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Received: 6 December 2019    Revised: 28 May 2020    Accepted: 20 July 2020

DOI: 10.1002/ijgo.13326

CLINICAL ARTICLE
Obstetrics

Effect of misoprostol with and without letrozole on the

induction of abortion for women with first‐trimester missed
abortion

Zahra Allameh1 | Maryam Goharian1 | Mohammad Eslamian2,*

1
Department of Obstetrics &
Gynecology, School of Medicine, Isfahan
University of Medical Sciences, Isfahan, Iran
2
Department of Surgery, School of
Medicine, Isfahan University of Medical
Sciences, Isfahan, Iran
*Correspondence
Mohammad Eslamian, Department of
Surgery, School of Medicine, Isfahan
University of Medical Sciences, Isfahan, Iran.
Email: mr.esl67@gmail.com
Funding Information
Isfahan University of Medical Sciences
Abstract
Objective: To determine whether addition of letrozole to a misoprostol‐based abortion
regimen can increase the rate of complete abortion.
Methods: The randomized, placebo‐controlled, double‐blind trial enrolled women with
missed abortion in the first trimester of pregnancy attending Sadooghi Hospital, Isfahan,
Iran, from 2016 to 2018. The women were randomly assigned to the study group, which
received 10 mg of letrozole daily for 3 days, followed by two doses of 800 μg of vagi‐
nal misoprostol at a 4‐hour interval, or the control group, which received a placebo,
followed by the same dose of misoprostol. Sonography was performed to check the
abortion status.
Results: In total, 120 women completed the study: 60 in the misoprostol plus letrozole
group, and 60 in the misoprostol only group. Complete abortion was documented for
93 (77.5%) women: 48 (80.0%) in the misoprostol plus letrozole group and 45 (75.0%) in
the misoprostol only group (P=0.80). The mean duration of induction in the misoprostol
plus letrozole and misoprostol only groups was 7.35 ± 3.54 hours and 8.2 ± 3.84 hours,
respectively (P=0.21).
Conclusion: Administration of misoprostol alone was found to be as effective as the
administration of misoprostol plus letrozole for first‐trimester missed abortion.

KEYWORDS
Letrozole; Medical abortion; Misoprostol; Missed abortion; Pregnancy

1 |  INTRODUCTION various prostaglandins, prostaglandin E1 (misoprostol) has received

Abortion is one of the most common complications of pregnancy. One
type of abortion, missed abortion, occurs in 15%–20% of clinically
diagnosed pregnancies and is the retention of pregnancy products in
1,2
the uterus for several days or weeks after death of the fetus.
Various medical and surgical methods have been used to manage
missed abortions. Surgical methods include dilatation and curettage,
and vacuum aspiration. Because these methods are expensive and
involve anesthesia, however, medical methods are generally preferred
over surgical methods for abortion.3 Medical approaches include pros‐
taglandins, both alone and in combination with other drugs.3–6 Among
marked attention because of its high safety and the possibility of out‐
patient use.7 Misoprostol is widely used for induction of delivery in
the second trimester, as well as curettage, therapeutic abortion, and
hemorrhagic treatment after term delivery.8
To increase the efficacy of treatment, some studies have tested a
combination of two medications such as mifepristone and misopros‐
tol, although this approach may be limited because of a lack of mifepri‐
stone.9 Other drugs that have been used for abortion in combination
with misoprostol are aromatase inhibitors. Aromatase converts andro‐
gens to estrogen,10 which is necessary for the continuation of preg‐
nancy. The aromatase inhibitor letrozole reversibly and competitively

Int J Gynecol Obstet 2020; 1–5 © 2020 International Federation of |  1

wileyonlinelibrary.com/journal/ijgo  
Gynecology and Obstetrics
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2       Allameh ET AL.
binds to iron in the P450 cytochrome and prevents estrogen produc‐
11
tion by aromatase.
Most studies have examined the effect of letrozole plus misopros‐
tol on the abortion of live embryos.12,13 Given the significance of spec‐
ifying an effective and safe method for termination of abortion and the
specific features of letrozole, such as its safety, cost‐effectiveness, and
availability, the aim of the present study was to examine the effect of
letrozole as premedication on the induction of abortion among women
with missed abortion in the first trimester of pregnancy.
2 |  MATERIALS AND METHODS
The present randomized, placebo‐controlled, double‐blind trial was
conducted among women who were referred to Sadooghi Hospital,
Isfahan, Iran, with missed abortion between January 1, 2016, and
December 31, 2018. The Ethics Committee of Isfahan University
of Medical Sciences approved the study (IR.MUI.REC.1392.3.243).
Informed consent was obtained from all women prior to enrollment.
The inclusion criteria were age older than 18 years, first‐trimes‐
ter pregnancy (gestational age >12 weeks) with missed abortion con‐
firmed by ultrasonography and hemoglobin level higher than 12 mg/
dL. The exclusion criteria were abnormalities in blood tests, including
complete blood count (CBC), prothrombin time (PT), partial thrombo‐
plastin time (PTT), international normalized ratio (INR), and fibrino‐
gen; history or clinical evidence of any thromboembolic impairment
or deep venous thrombosis; having an intrauterine device; current
or previous use of corticosteroids; history of any malignancy; exist‐
ing cardiovascular disease contraindicating misoprostol or letrozole;
and scars on uterus. In addition, women with drug sensitivity leading
to drug discontinuation, non‐referral for evaluation of complications
and consequences of abortion, abnormal vital signs, uncontrolled or
severe vaginal bleeding at follow‐up, and those who adopted other
treatments were excluded from the analysis.
Using a sample size estimation formula to make comparisons
between two ratios (incidence of complete abortion in the two
groups), the sample size required for the study was estimated to
be 63 women per group considering a confidence level of 95% and
a power of 80%. The women enrolled in the study were randomly
allocated to the two study groups by using Random‐Maker Software
Random Allocation.14
The medical history was obtained for all participants and the fol‐
lowing examinations were performed: complete blood count, blood
group, rhesus blood type, prothrombin time, partial thromboplastin,
international normalized ratio, and fibrinogen tests; and sonography
to confirm the missed abortion.
Starting on day 1 of treatment, women in the control group
received 500  mg of calcium carbonate (Razavi Pharmaceutical
Service Institute, Mashhad, Iran) daily for three consecutive days as
a placebo, followed by two doses of 800  µg of vaginal misoprostol
(four 200‐μg tablets, Sami Saz, Mashhad, Iran) spaced 4 hours apart.
Women in the study group received 10 mg of letrozole (four 2.5‐mg
tablets, Tehran Chemie, Tehran, Iran) daily for three consecutive
days, followed by two doses of 800 μg of vaginal misoprostol spaced
4 hours apart. All women also received 100 mg of doxycycline every
12 hours for 1 week.
In both groups, women with a gestation of less than 9  weeks
received outpatient treatment, and those with a gestation of more
than 9 weeks were treated in hospital. Inpatients were monitored after
misoprostol administration and their vital signs were checked every
4 hours. The women were discharged after 24 hours if there were no
problems such as vaginal bleeding or severe abdominal pain.
All women were advised to take acetaminophen tablets in case
of fever and chills, and one tablet of loperamide if diarrhea occurred.
Ondansetron was also suggested in the event of nausea and vomiting.
The women were advised to refer to the primary hospital in the case
of severe vaginal bleeding (more than two pad changes within 1 hour),
a fever of 39  °C or higher for more than 24  hours, severe abdom‐
inal pain, vomiting and diarrhea more than three times in 24  hours,
or development of a rash. If the women was rhesus‐negative and her
indirect Coombs test was negative, RhoGAM was administered within
72 hours of the onset of bleeding.
On day 7, sonography was performed to check the abortion status.
If the sonographer reported the total discharge of pregnancy prod‐
ucts from the uterus, complete success and efficacy of the drug were
recorded. In the case of partial discharge or non‐discharge of retained
pregnancy products, partial success or drug failure, respectively,
was recorded. In the case of partial or non‐discharge of the retained
products, if there was no severe bleeding and the woman desired to
continue medical treatment, vaginal misoprostol was administered
once more. The woman was re‐examined and underwent sonography
20  days later, and then underwent curettage if pregnancy products
were still retained.
The study data were analyzed by using SPSS version 25 (IBM,
Armonk, NY, USA). Basic descriptive statistics were calculated for
CONSORT 2010 Flow Diagram
Enrollment
Assessed for eligibility (n=170)
Excluded (n=44)
Not meeting inclusion criteria (n=18)
Declined to participate (n=22)
Other reasons (n=4)
Randomized (n=126)
Allocation
Allocated to intervention (n=63) Allocated to Control (n=63)
Lost to follow-up (give reasons) (n=1) Lost to follow-up (give reasons) (n=2)
Follow-Up
Discontinued intervention (give reasons) (n=2) Discontinued intervention (give reasons) (n=1)
Analyzed (n=30)
Analysis Analyzed (n=30)
F I G U R E 1   Flow diagram showing recruitment and analysis of the
study women
Allameh ET AL. |
      3

demographic data. The normality of continuous measures was assessed

by using Kolmogorov‐Smirnov test. To compare differences between
the misoprostol plus letrozole and misoprostol groups, Pearson χ2 test
was used for categoric variables and independent two‐tailed t test was
used for continuous variables. A P value of 0.05 or less was considered
statistically significant.

3 | RESULTS

During the study period, 126 women were enrolled and randomized to
receive misoprostol plus letrozole (n=63) or misoprostol only (n=63).
Subsequently, 3 women in each group were lost to follow‐up and
were excluded from the analysis. Ultimately, 120 pregnant women, 60
in the misoprostol only group and 60 in the misoprostol plus letrozole
group, were included in the study (Fig. 1).
Clinical and demographic characteristics, including age, gestational F I G U R E 2   Comparison of the percentage of complete and
incomplete abortion between the two study groups based on χ2 test
age, type of delivery, gravidity, and history of abortion, were approx‐
imately similar in the two groups (all P>0.05) (Table 1). Regarding the
treatment results, complete abortion was reported for 93 (77.5%)
women: 48 (80.0%) and 45 (75.0%) women in the misoprostol 4 | DISCUSSION
plus letrozole and misoprostol only group, respectively (P=0.80).
Correspondingly, the number of incomplete abortions was 27 (22.5%), The present study evaluated the efficacy of misoprostol plus letrozole
of which 12 (20%) and 15 (25%) were in the misoprostol plus letrozole versus misoprostol plus placebo for women with first‐trimester missed
and misoprostol only group, respectively (P=0.65) (Fig. 2). abortion, finding that the rate of complete abortion in the two groups
The mean induction duration in the misoprostol plus letrozole and was 80.0% and 75.0%, respectively. Although clinically the rate of
misoprostol only groups was 7.35 ± 3.54 hours and 8.2 ± 3.84 hours, complete abortion in the misoprostol plus letrozole group was higher
respectively. The difference was not statistically significant (P=0.21) than that in the misprostol only group, the difference was not statis‐
(Fig. 3). The incidence of complications including nausea, vomiting, tically significant. The duration of induction was also shorter in the
diarrhea, fever, and chills was similar in the two groups (all P<0.05) misoprostol plus letrozole group as compared with the misoprostol
(Table 2). group; again, however, the difference was not statistically significant.

T A B L E 1   Clinical characteristics of the study women by group.

Characteristics Misoprostol alone (n=60) Misoprostol + letrozole (n=60) P value

Gestational age, wk 7.92 ± 1.74 (6–12) 8.01 ± 1.54 (5–11) 0.75

Maternal age, y 30.33 ± 4.1 (22–38) 30.46 ± 4.25 (22–41) 0.86
Type of delivery 0.38
None 13 (21.7) 15 (25.0)
Vaginal 33 (55.0) 25 (41.7)
Cesarean 12 (20.0%) 15 (25.0)
Both 2 (3.3) 5 (8.3)
Gravidity 0.66
1 12 (20) 13 (21.7)
2 26 (43.3) 28 (46.7)
3 17 (28.3) 16 (26.7)
4 5 (8.3) 2 (3.3)
Previous abortion >0.99
No 52 (86.7) 52 (86.7)
Yes 8 (13.4) 8 (13.4)
a
Values are given as mean ± SD (range) or number (percentage).
 |
4       Allameh ET AL.

using 7.5 mg of letrozole daily for 3 days followed by 800 μg of vag‐

inal misoprostol. They reported rates of complete abortion of 80%
and 51.8%, respectively, and an induction duration of 6.1 ± 1.6 and
9.4  ±  2.2  hours, respectively (P<0.05). Another study reported that
the rate of complete abortion was 93.7% in the group taking 10 mg of
letrozole daily for 3 days followed by 600 μg of oral misoprostol and
68.7% in the misoprostol only group.22
In a study addressing pregnancy loss before 9 weeks of gestation,
Rezai et al.11 found that the rate of complete abortion after 10 mg of
letrozole daily for 3  days followed by 800  μg of vaginal misoprostol
was 84.1%, whereas that in the misoprostol only group was 78.5%
(P>0.05). Those findings were not statistically significant and in line
with the present observations. Abbasalizadeh et al.23 found that pre‐
treatment with letrozole and misoprostol for first‐trimester medical
abortion increased the rate of complete abortion significantly without
increasing adverse effects as compared with misoprostol alone.
F I G U R E 3   Comparison of the mean duration of induction The observed differences between the findings of the present
between the two study groups
study and the findings of the above studies can be attributed to differ‐
ences in treatment regimen, gestational age, race, genetics, and drug
structure in the various studies. The administration procedure of miso‐
Previous studies have reported different results after the vagi‐ prostol (i.e., vaginal vs sublingual or oral) may also explain differences
nal administration of misoprostol alone or in combination with other between the present results and those of other studies.
drugs. In one study, for example, a rate of 56.3% of complete abortion The complications observed in the present study were similar to
was reported after a first vaginal administration of 800  μg of miso‐ those reported in other studies. Furthermore, there were no signifi‐
prostol, and 92.4% after a second dose (1600  μg).15 Another study cant differences in complications such as diarrhea, vomiting, nausea,
reported a rate of 82.9% of complete abortion within 24 hours of the fever, or chills between the two groups. Nausea was the most common
vaginal administration of 800  μg of misoprostol. In other studies, a complication in both groups, and diarrhea and chills were the least.
rate of complete abortion of between 68% and 81% was reported for A limitation of the present study was the lack of evaluation of the
misoprostol alone.16–18 volume and severity of bleeding, which is one of the most important
Torky et al.19 reported a rate of complete abortion of 78% after the complications that can affect chills and lower blood pressure and other
administration of 10 mg of letrozole twice daily for 3 days followed by complications. Haj Seyed Javadi et al.22 evaluated the induction of
800 μg of vaginal misoprostol, as compared with a rate of 39% after abortion in the first trimester by misoprostol or misoprostol with letro‐
the administration of misoprostol alone (P<0.05). In a study of 46 zole. They reported a complete abortion rate of 69.7% and 30.3%, and
women with a gestation of less than 20 weeks, Javanmanesh et al.20 an incomplete abortion rate of 32.4% and 67.6%, respectively, in the
found that 3 days of administration of 10 mg of letrozole followed by misoprostol with letrozole and misoprostol groups, respectively. There
oral misoprostol led to a significantly higher rate of complete abor‐ were no differences between the two groups in bleeding, cervix os
tion as compared with misoprostol plus placebo. Similarly, Naghshine opening time, or time to complete abortion from drug induction and
et al.12 reported that a 3‐day course of letrozole (10 mg/daily) followed no medical complications.
by sublingual misoprostol was associated with a higher rate of com‐ Another limitation is that serum calcium levels were not checked
plete abortion (76.6%) versus misoprostol plus placebo (42.6%) among before the prescription of calcium carbonate as a placebo. Calcium
women with a gestation less than 17 weeks. carbonate affects uterine muscle contraction and might have syn‐
Elberg and Essadi21 also compared the effect of letrozole plus ergist effects with misoprostol. The restriction of missed abortions
misoprostol and misoprostol alone on first‐trimester missed abortion, to a gestational age of less than 12  weeks was another limitation.
Different outcomes might be reported in future studies by increasing
T A B L E 2   Complications among the study women by group. the gestational age.
Overall, the systemic biologic capability of misoprostol as a pros‐
Misoprostol alone Misoprostol + letro‐ P
Variables group (n=60) zole group (n=60) value taglandin‐1 synthetic analog has a marked effect on its vaginal use.24
Because of its low cost and minor adverse effects, misoprostol has
Nausea 45 (75.0) 42 (70.0) 0.54
been identified as a suitable alternative to dilatation and curettage
Vomiting 16 (26.7) 13 (21.7) 0.52
and avoids the risks of surgery and anesthesia.25 As a third‐gener‐
Diarrhea 9 (15.0) 9 (15.0) >0.99
ation aromatase inhibitor and also non‐steroidal inhibitor, letrozole
Fever 10 (16.7) 13 (21.7) 0.49
also has benefits including potent reversible and anti‐estrogenic
Chills 7 (11.7) 9 (15.0) 0.59
effects that prevent morphologic interference of the endometrium
Allameh ET AL.
and cervical mucosa.26 In addition, aromatase inhibitors have no
androgenic effects on progesterone or estrogen, and therefore raise
new opportunities in gynecology and might be considered a signif‐
icant therapeutic choice.27 However, further studies are needed to
get a more reliable conclusion on the use of these drugs for first‐tri‐
mester missed abortion.
In summary, the present study found that, as compared with
misoprostol alone, a combination of misoprostol with letro‐
zole did not lead to a higher frequency of complete abortion or a
shorter duration of induction among women with first‐trimester
missed abortion.
AUT HOR CONTRI BUTI O N S
Z.A, M.G., and M.E, designed the study; M.E. and M.G performed the
experiments; and M.E. analyzed the data. All authors discussed the
results and contributed to the final manuscript.
ACKNOWLE DGME N TS
Financial support was provided by the Isfahan University of Medical
Sciences, Isfahan, Iran (no. 396243).
CO NFLI CTS OF I NTE RE STS
The authors have no conflicts of interest.
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