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J Gynecol Obstet Hum Reprod xxx (2017) xxx–xxx

Available online at

ScienceDirect
www.sciencedirect.com

Original Article

Evaluation of effect of letrozole prior to misoprostol in comparison

with misoprostol alone in success rate of induced abortion
T. Behroozi-Lak a,*, S. Derakhshan-Aydenloo b, F. Broomand a
a
Reproductive Health Research Center, Department of Infertility, Urmia University of Medical Sciences, Urmia, Iran
b
Urmia University of Medical Sciences, Urmia, Iran

A R T I C L E I N F O A B S T R A C T

Article history: Background. – Abortion, spontaneous or induced, is a common complication of pregnancy and
Received 30 July 2017 exploration of available and safe regimens for medical abortion in developing countries seems crucial.
Received in revised form 27 October 2017 Aims. – The present study was aimed to assess the effect of letrozole in combination with misoprostol in
Accepted 2 November 2017
women eligible for legal therapeutic abortion with gestational age  14weeks.
Available online xxx
Materials and methods. – This clinical randomized trial was conducted on 78 women who were
candidate of medical abortion and eligible for legal abortion with gestational age  14 weeks that were
Keywords:
randomly divided into two groups of case and controls. Case group received daily oral dose of 10 mg
Letrozole
Misoprostol
letrozole for three days followed by vaginal misoprostol. In control group the patients received only
Abortion vaginal misoprostol. The rate of complete abortion, induction-of-abortion time, and side-effects were
assessed.
Results. – Complete abortion was observed in 30 patients (76.9%) in case group and 9 (23.1%) cases were
failed. In control group there was 16 (41.03%) complete abortions and 23 (58.97%) cases were failed to
abort. Patients with gestational age of between 6 and 10 weeks did not show significant difference in
both groups (P = 0.134). Regarding pregnancy remnants there were significant differences between two
groups (P = 0.034). The time form admission to discharge in case groups were significantly shorter than
those in control group (P = 0.001). The indication for curettage in case group was significantly less
than control group (P = 0.001).
Conclusion. – A 3-day course of letrozole (10 mg/daily) followed by misoprostol was associated with a
higher complete abortion and lower curettage rates and reduction in time from admission to discharge in
women with gestational age  14 weeks compared to misoprostol alone.
C 2017 Elsevier Masson SAS. All rights reserved.

Introduction observation [4]. The safety of the procedure has a dramatic

Abortion, spontaneous or induced, is a common complication of
pregnancy. The World Health Organization reported that annually
about 79 million unintended pregnancies excluding miscarriages
are occurring worldwide [1]. And annually, about 46 million
induced abortions occur in the world [2,3]. The estimation of the
total number of abortions is quite difficult, especially in developing
countries, and it is usually underreported due to the legal
restrictions a huge number of the inducted abortions are
performed in non-hygienic situations. The abortion might load
an undesirable cost to the families and health care system. Serious
complications such as maternal death, uterine rupture, and sepsis
may occur after abortions that are not taken place under medical
* Corresponding author.
E-mail address: t.behrooz2@yahoo.com (T. Behroozi-Lak).
importance in order to achieve a non-life threatening result.
Induced abortion can be performed by medical and surgical
methods. Medical abortion is the induction of early abortion by
consumption of special of medications and is named successful if it
is completed without the need of any surgical intervention. Also,
the medical approach is a safe and effective alternative to surgical
methods with a high level of patient satisfaction [5,6].
Prostaglandins and their analogs are widely used for medical
induced abortion. Misoprostol, a prostaglandin E1 analog, is used
widely for early abortion and has been shown to be a better
alternative to other prostaglandin substances due to feasibility,
simple and easy administration, low price, stability at room
temperature, and fewer systemic side-effects [7,8]. Sublingual and
vaginal are two common routes of misoprostol administration
with different pharmacokinetics and effectiveness. Sublingual
misoprostol reaches its peak concentration in a short time and
vaginal route has less adverse effects after administration [9]. The

https://doi.org/10.1016/j.jogoh.2017.11.002
2468-7847/ C 2017 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Behroozi-Lak T, et al. Evaluation of effect of letrozole prior to misoprostol in comparison with
misoprostol alone in success rate of induced abortion. J Gynecol Obstet Hum Reprod (2017), https://doi.org/10.1016/
j.jogoh.2017.11.002
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2 T. Behroozi-Lak et al. / J Gynecol Obstet Hum Reprod xxx (2017) xxx–xxx
range of reported successes rate of abortion induction with
misoprostol is quite different in several studies (between 37% and
86%) depending on the regimen, route of administration, and
dosage used. However, in combination with other drugs was more
effective [10–12]. Letrozole, aromatase inhibitors, in combined
with vaginal misoprostol shown that was more effective than
misoprostol alone with lower, but not significant induction-of-
abortion time in termination of pregnancy [13]. Letrozole is a third
generation aromatase inhibitor and its action is suppressing
estrogen production [14,15].
Misoprostol is a synthetic prostaglandin E1 analogue, manu-
factured as an oral preparation available as 200 mg tablets used to
prevent and treat gastroduodenal damage induced by nonsteroidal
anti-inflammatory drugs [16]. The most common adverse effects of
misoprostol are nausea, vomiting, diarrhea, abdominal pain, chills,
shivering, and fever, all of which are dose-dependent [17]. Miso-
prostol taken by pregnant women increases uterine tone and
contractions.
The success rate of abortion of mifepristone in combination
with misoprostol is significant, however, this medication is not
available in our country. Therefore, we decided to study effect of
letrozole prior to misoprostol in success rate of induced abortion.
In this study patients with missed abortion were included and
patients with failure pregnancy and incomplete abortion were not
included.
The aim of this study was to evaluate effect of letrozole prior to
misoprostol in comparison with misoprostol alone in success rate
of induced abortion in women with gestational age of  14 weeks.
Patients and methods
This clinical randomized trial study was conducted on
78 women who were candidate of medical abortion and eligible
for legal abortion with gestational age  14 weeks, attending
Motahari Hospital in Urmia, Iran.
The inclusion criteria were: good general health; older than the
age of legal consent (ie, older than 18 years); the gestational age
 14 weeks as confirmed by ultrasound scanning on day 1 of the
study, hemoglobin  10 g/L and diastolic pressure < 95 mmHg.
The exclusion criteria were: history or evidence of adrenal
pathology, steroid-dependent, cancer, porphyria, diastolic pres-
sure over 95 mmHg, bronchial asthma, arterial hypertension,
history or evidence of thromboembolism, severe or recurrent liver
disease, breast feeding, anomaly of fetus, regular use of prescrip-
tion drugs before admission to the study, any abnormal values in
pretreatment blood tests, namely complete blood picture, renal
and liver function tests. Individuals who fulfilled the selection
criteria and death of the fetus was confirmed by two separate
ultra-sonographies and were willing to participate gave their
informed written consent.
The study was approved by the Institutional Ethical Committee
of the Urmia University of Medical Sciences, Urmia, Iran. The study
was registered with the trial number IR.UMSU.REC.1395.436
The participants were randomized into the two groups of
39 patients each by the hospital pharmacists according to
computer-generated random numbers. Until the completion of
the study, both patients and the clinicians were blinded to the
group assigned.
Ultrasound examination was performed on eligible women to
confirm intrauterine pregnancy and the gestational age. After a
detailed history and a full body examination, complete blood
count, renal, and liver function were checked.
Women in case group were given 10 mg letrozole orally on days
1–3 followed by vaginal misoprostol each 12 hrs for 3 times. In
control group, the patients were received only vaginal misoprostol
Please cite this article in press as: Behroozi-Lak T, et al. Evaluation of effect of letrozole prior to misoprostol in comparison with
misoprostol alone in success rate of induced abortion. J Gynecol Obstet Hum Reprod (2017), https://doi.org/10.1016/
j.jogoh.2017.11.002
with the same method. The initial dose of misoprostol was 800 mg
per 12 h and transvaginally.
Until abortion was occurred within 3-dose misoprostol
administration, the regimen was continued. Where abortion was
not occurred 48 hours after termination of regimen or pregnancy
remnant after abortion was more than 15 mL, or hemorrhage was a
lot, the patient was undergone curettage. In cases with pregnancy
remnant less than 15 mL, the patients with the same remnants
were discharged and then these patients were followed by
ultrasonography after 1 week. If pregnancy remnant persisted in
control ultrasonography, the curettage was performed. Indications
for hospitalization of the patients were severe hemorrhage, pain,
anxiety of abortion within 3-day letrozole therapy and no abortion
with only letrozole (for vaginal misoprostol use).
In both group frequency of complete abortion, interval form
induction to complete exit of pregnancy products, frequency of
need for curettage, consumed misoprostol and side effects (nausea,
vomiting, diarrhea, fatigue, dizziness, headache, lower abdominal
pain, fever, rash, and chills or shivering) were assessed.
In case group patients, in each step of letrozole or misoprostol
administration, the administration of the medicine was stopped if
the abortion was achieved. In other patients the administration
was continued until achievement of abortion based on the study
design. Therefore, the total administration of letrozole and
misoprostol was not the same in patients.
The clinical criteria of successful abortion included lack of
severe hemorrhage and hemodynamic stability of patients after
abortion that avoided curettage. The sonographic criteria of
successful abortion included no pregnancy remnant or remnants
less than 15 mL in transvaginal ultrasonography, provided that the
remnants were cleared in one week follow up.
Statistical analysis
The sample size was calculated as 78 subjects using the
comparison of proportion formula with two-sided log-rank test,
a = 0.05, and 84% of power. All statistical analyses were done using
SPSS version 20 (SPSS Inc, Chicago, IL, USA). Descriptive data are
reported as mean  standard deviation, or number (percent) as
appropriate. Independent sample t-test, Chi-square test, and Kaplan-
Meier were used for data analysis. The level of significance is
considered to be P < 0.05.
Results
In the present study 78 patients were randomized into two
groups of 39 patients each. In control group only vaginal
misoprostol and in case group letrozole and vaginal misoprostol
were assessed. The demographic data are shown in Table 1. There
were no significant differences in age, gravidity, parity, history of
miscarriages, natural delivery and C-section and history of
abortion (P > 0.05). Despite randomized sampling, mean values
for gestational age based on ultrasonography was significantly
different between two groups (P < 0.05).
Complete abortion was observed in 30 patients (76.9%) in case
group and 9 (23.1%) cases were failed. In control group there was
16 (41.03%) complete abortions and 23 (58.97%) cases were failed
to abort. The successful rate of abortion was completely different in
case group compared to control group (P = 0.001). In case group
58.97% of the patients received only letrozole and 41.03% of the
patients received letrozole and misoprostol. In case group 1 (2.6%),
2 (5.1%), 2 (5.1%), 1 (2.6%) and 33 (84/6%) patients received 15, 20,
22.5, 25 and 30 mg letrozole, respectively.
Regarding the administered misoprostol doses, in case group 8
(50%), 1 (6.2%) and 7 (43.8%) patients received 800, 1600 and
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T. Behroozi-Lak et al. / J Gynecol Obstet Hum Reprod xxx (2017) xxx–xxx 3

Table 1
Comparison of demographic data of the patients in both groups.

Group Case Control P-value

Max. Min. Mean SD Max. Min. Mean SD

Age 44 year 19 year 29.56 year 6.09 year 44 year 19 year 28.31 year 0.381
Gravidity 7 1 2.46 1.48 6 1 2.46 1.21 0.638
Parity 6 1.03 6 1.03 1.16 0.932
Gestational age 13 week 5 week 7 week + 6 day + 2 week +1 day 14 week + 2 day 5 week 9 week + 1 day + 2 week + 3day 0.008
(ultrasonography)
Abortion number 6 0 3 0 0.371

2400 mg misoprostol, respectively. In control group 12 (30.8%), 6 curettage, therefore, there was significant difference between two
(15,4%) and 21 (53.8%0 of patients received 800, 1600 and 2400 mg groups (P = 0.012). The time form admission to discharge in case
misoprostol, respectively. Therefore, there were no significant groups were significantly shorter than those in control group
differences between two groups in dose of misoprostol consump- (P = 0.000) (Table 3).
tion (P = 0.346). The most common side effects in both groups was abdominal
The induction-to-abortion time following misoprostol admin- pain. The incidence of side effects was comparable for the two
istration in both case and controls are shown in Table 2. The groups also the severity of side-effects was not significantly
indication for curettage case group was significantly lower than different between groups (P > 0.05). In case and control groups
control group (P = 0.001) (Table 3). In case group, two (22.2%), four 11 and 4 women with gestational age of less than six weeks,
(44.4%) and three (33.3%) of patients were undergone curettage respectively, showed successful abortion. In case group 16 (69.6%)
because of failed abortion, severe hemorrhage and pregnancy and 7 (30.4%) patients with gestational age of between 6 and
remnant > 15 mL, respectively. In control group, 4 (17.4%), 10 10 weeks showed complete and failed abortions, respectively. In
(43.5%) and 9 (39.1%) of patients were also undergone curettage control group, 11 (47.8%) and 12 (52.2%) patients with gestational
because of failed abortion, severe hemorrhage and pregnancy age of between 6 and 10 weeks showed complete and failed
remnant, respectively. There were no significant differences abortions, respectively. Patients with gestational age of between
between two groups in terms of reason for curettage (P = 0.932). 6 and 10 weeks did not show significant difference in both groups
Regarding pregnancy, remnants there were significant diffe- (P = 0.134). In case group, 3 (60%) and 2 (40%) patients with
rences between two groups (P = 0.034) (Table 3). gestational age of more than 10 weeks showed complete and failed
In case group, three patients were ultrasonographically abortions, respectively. In control group, 1 (8.3%) and 11 (91.7%)
confirmed to undergo curettage and 30 (90.9%) of patients did patients with gestational age of more than 10 weeks showed
not need curettage. In control group 9 (36%) patients were complete and failed abortions, respectively and a significant
undergone curettage and 16 (64%) of patients did not need difference was observed between two groups (P = 0.022). Table 4
shows frequency of complete expulsion and no expulsion of fetus,
Table 2 and severe vaginal hemorrhage with letrozole alone and letrozole
The interval from misoprostol administration to abortion in hour. with misoprostol in both groups.
The interval from administration to abortion (hr) Total It should be noted that since half the patients showed successful
abortion with letrozole only, the misoprostol administration was
< 12 12–24 24–36 36–48 48–60 60–72 < 72
not performed for them in case group.
Group
Case
Number 8 1 1 1 2 1 0 14
Percent 57.1 7.1 7.1 7.1 14.3 7.1 0 100 Discussion
Control
Number 9 8 11 3 3 0 1 35 The present study is aimed to assess letrozole as a synergistic
Percent 25.7 22.9 31.4 8.6 8.6 0 2.9 100
agent in combination with misoprostol compared with misopros-
tol alone for medical abortion. Our results demonstrated an earlier
complete abortion rate of 57.1% in women requesting medical

Table 3
Frequency of curettage in both groups, frequency of pregnancy remnants in both
Table 4
groups following administration of misoprostol, The interval of hospitalization of
Frequency of abortion, no abortion and severe vaginal hemorrhage in two groups.
patients in both groups.
Group Status Type of effect Number (%)
Groups Case Control P-value
Case Abortion with letrozole Complete abortion 15 (38.46)
Numbers Percent Numbers Percent
Remnants < 15 CC 5 (12.82)
Curettage Remnants  15 CC 0 (0)
Yes 9 23.1 23 59.0 0.001 Abortion with letrozole and Complete abortion 5 (12.82)
No 30 76.9 16 41.0 misoprostol
Total 39 100.0 39 100.0 Remnants < 15 CC 6 (15.38)
Pregnancy remnants 15 CC  remnants 2 (5.13)
< 15 CC 11 84.6 8 47.1 0.034 No abortion 2 (5.13)
> 15 CC 2 15.4 9 52.9 Severe vaginal hemorrhage 4 (10.26)
Total 13 100.0 17 100.0 Control Abortion with misoprostol Complete abortion 8 (20.51)
The interval of hospitalization Remnants < 15 CC 8 (20.51)
< 3 days 12 50.0 5 12.8 0.001 15 CC  remnants 9 (23.08)
3–6 days 12 50.0 34 87.2 No abortion 4 (10.26)
Total 24 100.0 39 100.0 Severe vaginal hemorrhage 10 (25.64)

Please cite this article in press as: Behroozi-Lak T, et al. Evaluation of effect of letrozole prior to misoprostol in comparison with
misoprostol alone in success rate of induced abortion. J Gynecol Obstet Hum Reprod (2017), https://doi.org/10.1016/
j.jogoh.2017.11.002
G Model
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4 T. Behroozi-Lak et al. / J Gynecol Obstet Hum Reprod xxx (2017) xxx–xxx
abortion with the regimen of letrozole and misoprostol compared
to 25.7% in women with the regimen of misoprostol alone.
Others reported 56.3% of complete abortion after first
administration of 800 mg of misoprostol vaginally, and 92.4%
after administration of the second dose (1600 mg) [18]. About
82.9% of complete abortion within 24 h after vaginal administra-
tion of misoprostol (800 mcg) has been reported [19]. Also, the rate
of complete abortion between 68% and 81% has been reported by
others using misoprostol alone [20–23]. The rate of complete
abortion in the present study was 76.9% in women who received
letrozole and misoprostol alone, which was higher than other
reports. The variations between findings may explain by different
doses and gestational age in studied women.
The use of letrozole in combination with vaginal misoprostol
has been assessed by others and different results have been
reported. In one study following administration of letrozole (10 mg
for three days) in combination with a single dose of vaginal
misoprostol (800 mg), complete abortion rate was observed in
86.9% in pregnancies up to week 7 of gestation [24]. Others
reported that in a 7-day course of letrozole followed by vaginal
misoprostol a complete abortion rate about of 95% was observed
[25]. The regimen of vaginal misoprostol (800 mg) following
pretreatment with mifepristone (200 mg) and three days of
letrozole (10 mg/daily) with complete abortion rate of 98% has
also been reported [26].
In the present study there was no serious adverse event
following administration of letrozole.
The results of the present study demonstrated that complete
abortion rate was 76.9% with misoprostol after pretreatment with
three days of letrozole (10 mg) which was consistent with other
studies [24–27].
These variations may be explained by differences in gestational
age in studied women, duration of letrozole, and different doses of
administration. However, like previous studies letrozole in
combination with misoprostol was more effective than misopros-
tol alone.
The regimen used in the present study was well tolerated with
no major adverse events or specific side-effects and the compara-
ble to those in other group. Our study was in agreement with other
studies that showed similar side-effects between letrozole and
vaginal routes of misoprostol [28–31]. The differences between
findings can be a reason to perform more randomized trial for use
of the regimen with letrozole and misoprostol.
In our study, induction-to-abortion time in case group was
significantly shorter than the control group. In other study, the
median of 9.7 h in letrozole group compared to 10.9 in the control
group has been reported [29]. Other study reported a lower median
of induction-to-abortion in letrozole group compared to control
group. Other reports showed the median of 5.1 h, 7.5 h, 8.2 h, and
8.7 h, after combination of letrozole misoprostol administration
[24–26,31].
It should be taken into consideration that decision for
curettage in order to achieve abortion, is dependent on rate of
hemorrhage, clinical conditions and surgeon’s preferences. No
specific volume is reported for the remnants, therefore, we decided
to consider 15 mL or more in our study design as a limit for
performing curettage.
Conclusion
Our results showed that a 3-day course of letrozole
(10 mg/daily) followed by misoprostol was associated with a
higher complete abortion and lower curettage rates and reduction
in time from admission to discharge in women with gestational age
 14 weeks compared to misoprostol alone. However, further
Please cite this article in press as: Behroozi-Lak T, et al. Evaluation of effect of letrozole prior to misoprostol in comparison with
misoprostol alone in success rate of induced abortion. J Gynecol Obstet Hum Reprod (2017), https://doi.org/10.1016/
j.jogoh.2017.11.002
studies using different doses and longer duration may be
warranted.
Disclosure of interest
The authors declare that they have no competing interest.
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Please cite this article in press as: Behroozi-Lak T, et al. Evaluation of effect of letrozole prior to misoprostol in comparison with
misoprostol alone in success rate of induced abortion. J Gynecol Obstet Hum Reprod (2017), https://doi.org/10.1016/
j.jogoh.2017.11.002