Human Reproduction Vol.19, No.1 pp. 77±80, 2004 DOI: 10.

1093/humrep/deh001

Comparison between the sublingual and oral route of

misoprostol for pre-abortion cervical priming in ®rst
trimester abortions

Pikee Saxena1,3, Sudha Salhan2 and Nivedita Sarda2

1
Department of Reproductive Biomedicine, National Institute of Health and Family Welfare and 2Department of Obstetrics and
Gynecology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India

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3
To whom correspondence should be addressed at: Department of Reproductive Biomedicine, National Institute of Health and
Family Welfare, New Mehrauli Road, Munirka, New Delhi 110067, India. E-mail: pikeesaxena@hotmail.com

BACKGROUND: Misoprostol has been used for achieving cervical priming before suction evacuation (SE) by the
oral or vaginal route, although both routes have their shortcomings. We evaluated the ef®cacy of the sublingual
versus oral route of misoprostol for cervical priming before SE. METHODS: A prospective clinical trial was carried
out in 100 women with a period of gestation of between 6 and 12 weeks who were sequentially allocated to two
groups of 50 each. Both groups received 400 mg of misoprostol 3 h prior to SE by either the sublingual or the oral
route. RESULTS: Demographically, both groups were similar. For all periods of gestation, sublingual misoprostol
signi®cantly improved cervical dilation (P < 0.001) with a reduction in duration of surgery (P = 0.024) compared
with the oral route. Mean (6 6SD) pain scores for the sublingual and oral groups were similar (2.6 6 1.4 versus
3.5 6 1.1). No major complications occurred in either of the two groups. CONCLUSION: the sublingual route is an
effective alternative to oral administration of misoprostol for cervical dilation. To the best of our knowledge, this is
the ®rst study to compare the ef®cacy of the sublingual versus the oral route of misoprostol for cervical priming
before SE.

Key words: cervical priming/misoprostol/oral/sublingual/suction evacuation

Introduction
The traditional method for termination of early pregnancy has
been via surgical dilation of the cervix, followed by evacuation
by suction aspiration performed under anaesthesia or sedation.
It is an effective method with a success rate of >95% (Child
et al., 2001). As with any other surgical procedure, it is also
associated with slight risks from anaesthesia and surgery.
Medical abortion has been investigated as a non-invasive
option for early abortions as it avoids the risk of anaesthesia
and surgical trauma to the cervix, uterus and other organs. The
disadvantages of medical abortion are that medical supervision
and follow-up is of utmost importance, and that the longer time
that it takes leads to prolonged bleeding, which causes anxiety
for the patient. More importantly, medical abortion should be
attempted only if the patient has access to 24 h emergency
services, which makes it unsuitable for many rural areas.
In this study, we used 400 mg of sublingual or oral
misoprostol (Misoprost, Cipla Ltd, Patalganga, India) for
pharmacological cervical dilation in order to decrease the risk
of injury and to achieve additional bene®cial effects such as a
reduction in the short- and long-term complications, amount of
blood loss, pain intensity and duration of surgery, and to
improve operative ease for the surgeon. Recently, misoprostol
Human Reproduction vol. 19 no. 1 ã European Society of Human Reproduction and Embryology 2004; all rights reserved
has been used for cervical priming before suction evacuation
(SE) administered via the vaginal or oral route. The vaginal
route has been found to be more effective but has a poorer
patient acceptability compared with the oral route.
To date, we have found no evidence of a published
randomized study comparing the sublingual versus oral route
of misoprostol administration for ®rst trimester surgical
termination of pregnancy. The aim of the current study was
therefore to compare the ef®cacy of sublingual versus oral
misoprostol for cervical dilation during ®rst trimester SE.
Materials and methods
Following institutional ethical approval, written informed consent was
obtained from 100 women requesting ®rst trimester abortion of
pregnancy. They were enrolled in this prospective clinical trial carried
out at the Family Planning Services of a tertiary care hospital in India
during March and April 2002. The inclusion criterion was young
healthy women with a period of gestation of between 6 and 12 weeks.
Gestational age was estimated clinically and was con®rmed by
ultrasonography in cases where there was any doubt. Patients with a
history of previous uterine surgery, allergy or contraindications to
prostaglandins, infection, haemoglobin <9 g%, intrauterine contra-
ceptive device (IUCD) in situ, uterine anomaly and chronic maternal
77
P.Saxena, S.Salhan and N.Sarda
Table I. Patient characteristics
Sublingual (n = 50)
Mean age (6SD) 25.6 6 2.5
Range (years) 17±38
Mean parity 3.8 6 2
Range P1±P6
Mean gestational age (weeks) 7.9 6 2.1
Range 6±12
Religion (Hindus) 48 (96%)
Low socio-economic status 47 (94%)
Previous abortion 20 (40%)
NS = non signi®cant.
illness were excluded. Patients selected for the study were sequentially
allocated to two groups of 50 each. Patients recruited for the study
were told to self-administer 400 mg of misoprostol at 7 a.m. at home on
the day of scheduled surgery. They were to self-administer the drug by
either the oral or sublingual route as advised by the recruiting
investigator on the basis of sequential allocation. Patients were told to
report to the hospital at 9.30 a.m. on the day of surgery. On the day of
surgery, SE was carried out by the operating surgeon, who was
different from the recruiting investigator, on the basis of the time of
arrival of patients at the hospital and not necessarily in the order of
allocation. Therefore, the operating surgeon who was blinded to the
route of misoprostol administration could not predict the route of
administration during surgery.
A total of 128 patients were assessed for eligibility. Of these, 28
patients were excluded from the study as 19 of them did not meet the
inclusion criteria, six refused to participate and three were found to
have high blood pressure.
After taking a thorough history, a complete physical and pelvic
examination was done. Routine investigations including haemoglobin,
urine analysis, blood group and Rhesus antigens were carried out.
Pre-operatively, side effects associated with misoprostol including
pain, nausea, vomiting, diarrhoea, fever, shivering and bleeding per
vaginum were recorded.
Intra-operatively, the amount of cervical dilation before performing
SE was measured using Hegar dilators. The dilators were passed
through the cervix in descending order starting with size 12. The
largest Hegar's dilator passing through the internal os without
resistance was regarded as the dilation achieved. If the cervix had a
dilation which was appropriate or more for that period of gestation, no
further dilation was performed (Singh et al., 1998). In patients with
insuf®cient dilation, a paracervical block was given in order to
facilitate dilation and to reduce pain perception (Stubble®eld, 1998).
SE was done by using the appropriate size of Karman's cannula, which
was followed by curettage. The duration of surgery was measured
from the start of dilation until the end of curettage. Intra-operative
¯uid loss was measured with a graduated cylinder as the volume of
total uterine aspirate, after sieving away the products of conception
(Singh et al., 1998). The appropriate amount of liquor for that period
of gestation was subtracted from the amount measured in order to
calculate the amount of actual blood loss (Singh et al., 1998). Pain
intensity was measured during surgery after completion of curettage
and prior to insertion of an IUCD, tubal ligation or laparoscopic
sterilization. Recordings were made on a 0±10 numeric scale where
the severity at the extreme left of the scale was considered as 0, i.e. no
pain, and that at the extreme right of the scale was considered as
maximum, i.e. 10. To simplify our results, scores between 0 and 3
were considered to be mild pain, 4±6 moderate pain, and 7±10 severe
pain (requiring injectable analgesics) (Acute Pain Management
Guideline Panel, 1992).
78
Vaginal (n = 50) Signi®cance
26.8 6 3.4 NS
18±38
3.5 6 2.0 NS
P1±P6
8.0 6 1.8 NS
6±12
46 (92%) NS
47 (94%) NS
16 (32%) NS
Any cervical or uterine injuries ranging from super®cial cervical
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laceration to an ascending cervical tear, uterine perforation or injury to
any other intra-abdominal organs was noted. All patients underwent
IUCD insertion or laparoscopic sterilization during the same sitting by
choice.
Post-operatively, the incidence of nausea, vomiting, diarrhoea,
fever, shivering and bleeding per vaginum was noted. As a routine, all
patients received analgesics for 2 days and antibiotics for 5 days at
discharge from the hospital.
Follow-up was done twice, ®rst after 7±10 days and subsequently
after 1 month or the ®rst menstrual period. Any unscheduled hospital
visit was noted.
The difference in pre-operative cervical dilation was the main
outcome indicator for the calculation of sample size. Sample size was
estimated using the method described by Meinert (1986), with the
assumption of a error as 0.05 with a power of 0.95. The second
indicator was a 50% difference in successful cervical dilation of at
least 8 mm between the two routes. By this method, the sample size for
each route group should be 27. Assuming a 20% default at follow-up, a
sample size of 50 patients in each group was selected; therefore, the
total sample size was 100.
Statistical analysis was done using the BMDP 7.0 analytical
program (Biomedical Data Processor, Statistical Software, Los
Angeles, CA). The median initial dilation of the case and control
groups was compared using the Mann±Whitney non-parametric test.
The signi®cance of all other parameters was evaluated using the
Student t-test. A P-value of 0.05 was considered as signi®cant.
Results
No signi®cant difference was observed between the two
treatment groups with respect to age, parity, gestational age,
religion, socio-economic pro®le and number of previous
abortions (Table I). Pre-operatively, of the 50 patients who
were given sublingual or oral misoprostol, 20 (40%) versus 18
(36%) had spotting or slight bleeding 1±2 h after ingestion of
misoprostol, and 11 patients (22%) versus 10 (20%) com-
plained of mild spasmodic pain. None of them had heavy
bleeding or passage of the conceptus through the vagina during
the waiting period. No patient reported any nausea, vomiting or
diarrhoea, during the pre-operative period. Three patients (6%)
in the sublingual group compared with two (4%) in the oral
group developed fever, within 2±3 h after administration of
misoprostol.
A single experienced investigator conducted all the cases of
SE. During SE, ®ve (10%) patients in the sublingual group
compared with seven (14%) in the oral group were given a
 Sublingual versus oral misoprostol for cervical ripening

Table II. Intra-operative parameters Table IV. Incidence of post-operative side effects
POG 6±12 weeks Sublingual Oral Signi®cance Post-operative Misoprostol (n = 50) Oral (n = 50)
(n = 50) (n = 50)
Vomiting ± ±
Median ID (mm) 10 6 2.8 8 6 2.3 <0.001 Nausea 1 (2%) 2 (4%)
Range 0±12 0±12 Vaginal bleeding WNL WNL
Mean blood loss (ml) 16 6 6.9 17 6 7.4 0.140 Fever 3 (6%) 2 (4%)
Mean time (min) 4.4 6 1.5 5.2 6 1.8 0.024 Dizziness 1 (2%) 1 (2%)
Diarrhoea ± ±
POG = period of gestation.
ID = initial cervical dilation. WNL = within normal limits.

Table III. Intra-operative pain score Three patients (6%) found the taste of sublingual misoprostol
During surgery Misoprostol Oral Signi®cance unpleasant. Thirty-six patients out of 100 had a history of
previous abortion (using mechanical cervical dilation), and all

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(n = 50) (n = 50)
of them were more satis®ed by this method compared with the
Paracervical block 5 (10%) 7 (14%)
Pain score (mean 6 SD) 2.6 6 1.4 3.5 6 1.1 0.43 previous experience.
Mild 45 (90%) 43 (86%) During follow-up at 7±10 days or after 1 month, none of
Moderate 2 (4%) 3 (6%) these patients had any major complaints and their pelvic
Severe 3 (6%) 4 (8%)
examination revealed no abnormality.

paracervical block for mechanical cervical dilation, as these
patients had a cervical dilation less than that required for that
particular gestational age. The initial cervical dilation of both
groups ranged from 0 to 12 mm (Table II), with the sublingual
group having a signi®cantly higher median (6SD) value than
the oral group (10 6 2.8 versus 8 6 2.3 mm, respectively,
P < 0.001). The volume of blood loss varied from 8 to 31 ml at
different periods of gestation in the sublingual group compared
with 8±33 ml in the oral group (Table II). The duration of
surgery ranged from 2 to 6 min for the sublingual group
compared with 2.5±9 min for the oral group (Table II), with the
sublingual group having a lower overall mean operating time
(P = 0.024). For the operating surgeon, operative ease was
greater in the sublingual group where ®ve patients required
mechanical cervical dilation as compared with seven in the oral
group.
No major complication occurred in either of the two groups.
The majority of patients in both the sublingual and oral
misoprostol groups who already had good cervical dilation felt
mild pain (90% versus 86%) during surgery. The mean pain
score (Table III) of the sublingual group was 2.6 6 1.4,
compared with 3.5 6 1.1 in the oral group (P = NS).
Post-operatively, side effects were noted in both groups.
Their pro®le is depicted in Table IV. The incidence of nausea
was 2% versus 4% in the sublingual compared with the oral
group. Bleeding per vaginum was within normal limits in both
groups. There was no incidence of any episode of diarrhoea or
vomiting noted in any patient during our study. Three (6%)
subjects in the sublingual group compared with two (4%) in the
oral group developed hyperthermia and shivering which was
managed by cold sponging and injectable acetaminophen.
Patient acceptability of sublingual misoprostol as compared
with the oral route was similar in our study (96% versus 98%).
When questioned regarding the route of administration, 98%
patients stated that they would opt for the oral route in
preference to the sublingual route if the option were available.
Discussion
Due to lack of evidence from large randomized studies,
consensus has not been drawn regarding the optimal dose, time
interval and route of administration of misoprostol for pre-
abortion cervical priming. The vaginal route has been found to
be more bene®cial than the oral route (Lawrie et al., 1996;
Zieman et al., 1997; Danielsson et al., 1999) probably due to a
constant absorption leading to an accumulating plasma level
with fewer gastrointestinal side effects. Vaginal absorption of
misoprostol is inconsistent with large individual variations.
Sometimes remnants of tablets can be obtained from the vagina
hours after its administration. Therefore, although used widely,
the vaginal route may not be the ideal route of administration
for clinical practice.
On the other hand, misoprostol is rapidly absorbed through
the vascular buccal mucosa completely within 10±15 min
(Tang et al., 2002b). Recently a few pilot studies have been
performed on the use of sublingual misoprostol for medical
termination of pregnancy (Tang and Ho, 2001; Tang et al.,
2002b) and it has been found to be a very effective and
convenient route of administration.
Only one study conducted so far has evaluated the effect of
sublingual misoprostol for cervical ripening before SE (Saxena
et al., 2003) where it was found to be very e®cacious. Tang
et al. (2002a) have compared the pharmacokinetics of
misoprostol by the sublingual, oral and vaginal route, and the
vaginal route with addition of water. They found that
sublingual misoprostol achieved signi®cantly higher peak
serum concentrations (574.8 6 250.7 pg/ml) than oral
(287.7 6 144.3 pg/ml; P < 0.01) or vaginal (125.2 6 53.8 pg/
ml) routes. The time to peak was similar in both the sublingual
(26.0 6 11.5 min) and oral groups (27.5 6 14.8 min) and was
signi®cantly shorter than that in both vaginal groups. The area
under the misoprostol acid concentration versus time curve up
to 360 min was also signi®cantly higher with the sublingual
route (743.7 6 291.2 pg/h/ml) compared with the oral (402.8 6
151.6 pg/h/ml; P = 0.05) and vaginal (433.7 6 182.6 pg/h/ml)
79
P.Saxena, S.Salhan and N.Sarda
routes. This probably explains the signi®cantly higher cervical
dilation for all periods of gestation in our study.
Oral misoprostol is a safe drug, which is being used for
treatment of peptic ulcers without any serious reported side
effects (Zieman et al., 1997). Misoprostol, a prostaglandin E1
analogue, binds to myometrial cells causing strong myometrial
contractions leading to softening and dilation of the cervix.
This results in separation of the conceptus from the uterine
wall, thereby initiating the abortion process before SE. For
these reasons, ease of dilation improves while operative blood
loss and duration of surgery are reduced.
Out of a total of 50 patients in each group, three (6%) in the
sublingual group and four (8%) in the oral group did not
respond to misoprostol in terms of dilation of the cervix. The
lack of response in 7% of our patients may have been due to the
lack of EP-3/EP-2 prostanoid receptors (Okanlomo and
Ngotho, 1999). These receptors are speci®c for misoprostonic
acid, the diesteri®ed derivative of misoprostol which is the
active metabolite producing a biphasic effect (Okanlomo and
Ngotho, 1999). These receptors are known to increase in
number with increasing gestational age. It is of paramount
importance to explain to these women that pregnancy termin-
ation is mandatory and continuation of pregnancy may be
associated with VIth and VIIth nerve palsies associated with a
limb reduction defect or arthrogyposis congenital multiplex
(Okanlomo and Ngotho, 1999).
In cases of SE, misoprostol is required only for cervical
priming. Long lasting and continuously increasing levels of
misoprostol are not required as they are in cases of medical
abortion. Therefore, a route which provides a faster and a
higher plasma level is preferable. In fact, further studies should
be done to evaluate whether dose and time interval of
sublingual misoprostol can be reduced further without
compromising its ef®cacy.
In conclusion, the sublingual route of misoprostol is
preferable because of a high systemic concentration due to
avoidance of ®rst pass-metabolism in the liver, resulting in
many bene®cial effects as discussed above. At the same time,
the unwanted gastrointestinal side effects are reduced to some
80
extent compared with oral administration (El-Rafaey and
Templeton, 1994).
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Submitted on May 28, 2003; resubmitted on August 19, 2003; accepted on
September 17, 2003