was no statistically significant difference in Bishop score
(P=0.761) between vaginal and sublingual administrations
(Table2). There were no significant differences either when
analyzing secondary results, such as need of medication to
continue labor induction, presence of complications, mode
of delivery, Apgar score, and umbilical cord pH (Tables3,
4).
Discussion
Cervical ripening is a fundamental process in the immature
cervix or non-favorable cervix to accomplish successful

13
 Arch Gynecol Obstet

Table1Demographic characteristics of the population

Sublingual misoprostol Vaginal misoprostol P
Media (standard deviation) Media (standard deviation)

Age (years) 23.75 (6.10) 24.94 (6.92) 0.357

Gestational age (weeks) 39.92 (1.37) 40.02 (1.45) 0.726
Vaginal birth 0.86 (1.36) 1.27 (1.74) 0.186
Bishops score at the beginning 2.80 (1.27) 3.06 (1.22) 0.303
N (%) N (%)

Smoking 14 (27.45) 13 (25.49)

Diabetes 7 (13.73) 5 (9.80)
Hypertensive pregnancy status 11 (21.56) 12 (23.53)
Urinary infection 4 (7.84) 2 (3.92)
Intrauterine growth restriction 3 (5.88) 1 (1.96)
All patients 51 (50) 51 (50)

Table2Main result Table4Neonatal outcome

Sublingual Vaginal mis- RR CI P Misoprostol Misoprostol vaginal. P

misoprostol. oprostol. sublingual. N (%)
Media (stand- Media (stand- N (%)
ard deviation) ard deviation)
Apgar score at 1min 8.39 (1.30) 8.63 (0.60) 0.242
Bishop score 5.47 (3.66) 5.25 (3.46) 0.761 Apgar score at 5min 9.57 (0.81) 9.73 (0.57) 0.259
at 6h pH cord blood gas 7.23 (0.85) 7.23 (0.95) 0.927

labor induction. The American College of Obstetricians

and Gynecologists (ACOG) has indicated that the use of
misoprostol is safe and effective when used for cervical
ripening [6]. Nevertheless, there is still controversy as to
which the most efficient route for its administration is. Our
study aims at analyzing this point.
We proposed to study its effects in the population that
is in general target of this medication, nulliparae, or pri-
miparae, with a non-favorable cervix. Table 1 shows that
the mean parity was 0.86 and 1.27 for the patients who
received misoprostol through sublingual and vaginal
routes, respectively, and mean Bishop score was 2.80 and
3.06 respectively, being non-favorable when lower than 4
[1]. Randomization allowed not to have statistical differ-
ences among study groups in these two parameters.
Global analysis yields a significant difference in Bishop
score (P<0.05) at 6 h after administration of misoprostol
regardless of the route of administration, confirming the
effect that this medication has on cervical ripening, as it
had been concluded previously in several international
studies, most of them stemming from Cochrane revisions
[1315].
There is no significant difference in the mean Bishop
score at 6h after administration of misoprostol when com-
paring vaginal versus sublingual routes (P=0.761). This
confirms the previous results obtained in a study developed
by Sharami etal. [16] in 2014. Even if the dose was differ-
ent, 25 g for the sublingual route and 50 g for vaginal
route, this is the only study that assessed cervical modifi-
cations as a consequence of administration of misoprostol
through different routes.
Among study weaknesses, sample size may not be ade-
quate to find small differences. In this way, the standard

Table3Maternal outcome Sublingual Vaginal misoprostol. RR CI P

misoprostol. N (%)
N (%)

Tachysystole 1 (1.96) 3 (5.88) 3.125 0.31431.094 0.617

Cesarean section 10 (21.28) 7 (13.73) 1.533 0.5344.405 0.635
It requires further dose 41 (80.39) 37 (72.55) 0.645 0.2561.626 0.872
of misoprostol
Labor within 6h 8 (15.69) 7 (13.73) 0.855 0.2852.564 0.078

13
Arch Gynecol Obstet
deviation found for each group was higher than at the
beginning of the research, which may be indicating a need
to increase the sample size to detect significant differences.
In spite of that, we believe that the absence of important
cervical modifications, even using our sample size, indi-
cates that there is no clinically relevant difference between
the administration routes used. On another note, our data
may be used for further meta-analyses that may answer our
clinical question with greater precision.
Since the result of the administration of the medication is
the same in the uterine cervix regardless of the administra-
tion route, this may be due to a systemic effect, giving greater
importance to serum levels. This confirms the previous pub-
lications, such as the one from Tang etal. [12] in 2002 that
present pharmacokinetic data that support the hypothesis
that oral and sublingual administration routes are associated
with faster beginning of action and higher bioavailability
than other routes. This may be explained due to the presence
of a vast sublingual vascular net and a less acid pH than at
the vaginal level. In additions, it opens the possibility to opt
for another route other than the most frequently used, vagi-
nal route, given that even if it was not studied in this par-
ticular research, it may be more convenient to administer
misoprostol through sublingual route, since it causes less dis-
comfort to the patient. Nassar etal. [17] in 2007 and Zahran
etal. [18] in 2009 compared the degree of satisfaction in the
patient for each administration route and confirmed our con-
clusions. They reported a better experience during labor care
and better predisposition to induction of labor in future preg-
nancies with the sublingual use. Sublingual route presents an
easier administration, does not require previous technician
preparation, may even be self-administered by the patient,
and implies lower costs not even requiring the use of gloves
as in the case of the vaginal route.
The presence of tachysystole was detected as a complica-
tion. In our study, a higher number were detected associated
with the vaginal use (5.88%), but there is no significant dif-
ference in this point. Previous papers by Caliskan etal. [19],
Nassar etal. [17], and Zahran etal. [18], which used the same
doses than our research, confirm the latter In addition, using
smaller doses as in Feitosa etal. [20] in 2005, of 25g, and nationally [1720]. When analyzing the patients in labor
did not find significant differences either in relation to the
administration route. If we analyze our results in relation to
the ones obtained in the study by Carlan etal. [21], we can
find that this complication is not linked to the administra-
tion route, but rather, it is dose-dependent, since in Carlans
research, the use of higher doses (from 200 to 300g in sub-
lingual administration) and dosing schedules every 4h dem-
onstrated a higher percentage of tachysystole, reaching 38%
in the sublingual administration group. In all our cases of
tachysystole, resolution was spontaneous, not requiring use of
tocolytic drugs and not causing harm to the fetus. Since this
complication entails risks specially for scarred uterus, and at
the fetal level, further studies are necessary to determine the
safest and most effective dose of misoprostol.
Regarding mode of delivery, there was no statistically
significant difference between vaginal birth and cesar-
ean section. This is of utmost importance given the global
tendency aiming at decreasing the percentage of cesarean
sections. No differences were found among previously pub-
lished data in the mentioned studies.
Apgar score did not present significant differences in
both groups. The same happens when analyzing the cate-
gorized variable for moderate and severe neonatal depres-
sions. This confirms data published in the previous studies
[1621].
Umbilical cord pH did not present significant differences
either, although in this case, only a percentage of the total
births could be analyzed. In our institution, umbilical cord
blood gases is not a routine procedure for all deliveries and
neonatologists performed this study when they suspected com-
promised neonatal wellbeing associated with fetal hypoxia.
We could assume that in the cases in which no umbilical cord
gasometry was obtained, their parameters were not altered.
Accordingly, we did not find any adverse results at the fetal
health level, regardless of the administration route. Other stud-
ies that compare mechanical methods to misoprostol do not
observe significant adverse fetal results either [22].
Administration of 50 g sublingual misoprostol proved
in our study to be safe both at the maternal level (non-
scarred uterus) and at the fetal level in the cases in which
it was indicated, given that it showed no significant differ-
ences in the analyzed parameters in relation to the vaginal
route. Accordingly, we did not find any adverse results at
the fetal health level, regardless of the administration route,
which was also reported in the previous research by Eze-
chukwu etal. [23].
In relation to the procedure after the first dose of mis-
oprostol, there are no significant differences in relation to
the need of medication (misoprostol or oxytocin) to con-
tinue with cervical ripening and or induction of labor,
which is also coherent with other studies conducted inter-
before concluding 6h after administration of misoprostol,
we did not find significant differences in the administration
route. Both routes are equally effective not just for cervical
ripening, but also as inductors of labor (Table3).
Conclusion
There is no statistically significant difference in terms of
the route of administration, sublingual or vaginal, for cervi-
cal ripening when using misoprostol 50g.
13

Compliance with ethical standards
Conflict of interest Author A Conde declares that he has no conflict
of interest. Author S Ben declares that he has no conflict of interest.
Author P Grimaldi that she has no conflict of interest. Author V Varela
declares that she has no conflict of interest. Author J Tarigo declares
that she has no conflict of interest. Author S Artucio declares that he
has no conflict of interest. Author C Sosa declares that he has no con-
flict of interest. Author J Alonso declares that he has no conflict of
interest.
Ethical approval All procedures performed in studies involving
human participants were in accordance with the ethical standards of
the institutional and/or national research committee and with the 1964
Helsinki declaration and its later amendments or comparable ethical
standards. Informed consent was obtained from all individual partici-
pants included in the study.
The authors have no financial relationships related research. Authors
state that they have had full control of all primary data and they agree
to allow the Journal to review their data if requested.
References
1. Maul H, Mackay L, Garfield RE (2006) Cervical ripening: bio-
chemical, molecular, and clinical considerations. Clin Obstet
Gynecol 49:551
2. Word RA, Li XH, Hnat M, Carrick K (2007) Dynamics of cer-
vical remodeling during pregnancy and parturition: mechanisms
and current concepts. Semin Reprod Med 25:69
3. Timmons BC, Mahendroo M (2007) Processes regulating cervi-
cal ripening differ from cervical dilation and postpartum repair:
insights from gene expression studies. Reprod Sci 14:53
4. Keirse MJ (2006) Natural prostaglandins for induction of labor
and preinduction cervical ripening. Clin Obstet Gynecol 49:609
5. Vaknin Z, Kurzweil Y, Sherman D (2010) Foley catheter balloon
vs locally applied prostaglandins for cervical ripening and labor
induction: a systematic review and metaanalysis. Am J Obstet
Gynecol 203:418
6. ACOG Committee on Practice Bulletins (2009) Obstetrics.
ACOG Practice Bulletin No. 107: Induction of labor. Obstet
Gynecol 114:386
7. Keirse MJ (1993) Prostaglandins in preinduction cervical ripen-
ing. Meta-analysis of worldwide clinical experience. J Reprod
Med 38:89
8. Prins RP, Neilson DR Jr, Bolton RN et al (1986) Preinduction
cervical ripening with sequential use of prostaglandin E2 gel.
Am J Obstet Gynecol 154:1275
13
Arch Gynecol Obstet
9. Farah LA, Sanchez-Ramos L, Rosa C etal (1997) Randomized
trial of two doses of the prostaglandin E1 analog misoprostol for
labor induction. Am J Obstet Gynecol 177:364
10. Wing DA, Park MR, Paul RH (2000) A randomized comparison
of oral and intravaginal misoprostol for labor induction. Obstet
Gynecol 95:905
11. Wolf SB, Sanchez-Ramos L, Kaunitz AM (2005) Sublingual
misoprostol for labor induction: a randomized clinical trial.
Obstet Gynecol 105:365
12. Tang OS, Schweer H, Seyberth HW et al (2002) Pharmacoki-
netics of different routes of administration of misoprostol. Hum
Reprod 17:332
13. Alfirevic Z, Aflaifel N, Weeks A (2014) Oral misoprostol for
induction of labour. Cochrane Database Syst Rev 6:CD001338
14. Hofmeyr GJ, Glmezoglu AM, Pileggi C (2010) Vaginal mis-
oprostol for cervical ripening and induction of labour. Cochrane
Database Syst Rev. doi:10.1002/14651858.CD000941
15. Austin SC, Sanchez-Ramos L, Adair CD (2010) Labor induc-
tion with intravaginal misoprostol compared with the dinopros-
tone vaginal insert: a systematic review and metaanalysis. Am J
Obstet Gynecol 202:624.e1
16. Sharami SH, Milani F, Faraji R, Bloukimoghadam K, Salamat F,
Momenzadeh S, Ebrahimi H (2014) Comparison of 25 g sub-
lingual and 50g intravaginal misoprostol for cervical ripening
and labor: a randomized controlled equivalence trial. Arch Iran
Med 17(10):652656
17. Nassar AH, Awwad J, Khalil AM, Abu-Musa A, Mehio G, Usta
IM (2007) A randomized comparison of patient satisfaction with
vaginal and sublingual misoprostol for induction of labour at
term. BJOG 114:12151221
18. Zahran K, Shahin A, Abdellah M, Elsayh K (2009) Sublingual
versus vaginal misoprostol for induction of labor at term: a rand-
omized prospective placebo-controlled study. J Obstet Gynaecol
Res 35(6):10541060
19. Caliskan E, Bodur H, Ozeren S, Corakci A, Ozkan S, Yucesoy
I (2005) Misoprostol 50 mg sublingually versus vaginally for
labour induction at term. Gynecol Obstet Invest 59:155156
20. Feitosa FEL, Sampaio ZS, Alencar CA Jr, Amorim MMR,
Passini R Jr (2006) Sublingual versus vaginal misoprostol for
induction of labour. Int J Gynaecol Obstet 94:9195
21. Carlan SJ, Blust D, OBrien WF (2002) Buccal versus intravagi-
nal misoprostol administration for cervical ripening. Am J Obstet
Gynecol 186(2):229233
22. Mizrachi Y, Levy M, Bar J, Kovo M (2016) Induction of labor
in nulliparous women with unfavorable cervix: a comparison
of Foley catheter and vaginal prostaglandin E2. Arch Gynecol
Obstet 294(4):725730. doi:10.1007/s00404-016-4026-9
23. Ezechukwu PC, Ugwu EO, Obi SN, Chigbu CO (2015) Oral ver-
sus vaginal misoprostol for induction of labor in Enugu, Nigeria:
a randomized controlled trial. Arch Gynecol Obstet 291(3):537
544. doi:10.1007/s00404-014-3429-8