Short-Communication

Effect of misoprostol with and without evening primrose (Oenothera biennis)

on induction of missed abortion
Mozhgan Mahmoodinasab1, Marzeyeh Loripoor2,*, Reza Vazirinejad3, Fariba Aminzadeh4
1
Department of Midwifery, School of Nursing and Midwifery, Rafsanjan University of Medical Sciences,
Rafsanjan, Iran
2
Department of Midwifery, School of Nursing and Midwifery; Geriatric Care Research Center, Rafsanjan
University of Medical Sciences, Rafsanjan, Iran
3
Department of Epidemiology and Statistics, School of Medicine, Social Determinants of Health Research
Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
4
Department of Obstetrics and Gynecology, Faculty of Medicine, Nik Nafs Educational and Medical Center,
Rafsanjan University of Medical Sciences, Rafsanjan, Iran

Article history:
Received: Oct 28, 2021 Abstract
Received in revised form: Objective: To determine whether addition of evening primrose to
Apr 18, 2022 a misoprostol-based abortion regimen can increase the success of
Accepted: May 15, 2022 abortion.
Epub ahead of print Materials and Methods: In this randomized clinical trial., 148
women referring to Niknafas Hospital in Rafsanajn with diagnosis
* Corresponding Author:
of missed abortion were randomly allocated into two 74-subject
Tel: +98-09133937334
Fax: +98-03434258497 groups. The intervention group used 2000 mg vaginal evening
[email protected] primrose capsules the night before the hospitalization, while the
control group did not receive any medication. Both groups
Keywords: received an initial dose of 800 μg of vaginal misoprostol after
Missed abortion admission and the next dose was given three hours later if
Misoprostol necessary.
Evening primrose Results: The two groups had significant differences in terms of
Cervix preparation full abortion, consistency and dilatation of cervix, duration
between the first dose of misoprostol until the ejection of fetus, the
misoprostol dose administered, and the level of vaginal bleeding
during the hospitalization. They had no significant differences
regarding curettage, duration of hospitalization, or side effects.
The mean pain score had no significant difference between the two
groups, though the score was lower in the intervention group
(p>0.05).
Conclusion: Administration of vaginal evening primrose before
vaginal misoprostol was found to be more effective compared to
misoprostol alone in missed abortion.

Please cite this paper as:

Mahmoodinasab M, Loripoor M, vazirinejad R, Aminzadeh F. Effect of misoprostol with and without evening
primrose (Oenothera biennis) on induction of missed abortion. Avicenna J Phytomed, 2023. Epub ahead of
print.

Epub ahead of print 1

 Mahmoodinasab et al.

Introduction sublingually (Gemzell‐Danielsson, 2007).

Missed abortion is a common and Use of misoprostol is not always
constantly growing condition observed in successful as 15-40% of cases need
15-20% of diagnosed pregnancies (Neilson additional misoprostol doses which leads
et al., 2013; Jurkovic et al., 2013, Graziosi to prolongation of the treatment process
et al., 2004; Muffley et al., 2002; (Obstetrics, 2017; Neilson et al., 2006;
Niinimäki et al., 2011) and it has been Chen and Creinin, 2007; Zhang et al.,
defined as empty pregnancy sac or fetus 2005; Robledo et al., 2007; Creinin et al.,
without cardiac activity and without 2006).
spontaneous abortion (Neilson et al., Use of mifepristone before misoprostol
2013). boosts the abortion-inducing properties of
Treatment of missed abortion includes misoprostol, causing complete abortion in
one of the anticipation, pharmacological, 95% of pregnancies with the age of 65
and surgical methods (Jurkovic et al., days after fertility and 93% of pregnancies
2013). The surgical method of discharging with 64-70 days (Chen and Creinin, 2015;
the uterus contents has long been the Abbas et al., 2015). Although the national
standard treatment (Graziosi et al., 2004). Institute for health and care excellence
Nevertheless, it has the risks of damaging (NICE) did not show any benefit of
the uterus and cervix, uterine adhesions, applying mifepristone before misoprostol
bleeding, infection, possible anesthesia based on the results of a clinical trial in
complications, and possible adverse effects 2012 and thus did not recommend
on subsequent pregnancies (Niinimäki et administering mifepristone before
al., 2011; Graziosi et al., 2004). The results misoprostol, later the results of a large
of a meta-analysis on comparing the double-blind clinical trial controlled with
anticipation and surgical methods placebo indicated that the combination of
indicated that the risk of infection and mifepristone and misoprostol would have a
psychological problems was similar in better impact on discharging the uterus
both methods, but the costs are lower in (Chu et al., 2020). Nevertheless,
the anticipation method. Nevertheless, in mifepristone is expensive and unavailable
the anticipation method, incomplete in many centers (Raymond et al., 2017).
abortion and the need for surgery to Accordingly, it seems identification of an
discharge the uterus contents, increased effective and yet less expensive and more
bleeding, and blood transfusion are more available drug would be practical and
probable (Nanda et al., 2012). useful to boost the effect of misoprostol in
Pharmacotherapy is the preference of cases of missed abortion.
most women, while also being The use of herbal medicine as an
recommended by international clinical alternative treatment has been embraced
guidelines (Chen and Creinin, 2007; Zhang throughout the world (Dermani, 2021).
et al., 2005). The success rate of medical The oil of evening primrose (Oenothera
treatment is very variable and has been biennis) contains large amounts of linoleic
reported to range from 13 to 90% acid and gamma-linoleic acid, which
(Gemzell‐Danielsson et al., 2007). directly converts unsaturated fatty acid to
Misoprostol is commonly used for medical prostaglandin (Babazadeh and Keramat,
treatment (Robledo et al., 2007). 2011). Various studies have shown its
According to the International Federation impact on cervix preparation before or
of gynecology and obstetrics in 2017, the during induction of labor as well as before
recommended dose of misoprostol for gynecology operations that require cervix
treating missed abortion is 800 μg every preparation (Najafi et al., 2019; Shahali et
three hours up to two doses vaginally, or al., 2018; Vahdat et al., 2015).
600 μg every three hours up to two doses

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 EPO and induction of missed abortion

Considering the effects observed for The first person would pick up one card
evening primrose in studies and since so and enter the relevant group. The next
far no research has been conducted person would be allocated to the opposite
regarding the effect of the plant alongside group without picking up any cards, until
misoprostol in treating missed abortion, the samples were completed. Both groups
this study was performed to investigate the were recommended to refer in the morning
effect of misoprostol with and without of the next day for induction of abortion,
evening primrose on the induction of with the intervention group used two 1000-
missed abortion mg evening primrose capsules vaginally
made by Barij pharmaceutical company at
night before sleep, while the control group
Materials and Methods did not receive any intervention. Similar
This randomized clinical trial was studies were used to determine the dose of
performed on women diagnosed with evening primrose (Nonette, 2017; Vahdat
missed abortion referring to Niknafas et al., 2015; Kalati et al., 2018; Girlie,
maternity Hospital in Rafsanjan from 2015). In the next morning, once the
February 2020 to June 2020, as approved participants referred to the study center,
by the ethics committee of Rafsanajn after examining vital signs, bleeding, and
University of medical sciences with the cervix status, their hospitalization file was
ethics code of IR.RUMS.REC.1398.146 created and 800 μg of misoprostol
and code IRCT20160308026971N8 from suppository made by Samisaz
Iranian registry of clinical trials. pharmaceutical company (Mashhad, Iran)
The sample size was calculated as 59 was embedded in the posterior fornix for
in group based on the study by Jamilian et both groups. The next dose would be
al. (Jamilian et al., 2015), with confidence repeated three hours later if necessary. The
interval of 95% and statistical power of next morning abdominal sonography was
80%. Considering possible attrition, 74 performed to diagnose complete or
subjects were considered in each group. incomplete abortion for all participants.
The inclusion criteria were diagnosis of The data related to the studied variables
missed abortion based on two sonography was extracted from the women's files,
tests (as confirmed by the second while the information including pain score,
sonography or with a 7-day interval by the nausea, diarrhea, headache, abdominal
same sonographer), signing written cramps, fever and chills that were not
informed consent form to participate in the recorded in the file was asked by a trained
study, no contraindication use of evening expert and recorded in a checklist. To
primrose and misoprostol, and no severe determine the pain intensity, visual analog
vaginal bleeding. In case of not using scale (VAS) was used and scores 1-3
evening primrose or improper using as represented mild, 4-7 moderate, and 8-10
well as, start of bleeding before using severe pain (Bikmoradi et al., 2014).
evening primrose and referral to the The collected data were inputted into
surrounding cities for treatment follow-up, SPSS 16 and chi-square test was used for
the subject would be excluded. qualitative variables while independent t-
For random allocation of the subjects test was employed for comparing
into the intervention and control groups, quantitative variables of the two groups. In
the simple randomization method was some cases, its alternative test, i.e. Fisher
used, number 1 was considered for exact test was used to compare the two
intervention and 2 for the control group, groups. A p<0.05 was considered
and cards 1 and 2 were placed inside in a statistically significant.
box in which the numbers were not visible.
 Mahmoodinasab et al.

Results to each of the intervention and control

During the study, 183 subjects were group. In each group, 4 subjects were
investigated for inclusion into the research, excluded, and analysis was performed for
and eventually 74 were randomly assigned 70 subjects in each group (Figure 1).

Figure 1. The study CONSORT chart

Demographic findings indicated that the misoprostol, the time between the first
mean age in the intervention group was dose of misoprostol and discharging the
29.46±6.83 years and in the control group uterus contents, the level of vaginal
it was 30.43±6.82 years, and the two bleeding during hospitalization, and dose
groups did not show a significant of misoprostol required showed significant
difference in this regard (p=0.401). The differences between the two groups
two groups were well matched with each (p<0.05). Regarding duration of
other in terms of other personal hospitalization, curettage, or side effects
characteristics (p>0.05) (Table 1). such as nausea, diarrhea, headache,
In five subjects of the evening primrose abdominal cramps, or fever, there was no
group, before receiving misoprostol, the significant difference between the two
abortion process had been started and they groups. The mean pain score was lower in
did not receive misoprostol, but in the the intervention group compared to the
control group all subjects received control, though this difference was not
misoprostol (p<0.05). significant (p>0.05) (Table 2).
According to the results, there was no In the intervention group, four subjects
significant difference between the two had no tissue discharge in response to the
groups regarding vital signs or vaginal medical treatment. This number was 13 in
bleeding before use of misoprostol the control group, and there was a
(p>0.05). Concerning complete abortion, significant difference between the two
dilatation, and cervix consistency, in the groups in this regard (p<0.05).
examination before embedding

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 EPO and induction of missed abortion

Table 1. Comparison of the personal characteristics of the intervention (Evening Primrose and misoprostol)
and control (misoprostol alone) groups
Trait Intervention (Evening Control (misoprostol p-value
Primrose and alone)
misoprostol)
BMI (kg/m2) Mean±SD Mean±SD 0.921*
25.78±4.43 25.71±3.92
Gestational age as measured by LMP (weeks) 11.36±3.99 11±3.66 0.593*
Gestational age as measured by sonography (weeks) 10.47±9.02 9.53±3.91 0.424*
No of pregnancies Primigravida 25 (35.7%) 16 (22.9%) 0.095**
Multigravida 45 (64.3%) 54 (77.1%)
No of abortions Without history of 50 (71.4%) 47 (67.1%) 0.653**
abortion
History of one previous 17 (24.3%) 18 (25.7%)
abortion
History of two abortions or 3 (4.3%) 5 (7.1%)
more
History of curettage Yes 9 (12.9%) 17 (24.3%) 0.08**
No 61 (87.1%) 53 (75.7%)
Type of delivery No history of delivery 32 (45.7%) 20 (28.6%) 0.098**
Natural delivery 20 (28.6%) 29 (41.4%)
C-section 18 (25.7%) 21 (30%)
*Independent t-test, **Chi-square test, ***Fisher Exact test. 1Body Mass Index. 2Last Menstrual Period

Table 2. Comparing the studied variables between the intervention (Evening Primrose and misoprostol)
and control (misoprostol alone) groups
Group Intervention (Evening Control p-value
Primrose and misoprostol) (misoprostol alone)
Misoprostol dose (μg) Mean±SD Mean±SD 0.003*
987.86±559.40 1275.71±582.46
Duration of hospitalization (days) 2.03±0.24 2.04±0.20 0.704*
The time taken from the first misoprostol 8:05±4:33 13:09±8:36 0.000*
dose until fetal ejection (hour:minute)
Pain score (VAS) 6.69±2.76 7.18±2.89 0.305*
Vaginal bleeding at the entry Without bleeding 46 (65.7%) 51 (72.9%) 0.637**
Spotting 20 (28.6%) 17 (24.3%)
Mild 3 (4.3%) 2 (2.9%)
Moderate 1 (1.4%) 0 (0%)
Sever 0 (0%) 0 (0%)
Cervix dilatation Open 19 (27.1%) 6 (8.6%) 0.004**
Close 51 (72.9%) 64 (91.4%)
Cervix consistency Soft 39 (55.7%) 19 (27.1%) 0.001**
Hard 31 (44.3%) 51 (72.9%)
Administering misoprostol Yes 65 (92.9%) 70 (100%) 0.023***
No 5 (7.1%) 0 (0%)
Amount of bleeding during Mild 63 (90%) 52 (74.3%) 0.043**
hospitalization Moderate 6 (8.6%) 17 (24.3%)
Severe 1 (1.4%) 1 (1.4%)
Response to medical Yes 66 (94.3%) 53 (75.7%) 0.002**
treatment No 4 (5.7%) 17 (24.3%)
Type of abortion Complete abortion 8 (11.4%) 1 (1.4%) 0.016***
Incomplete abortion 62 (88.6%) 69 (98.6%)
Curettage Yes 62 (88.6%) 60 (85.7%) 0.614**
No 8 (11.4%) 10 (14.3%)
Nausea Yes 17(24.3%) 15 (21.4%) 0.687**
No 53 (75.7%) 55(78.6%)
Headache Yes 5(7.1%) 6(8.6%) 0.753**
No 65 (92.9%) 64(91.4%)
Abdominal cramps Yes 8(11.4%) 14 (20%) 0.164**
No 62 (88.6%) 56 (80%)
Diarrhea Yes 19 (27.1%) 20 (28.6%) 0.85**
No 51 (72.9%) 50 (71.4%)
Fever Yes 0 (0%) 1 (1.4%) 0.31**
No 70 (100%) 69 (98.6%)
*Independent t-test, **Chi-square test, ***Fisher Exact test. Visual Analogue Scale
 Mahmoodinasab et al.

Discussion al., 2018; Allameh et al., 2020;

This study explored the effect of Abbasalizadeh et al., 2018), but the
misoprostol with evening primrose and necessity of further studies has also been
misoprostol alone in treating missed recommended in this regard (Nash et al.,
abortion. According to the results, the 2018). In spite of the significant difference
hybrid treatment had a greater efficacy in between the two groups in terms of
treating missed abortion compared to complete abortion, the curettage did not
treatment with misoprostol alone. In five differ significantly between them. Possibly
subjects (7.1%) of the women in this could reflect the over-cautiousness of
intervention group, upon receiving evening less experienced gynecologists to ensure
primrose alone, the abortion process was completion of abortion before hospital
initiated and they did not receive discharge rather than the real need for
misoprostol. This was unexpected for the surgical treatment.
researchers since this study was performed According to the results, dilatation and
presuming that evening primrose could cervix consistency was significantly
probably boost the effect of misoprostol different between the evening primrose
while it would not be the initiator of and control groups. The impact of evening
abortion. Since its 2000 mg dose could primrose flower on cervix preparation has
induce abortion in these five people, it been confirmed in several studies (Najafi
seems that using higher doses of evening et al., 2019; Vahdat et al., 2015; Tanchoco
primrose, percentage of abortion with it and Aguilar, 2015), and it was shown to be
and without misoprostol could be more effective than misoprostol in some
increased. In a study by Nouri et al. studies (Mirzadeh et al., 2020).
(2021), evening primrose was also more Inconsistent results are related mostly to its
effective than misoprostol in cervix oral administration (Jahdi et al., 2016;
dilatation before surgery and the Moradi et al., 2021).
researchers proposed it as a suitable The mean dose of misoprostol used in
alternative to misoprostol in these cases the present study had significant
(Nouri et al., 2021). differences between the intervention and
Results showed that the intervention control groups. In another studies also the
and control groups were significantly dose of misoprostol required was lower
different in terms of rate of complete when given in combination with
abortion, which was higher in the evening mifepristone and castor oil compared to
primrose plus misoprostol group compared misoprostol alone (Chu et al., 2020;
to the misoprostol alone group. Jamilian and Heydari, 2015). In a study by
The efficacy of the combined treatment Naghshineh et al. (2015), the administered
of mifepristone and misoprostol has been dose of misoprostol plus letrozole was
shown in various studies (Chu et al., 2020; lower compared to the misoprostol alone,
Warden et al., 2019). However, but the difference was not significant
considering the higher price of (Naghshineh et al., 2015). With reducing
mifepristone compared to evening the misoprostol dose, its complication
primrose and its unavailability in many would also diminish while the patient
countries as well as the greater tendency of satisfaction will increase (Chen and
women for using plant-based compounds Creinin, 2007; Zhang et al., 2005). The
(Babazadeh and Keramat, 2011; Movahed results also indicated fewer complications
et al., 2010), it seems that evening in the evening primrose group, though the
primrose could be a suitable alternative. difference between the two groups was not
The greater efficacy of misoprostol plus significant.
letrozole combined treatment has also been According to the results, there was a
shown in some studies (Behroozi-Lak et significant difference between the two

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 EPO and induction of missed abortion

groups regarding the time interval between Ohannessian et al. (2016) was also lower
administering the first dose of misoprostol in the misoprostol plus mifepristone group
until fetal ejection. This is in line with the compared to the misoprostol plus
shorter intervention in the study by mifepristone alone (Ohannessian et al.,
Ohannessian et al. (2016) in misoprostol 2016). In a study by Shahali et al. (2018)
and mifepristone group compared to and Kalati et al. (2016) , although bleeding
treatment with each of them alone for was lower in the evening primrose group,
cervix preparation for abortion surgical this difference was not statistically
treatment (Ohannessian et al., 2016). significant (Shahali et al., 2018; Kalati et
However, it is incongruent with the al., 2016).
findings of Allameh et al. to compared Use of 2000 mg vaginal evening
effect of misoprostol alone with primrose the night before induction of
misoprostol plus letrozole in treating abortion plus vaginal misoprostol in
missed abortion (Allameh et al., 2020). It women suffering from missed abortion had
can be stated that the results of the present a greater efficacy compared to vaginal
research are more consistent with the study misoprostol alone. This could cause higher
findings of the effect of combined cases of complete abortion, lower dose of
treatment with mifepristone and misoprostol required, lower duration of
misoprostol rather than the combined discharging the pregnancy products and
treatment of letrozole plus misoprostol. It less bleeding without increasing the side
seems that combined treatment with effects.
evening primrose and misoprostol is Overall, since no study was found
preferred over letrozole and misoprostol, regarding the effect of evening primrose
though further studies are still required. plus misoprostol in treating missed
In the present study, in spite of the abortion, further research is recommended
lower pain in the intervention group, the in this regard.
difference between the two groups was not
significant. Also, in a study by Shahali et Acknowledgment
al. (2018), there was no significant The cooperation of the research and
difference between intervention and technology Deputy of Rafsanjan
control groups regarding pain intensity University of medical sciences, authorities,
(Shahali et al., 2018). The pain during physicians, and midwives of Niknafas
speculum insertion and injection for educational healthcare center as well as all
hysterosalpingography was lower in women participating in this research is
women who received evening primrose in highly appreciated.
a study by Shahnamnia et al. (2019)
(Shahnamnia et al., 2019), which is Conflicts of interest
possibly due to the differences in the doses The authors have declared that there is
of evening primrose and pain quality no conflict of interest.
between the two studies.
There was no significant difference
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