Key words
letrozole - first trimester miscarriage - medical management
Schlüsselwörter
Letrozol - Fehlgeburt im 1. Trimenon - medizinische Behandlung
Introduction
Misoprostol is a prostaglandin that causes myometrial contractions, cervical softening
and dilatation. It is used to induce abortion and labor and to treat atonic postpartum
hemorrhage and
peptic ulcers [1]. It has the advantage of being cost-effective and stable with a low rate of side
effects, which has led to it being included in the World Health
Organization list of essential medications [2]. Misoprostol is licensed for use to induce miscarriage in Egypt. It has not been
licensed to induce labor or
miscarriage in certain countries such as Germany, but it is used off-label to
induce labor in the UK [3] and in Germany.
Misoprostol by itself is used for the medical management of miscarriage as an alternative
to surgery, with a success rate of between 65 and 93%. It is more effective in the
early stages of
pregnancy, where it also has the advantage of being cheaper, less invasive and
avoiding surgical complications. Misoprostol is also used in combination with other
medications such as
mifepristone and methotrexate to increase the success rate [4].
Mifepristone used in combination with misoprostol achieved higher rates of completed
abortions of up to 95% [5] and is recommended for pretreatment in abortion
and medical miscarriage, but a cheaper and widely available alternative is needed,
especially in developing countries.
Cesarean section (CS) rates are increasing worldwide, and many patients with a scarred
uterus will need management of miscarriage. Uterine rupture is one of the complications
which can occur
in women with uterine scarring and this risk increases with the use of prostaglandins
such as misoprostol but is very rare in first trimester miscarriage. There are different
protocols for
different doses of misoprostol used in women with previous CS. This includes reducing
the dose of misoprostol to 100 µg, administering doses less frequently or changing
the administration
route of misoprostol from vaginal to oral. However, there is no evidence-based
protocol on adjusting the dose for women with previous CS [6]. The use of
misoprostol to induce labor is contraindicated in many international guidelines
because the risk of uterine rupture was found to increase by up to 18% in one study,
even when a very low dose
of 25 µg was administered [7].
Letrozole is an oral aromatase inhibitor which has been approved by the FDA [8]. Its anti-estrogen effect has been shown to be useful in the pretreatment of
pregnancy terminations when combined with misoprostol. It can therefore replace
mifepristone, which is expensive and not available in many countries [9].
The use of letrozole in combination with misoprostol to obtain higher rates of completed
abortion was evaluated by Lee et al. [10]. In their study letrozole was
administered for 3 days followed by misoprostol and achieved a success rate of
86.9%. In a pilot study by Yeung et al., a letrozole protocol was used for 7 days
and achieved a 95% success rate
[11]. In another pilot study [12] by Chai and Ho, mifepristone and letrozole were administered prior to misoprostol
and achieved
a 98% rate of complete abortion. But larger trials are needed to establish the
clinical efficacy of pretreatment with letrozole to achieve complete miscarriage.
This randomized case control study aimed to compare the safety and efficacy of misoprostol
alone or in combination with letrozole in the medical management of first trimester
missed
miscarriage.
Materials and Methods
This prospective randomized study was carried out in Al-Azhar University Hospitals,
Al-Galaa Teaching Hospital, October 6th University Hospital and Airforce Specialized
Hospital.
Ethical approval
The Ethical Committee of Al-Azhar University approved this study on June 9th, 2015.
All women recruited to the study gave their informed consent prior to enrolment in
the study. Women with
previous CS were counseled about the risk of uterine rupture associated with
misoprostol.
All women (n = 552) ([Fig. 1]) who were diagnosed with unexplained first trimester miscarriage between July 2015
and June 2016 were approached for enrolment
into the study. Missed miscarriage was diagnosed by the ultrasound finding of
no fetal cardiac activity in the fetal pole. Women with a closed cervix and no products
of conception in the
cervical canal were included in the study. Exclusion criteria included a previous
attempt to terminate the pregnancy, abnormal uterine lesions such as fibroids or congenital
malformations,
pregnancy despite an intrauterine contraceptive device (a known cause of miscarriage),
medical disorders such as cardiac or hemorrhagic disease, and known hypersensitivity
to any of the
medications used. A total of 114 women were excluded from the study.
Fig. 1 Consort flow-chart of the cases.
A detailed medical history was taken of all women included in the study (n = 438)
and included the date of the first day of the last menstrual period to calculate gestational
age. All women
underwent physical examination including local examination to assess the cervix.
Investigations performed included blood group analysis, Rh typing, screening for thrombophilia,
karyotyping
of both partners and ultrasound to confirm the diagnosis.
Women were divided into 2 groups with 219 in each group. The first group (placebo
group) received a placebo of inert material twice daily for 3 days, followed by 800
micrograms of
misoprostol administered vaginally on the 4th day of enrolment. The second group
(letrozole group) received letrozole 10 mg twice daily for 3 days followed by 800
micrograms of misoprostol
administered vaginally on the 4th day of enrolment. The misoprostol dose was
not changed for women with prior CS as there is no recognized protocol to adjust the
dose for women with previous
CS, and also so as not to affect the study results.
All women were told to record the date of the first vaginal bleeding; the date of
first passage of tissue pieces; lower abdominal pain of any degree, with pain assessed
using a pain visual
analog score; vaginal bleeding of any degree; any side effects such as nausea,
vomiting, fever and shivering; any return to hospital for severe pain, bleeding or
intolerable side effects;
and to return to hospital on the 7th day after administration of misoprostol.
An ultrasound scan was done on the 7th day after misoprostol administration to monitor
the outcome. Surgical
evacuation was performed if there was missed or incomplete miscarriage.
Primary outcome measures were the rate of complete miscarriages achieved and the induction-to-abortion
interval in each group. Secondary outcome measures were the start of vaginal bleeding
and any side effects (nausea, vomiting, fever, severe pain and severe bleeding)
in both groups.
Randomization and blinding
Patients allocated into the study were randomized into either of two groups using
a computer-generated list at a 1 : 1 ratio. Concealment was achieved using opaque
envelopes, to blind the
pysicians, while to blind the patients, the placebo tablet was methylcellulose
resembling letrozole in shape.
Sample size calculation
The sample size was calculated with 219 subjects in each arm of the study, using the
formula for comparison of proportion with alpha = 0.01, beta = 0.05, and power = 95%.
The aim was to
increase the percentage of complete miscarriages achieved with letrozole pretreatment
before misoprostol in women with first trimester missed miscarriage.
Statistical analysis
Data were analyzed using the Statistical Program for Social Science (SPSS) version
20.0. Quantitative data were expressed as mean ± standard deviation (SD). Qualitative
data were expressed
as frequency and percentage.
Independent t-test of significance was used to compare 2 means. Chi-square (χ2) test was used to compare proportions of 2 qualitative parameters. Probability (p-value):
p > 0.05 was considered insignificant, p ≤ 0.05 was considered significant, and
p < 0.001 was considered highly significant.
Results
This study compared two treatment modalities for the medical management of missed
miscarriage. The first group was given placebo and misoprostol, while the second group
received pretreatment
with letrozole followed by misoprostol. There were no significant differences
in age and gestational age between the two groups ([Table 1]).
Table 1 Comparison of demographic data.
|
Demographic data
|
Group 1 (placebo)
|
Group 2 (letrozole)
|
p-value
|
|
Age
|
|
|
0.863
|
|
Mean ± SD
Range
|
26.62 ± 4.30
19 – 40
|
26.52 ± 3.87
19 – 35
|
|
|
Body mass index
|
|
|
0.0163
|
|
Mean ± SD
Range
|
25.81 ± 2.7
16.53 – 33.33
|
25.12 ± 3.3
19.37 – 37.46
|
|
|
Gestational age
|
|
|
0.065
|
|
Mean ± SD
Range
|
48.83 ± 8.00
35 – 62
|
50.19 ± 7.478
35 – 63
|
|
|
Gravidity
|
|
|
0.742
|
|
Gravida 1
|
46
|
54
|
|
|
Gravida 2
|
61
|
55
|
|
|
Gravida 3
|
22
|
22
|
|
|
Gravida 4
|
4
|
7
|
|
|
Gravida 5
|
86
|
81
|
|
|
Parity
|
|
|
0.891
|
|
Para 0
|
59
|
66
|
|
|
Para 1
|
57
|
52
|
|
|
Para 2
|
20
|
19
|
|
|
Para 3
|
3
|
4
|
|
|
Para 4
|
80
|
78
|
|
|
Previous cesarean section (CS)
|
|
|
0.117
|
|
No previous CS
|
92
|
116
|
|
|
1 previous CS
|
92
|
77
|
|
|
2 previous CS
|
21
|
19
|
|
|
3 previous CS
|
11
|
4
|
|
|
4 previous CS
|
3
|
3
|
|
Comparison of gravidity
The distribution of gravidity in the placebo group was 46 primigravida, 61 gravida
2, 22 gravida 3, 4 gravida 4, and 86 gravida 5. Distribution in the letrozole group
was 54 primigravida,
55 gravida 2, 22 gravida 3, 7 gravida 4, and 81 gravida 5. There was no significant
difference between groups (p = 0.742).
Comparison of previous cesarean sections
The distribution of women with previous cesarean section (CS) in the placebo group
was 92 women with no previous CS; 92 with 1 previous CS; 21 with 2 previous CS; 11
with 3 previous CS; and
3 with 4 previous CS. In the letrozole group 116 women had no previous CS; 77
had 1 previous CS; 19 had 2 previous CS; 4 had 3 previous CS; and 3 had 4 previous
CS. There was no significant
difference between groups (p = 0.117). There was no reported case of uterine
rupture.
Comparison of hemoglobin levels before and after termination
Mean hemoglobin before treatment in the placebo group was 10.90 g/dl (range: 9 – 12 g/dl).
Mean hemoglobin in the letrozole group was 10.86 g/dl (range: 9 – 12 g/dl). There
was no
significant difference between groups (p = 0.676). Mean hemoglobin after treatment
was 10.41 g/dl in the placebo group (range: 8.5 – 11.5 g/dl) and 10.49 g/dl (range:
8.8 – 11.9 g/dl) in the
letrozole group, with no significant difference between groups (p = 0.495).
Significant clinical data
[Table 2] shows that more women had complete miscarriage in the letrozole group than in the
placebo group. The difference was highly significant
(p < 0.001).
Table 2 Comparison of failure rates between groups.
|
Failure rate
|
Group 1 (placebo)
|
Group 2 (letrozole)
|
Chi-square test
|
|
n
|
%
|
n
|
%
|
p-value
|
|
No (complete miscarriage)
|
85
|
39
|
171
|
78
|
< 0.001
|
|
Yes (incomplete miscarriage)
|
134
|
61
|
48
|
22
|
Women in the letrozole group had a shorter time to induction and complete miscarriage
after misoprostol than women in the placebo group; the difference was highly significant
(p < 0.001)
([Table 3]).
Table 3 Comparison of onset and duration of vaginal bleeding and onset of passing products
of conception (clinical data).
|
Clinical findings
|
Group 1 (placebo)
|
Group 2 (letrozole)
|
p-value
|
|
Time to 1st vaginal bleeding after administration of misoprostol, days
|
|
|
< 0.001
|
|
Mean ± SD
Range
|
2.30 ± 0.64
1 – 4
|
1.33 ± 0.29
1 – 3
|
|
|
Time to induction of abortion after administration of misoprostol, days
|
3.09 ± 0.99
|
1.42 ± 0.50
|
< 0.001
|
|
Mean ± SD
Range
|
2 – 7
|
1 – 2
|
|
|
Time to 1st product of conception passed after administration of misoprostol, days
|
3.50 ± 1.55
|
2.09 ± 0.70
|
< 0.001
|
|
Mean ± SD
Range
|
2 – 9
|
1 – 7
|
|
Vaginal bleeding started earlier in the letrozole group compared to the placebo group,
and the difference was highly significant (p < 0.001) ([Table 3]).
Women in the letrozole group also started to pass products of conception earlier
than women in the placebo group, and the difference was highly significant (p < 0.001)
([Table 3]).
Comparison of side effects
More women experienced nausea and vomiting in the letrozole group than in the placebo
group, and the result was significant (p = 0.002) ([Table 4]). There
were no significant differences between groups with regard to the incidence of
fever, severe pain, and severe bleeding needing surgical management ([Table
4]).
Table 4 Comparison of side effects of medication.
|
Side effects
|
Group 1 (placebo)
|
Group 2 (letrozole)
|
Chi-square test
|
|
No
|
%
|
No
|
%
|
p-value
|
|
Nausea and vomiting
|
7
|
3
|
37
|
17
|
0.002
|
|
Fever
|
16
|
7
|
9
|
4
|
0.152
|
|
Severe pain
|
15
|
7
|
24
|
11
|
0.132
|
|
Severe bleeding needing evacuation
|
48
|
22
|
36
|
16
|
0.141
|
Discussion
The present study showed a higher rate of complete miscarriages in the group which
received additional letrozole (78%) compared to the control group (39%). The interval
between induction and
abortion was shorter in the letrozole group (1.42 days) compared to the placebo
group (3.09 days) ([Tables 2] and [3]).These
results are similar to the success rates of other studies, with a success rate
of 78% for the letrozole group in our study and a rate of 76.7% reported for the letrozole
group in the study by
Naghshineh and colleagues [13].
The current study has the advantage of being a randomized study with a power of 95%.
The main limitation in our study is the lack of long-term follow-up, and the need
to test different
misoprostol doses, especially in women who have had previous cesarean section.
In their study, Lee and co-workers [10] reported a significant difference in favor of the letrozole/misoprostol group; the
rate of complete abortions in their
study was higher than that found in our study, and amounted to 86.9% of pregnancies
up to 7 weeks of gestation and 93.3% of pregnancies up to 9 weeks of gestation; however,
their study
included fewer numbers of women and they only administered letrozole 10 mg once
daily, whereas in our study letrozole 10 mg was administered twice daily. Another
pilot study [11] used a 7-day course of letrozole followed by vaginal misoprostol and reported an
even higher rate of complete abortions (95%), which could be explained by the
longer period of administration of letrozole. A possible explanation for the difference
in results could be the different treatment regimens and the differences in gestational
age. In our
study, letrozole 10 mg was administered twice a day and not once a day as in the
study by Yeung et al. [11].
Our study showed a faster interval to onset of vaginal bleeding and a shorter duration
in the letrozole group; the interval between administration of medication and onset
of expulsion of the
products of conception was also shorter in the letrozole group, which is similar
to the results reported in other studies [10], [13].
In a study which attempted to determine the mechanism by which letrozole acts in medical
abortions, Lee and co-workers [14] examined the effect of letrozole on
the expression of steroid receptors in the placentas of 2nd trimester women undergoing
medical termination of pregnancy. They concluded that the expression of progesterone
receptor
transcripts, estrogen receptor-alpha and estrogen receptor-alpha protein were
all suppressed by letrozole in the placentas of women receiving letrozole; however,
their study only examined
second trimester terminations and not terminations in the first trimester of pregnancy.
Yung et al. [15] evaluated the effect of letrozole-induced estradiol
suppression on the reduction of progesterone receptor expression and apoptosis
in the first trimester using immune-histochemical staining of progesterone receptors
in a double-blinded
randomized placebo-control trial and found no differences in the expression of
progesterone receptors and apoptotic markers in decidual tissue after pretreatment
with letrozole for 7 days
before first trimester abortion. In a randomized controlled trial, Lee and co-workers
[16] measured the effect of letrozole on uterine artery Doppler indices
prior to surgical termination of first trimester pregnancy and found significant
decreases in both pulsatility and resistance index in the letrozole group, which suggests
that blood flow
changes might play a role in the mechanism of action of letrozole.
The study of Lee et al. [10] showed that estradiol levels were significantly lower after the administration of
letrozole in first trimester inductions of
abortion. Estrogens are known to induce the expression of estrogen receptors (ER)
and progesterone receptors (PR). This suggests that letrozole may act by suppressing
ER and PR. The role of
estradiol in supporting pregnancy had not yet been as clearly elucidated as the
role of progesterone. A study by Albrecht and co-workers [17] on pregnant baboons
showed that estradiol depletion using aromatase inhibitors induced abortion. This
suggests a role for estrogen in placental development and function. Other studies
such as those of Dunk et al.
[18], Schiessl et al. [19], and Albrecht et al. [20], suggested that the endothelial growth
factor family and the angio-protein family play a role in the remodeling of spiral
arteries. Letrozole was found to suppress endothelial growth factor in those studies.
Both regimens were tolerated by most women, with a few women reporting side effects
such as low-grade fever and severe pain in addition to nausea and vomiting; this finding
agreed with the
results of other previous studies [21], [22], [23], [24]. All the
studies found that side effects were associated with the administration of misoprostol,
with more side effects associated with the sublingual route. They reported comparable
rates of side
effects for nausea, vomiting and fever for vaginally administered misoprostol
[21], [22], [23], [24]. There were no significant differences in side effects between groups, with the
exception of rates of nausea and vomiting which were
significantly higher in the letrozole group. This could be explained by the higher
risk of developing side effects when using two medications (letrozole and misoprostol).
The current study had
a higher rate of nausea and vomiting than the rate reported by Lee et al. [10] because letrozole was given twice daily compared to once daily. The proportion of
women with severe bleeding who needed surgical evacuation was lower in the letrozole
group, but the difference was not statistically significant; none of the women had
a marked drop in
hemoglobin level or required blood transfusion.
Conclusion
The addition of letrozole to misoprostol improved the success rate and decreased the
interval between induction and expulsion in women with first trimester miscarriage.
However, the number of
women complaining of nausea and vomiting increased. Further larger studies are
needed to determine the optimum treatment protocol to achieve the highest success
rate and the lowest rate of
side effects.
Trial registration number: PACTR201701001973403 Pan African Clinical Trials Registry www.pactr.org
Letrozole vs. Placebo Pretreatment in the Medical Management of First Trimester Missed
Miscarriage: a Randomized Controlled Trial
Haitham A. Torky, Heba Marie, ElSayed
ElDesouky, Samy Gebreel, Osama Raslan, Asem A. Moussa, Ali M. Ahmad, Eman Zain,
Mohamed N. Mohsen
Geburtsh Frauenheilk 2018; 78: 63–69
doi:10.1055/s-0043-122499
“Material and Methods”
Under the heading “Randomization and blinding” the sentence should read in full: Concealment
was achieved using opaque envelopes, to blind the pysicians, while to blind the patients,
the
placebo tablet was methylcellulose resembling letrozole in shape.
“Results”
In the 1st paragraph, the last sentence correctly reads: There were no significant
differences in age and gestational age between the two groups ([Table
1]).
Under the heading “Comparison of gravidity”, the p-value has been corrected in the
last sentence of the 1st paragraph. Correct is: p = 0.742.
Under the heading “Comparison of previous cesarean sections”, the p-value has been
corrected in the penultimate sentence. Correct is: p = 0.117.
[Table 1] has been corrected. Correct is:
Table 1 Comparison of demographic data.
|
Demographic data
|
Group 1 (placebo)
|
Group 2 (letrozole)
|
p-value
|
|
Age
|
|
|
0.863
|
|
Mean ± SD
Range
|
26.62 ± 4.30
19 – 40
|
26.52 ± 3.87
19 – 35
|
|
|
Body mass index
|
|
|
0.0163
|
|
Mean ± SD
Range
|
25.81 ± 2.7
16.53 – 33.33
|
25.12 ± 3.3
19.37 – 37.46
|
|
|
Gestational age
|
|
|
0.065
|
|
Mean ± SD
Range
|
48.83 ± 8.00
35 – 62
|
50.19 ± 7.478
35 – 63
|
|
|
Gravidity
|
|
|
0.742
|
|
Gravida 1
|
46
|
54
|
|
|
Gravida 2
|
61
|
55
|
|
|
Gravida 3
|
22
|
22
|
|
|
Gravida 4
|
4
|
7
|
|
|
Gravida 5
|
86
|
81
|
|
|
Parity
|
|
|
0.891
|
|
Para 0
|
59
|
66
|
|
|
Para 1
|
57
|
52
|
|
|
Para 2
|
20
|
19
|
|
|
Para 3
|
3
|
4
|
|
|
Para 4
|
80
|
78
|
|
|
Previous cesarean section (CS)
|
|
|
0.117
|
|
No previous CS
|
92
|
116
|
|
|
1 previous CS
|
92
|
77
|
|
|
2 previous CS
|
21
|
19
|
|
|
3 previous CS
|
11
|
4
|
|
|
4 previous CS
|
3
|
3
|
|
[Table 2] has been corrected. Correct is:
Table 2 Comparison of failure rates between groups.
|
Failure rate
|
Group 1 (placebo)
|
Group 2 (letrozole)
|
Chi-square test
|
|
n
|
%
|
n
|
%
|
p-value
|
|
No (complete miscarriage)
|
85
|
39
|
171
|
78
|
< 0.001
|
|
Yes (incomplete miscarriage)
|
134
|
61
|
48
|
22
|
[Table 3] has been corrected. Correct is:
Table 3 Comparison of onset and duration of vaginal bleeding and onset of passing products
of conception (clinical data).
|
Clinical findings
|
Group 1 (placebo)
|
Group 2 (letrozole)
|
p-value
|
|
Time to 1st vaginal bleeding after administration of misoprostol, days
|
|
|
< 0.001
|
|
Mean ± SD
Range
|
2.30 ± 0.64
1 – 4
|
1.33 ± 0.29
1 – 3
|
|
|
Time to induction of abortion after administration of misoprostol, days
|
3.09 ± 0.99
|
1.42 ± 0.50
|
< 0.001
|
|
Mean ± SD
Range
|
2 – 7
|
1 – 2
|
|
|
Time to 1st product of conception passed after administration of misoprostol, days
|
3.50 ± 1.55
|
2.09 ± 0.70
|
< 0.001
|
|
Mean ± SD
Range
|
2 – 9
|
1 – 7
|
|
[Table 4] has been corrected. Correct is:
Table 4 Comparison of side effects of medication.
|
Side effects
|
Group 1 (placebo)
|
Group 2 (letrozole)
|
Chi-square test
|
|
No
|
%
|
No
|
%
|
p-value
|
|
Nausea and vomiting
|
7
|
3
|
37
|
17
|
0.002
|
|
Fever
|
16
|
7
|
9
|
4
|
0.152
|
|
Severe pain
|
15
|
7
|
24
|
11
|
0.132
|
|
Severe bleeding needing evacuation
|
48
|
22
|
36
|
16
|
0.141
|
