Abstract
Objective: To evaluate the efficacy and side effects of each
medication regime, a comparison was drawn between the administration of
misoprostol with the combined use of misoprostol plus oxytocin and
misoprostol plus methylergometrine for full expulsion of retained
intrauterine tissues in patients who underwent a miscarriage.
Design: randomized, double-blind, clinical trial
Setting: gynecology and obstetrics clinic in Jahrom, Southern
Iran
Population: 90 patients with gestational age below 12 weeks and
having undergone a recent miscarriage.
Methods: They were randomly allocated into three groups after
being screened for underlying diseases and coagulative blood disorders.
For the first group, labeled as the control group, misoprostol was
administered alone, while as, the combination of misoprostol plus
methylergometrine and misoprostol plus oxytocin was prescribed for the
second and third groups, respectively.
Main Outcome Measures: Primary: Expulsion of retained products
of conception; Secondary: Pain, Hemorrhage
Results: Despite no significant statistical difference being
observed in the expulsion of retained products of conception (RPOC)by
the administration of misoprostol alone or with combined medical therapy
of misoprostol with oxytocin or methylergometrine (P-value<
0.329), all of them showed a successful treatment. Additionally, the
patients treated with misoprostol and oxytocin showed good results in
expelling the RPOC(P=0.013); while as, those treated by misoprostol plus
methylergometrine reported controlled pain and hemorrhage after an
abortion fiP=0.004).
Conclusion: The course of medications viz. methylergometrine,
oxytocin, and misoprostol indicated a successful outpatient treatment in
patients that had experienced a miscarriage or an incomplete abortion.
They are cost-effective and have shown lesser side effects.
Keywords: Outpatient treatment, medical abortion, miscarriage,
first trimester, retained products of conception (PROC)
Introduction
Globally, the complications succeeding a spontaneous or an unsafe
abortion have been recognized as an impediment to women’s general
well-being 1. A systematic and analytical study from
the World Health Organization (WHO) conducted in 2014 estimated a
mortality rate of 7.9% in mothers who take on an unsafe or spontaneous
abortion 2. Another study from 2017 revealed that 18%
of all the pregnancies in the USA wereabortedwith80% of them being
related to a gestational age of fewer than 10 weeks 3.
The prevalent long-term complications of intrauterine tissue retention
include infertility, hemorrhage, intrauterine adhesion, coagulation
disorders, infection, and finally death which are in a linear
relationship with age advancement 4. In contrast to
curettage and manual vacuum aspiration, medical therapy by misoprostol,
also known as prostaglandin, is considered a safe, non-invasive, and
effective alternative method in the management of intrauterine fetal
death 5-7. In a study released in 2004 by Kehinde et
al., it was illustrated that 600 micrograms of oral misoprostol intake
could lead to full expulsion of retained tissue 8.
Frequent studies have been carried out to ascertain the expulsion rate
of persistent placental or trophoblastic tissue, to compare oxytocin
efficacy on uterine smooth muscle contractions, and also to relate the
prophylactic effects of methylergometrine on postpartum hemorrhage9-12. These studies have compared different forms of
drug choices such as single drug administration or a combined medical
therapy during hospitalization. But unfortunately, no record of
outpatient treatment for residual tissue expulsion in patients with
first-trimester incomplete abortion was found.
This study has been carried keeping in mind the significance of full
expulsion of the retained products of conception (RPOC) after a
miscarriage to avoid hospitalization during the COVID-19 crisis. To
evaluate the efficacy and side effects of each medication regime, a
comparison was drawn between the administration of misoprostol with the
combined use of misoprostol plus oxytocin and misoprostol plus
methylergometrine for full expulsion of retained intrauterine tissues in
patients who underwent a miscarriage. The outcome was used to evaluate
whether outpatient treatment could be substituted with a surgical
approach as a safe maneuver.
Method
Study Design
This double-blind clinical trial was performed on patients who referred
to the gynecology and obstetrics clinic affiliated to Jahrom University
of Medical Sciences with miscarriage and a gestational age being below
12 weeks from March to July in 2020.
After taking a comprehensive history from each patient, the data
obtained was registered in the relevant code sheets. After being matched
in terms of gestational age, the next step involved the random
categorization of patients into three distinctive groups. To follow the
double-blind study format, none of the patients were given details of
the category they were allotted. Furthermore, the radiologist examined
the images without prior knowledge about the status of these patients.
Subsequently, the patients were checked for the status of success rates
of pregnancy tissue expulsion.
Participants
According to a study conducted by Paris et al in 202013, a sample size of90 patients was obtained,
estimating a standard deviation of 0.85, confidence interval of 95%,
and power of 80%; utilizing Altman nomogram for matching sample sizes
of these groups estimateda15 percent dropout rate (using G-Power
software for sample size determination). Therefore, 90 patients were
selected for the study and were randomly allocated into three different
groups.
The eligibility criteria assigned for the patients to enter the study
were as follows: gestational period below 12 weeks as confirmed by
sonography & LMP; spontaneous and/or incomplete abortion diagnosed by
sonography; and vaginal bleeding history in the current pregnancy that
encouraged patients to pursue outpatient treatment to expel RPOC.
However, the exclusion criteria that disqualified the patients for the
study were following: hypersensitivity to misoprostol or certain
prostaglandins; drug limitations for taking prostaglandins in patients
with asthma, glaucoma and hypertension, hepatic disorders, seizure
history, history and/or presence of thromboembolism; smoking habits;
IUD; Hb <10 mg/dl; temperature> 38º C and
finally, pelvic infection or sepsis that caused patient’s discontentment
for outpatient treatment. Moreover, an unstable hemodynamic status was
considered among the exclusion criteria.
Intervention
A thorough and organized history was obtained from the patients who met
the criteria to participate in the study. Additionally, they received a
special written consent form to acquaint them with the research
objectives and were thereof categorized into three different groups in
terms of gestational age. The first group of the patients was designated
to be the control group and was given misoprostol 200 mg (Misoglandin,
Samisaz Co, Mashhad, Iran) every 6 hours sublingually and 3
suppositories through the posterior vaginal fornix per night14,15.
The second and third groups followed different medication regimes as
their treatment. in the third group, misoprostol 200 mg was prescribed
in the form of sublingual tablet intake every 6 hours and 3
suppositories through the posterior vaginal fornix combined with
intramuscular methylergometrine 0.2 mg (Minoo Co, Tehran, Iran) thrice a
day. These groups were also advised to refer to the closest clinic to
take the injection cautiously 15.
On the other hand, the third group was prescribed misoprostol 200 mg
sublingually every 6 hours and 3 suppositories through the posterior
vaginal fornix every night. Also, this group was simultaneously
administered with oxytocin (Vetocin, Aburaihan Pharma Co., Tehran,
Iran), 30 units in the morning, and 30 units intramuscularly in the
afternoon, and was advised to refer to the nearest health care center
for taking these injections 15.
Likewise, in those patients with negative Rh, intramuscular Rhogam 300
mg injection was prescribed for preventing iso-immunization16. So, all the patients received treatment in the
outpatient setting. After a 3-day interval, sonography was performed on
each group to check the size of residual mass to assess the success rate
of the undergoing outpatient treatment. The sonography was performed by
an expert radiologist which was blinded to the therapeutic regime of the
patient. Moreover, the course of the medication regime was repeated
three times in the case of sonographic detection of endometrial mass. At
last, a failure of the study was ascertained even with a slight
detection of tissue residue under sonography, and patients with medical
treatment failure were then advised to undergo other approaches such as
surgery or curettage to remove the RPOC.
Data Collection
A demographic questionnaire used to gather information about age, sex,
weight, blood pressure, existing underlying diseases, and the
gestational age of the patients was given to the patients to fill in.
Also, sonographic studies were employed to confirm intrauterine death.
After a 3-day outpatient intervention, the patients were asked to refer
to the gynecology and obstetrics clinic affiliated to Jahrom University
of Medical Sciences for further follow up. In this follow-up session,
data such as spotting in pregnancy, pain, bleeding, and finally
successful expulsion of RPOC were asked and recorded carefully in
relevant code-sheets. For the assessment of the pain severity in the
patients, the Visual Analogue Scale system (VAS), a 10 cm scaled ruler
was used to show the degree of the pain in these patients; such that 0
and 10 were its two extremes representing no pain and worst pain,
respectively. Data during follow-up were recorded in a blinded fashion
and by using forms that were prepared in advance. Furthermore, 1-3 score
denoted a relative pain, 4-6 a moderate pain, and 7-10 a severe pain
overall 17. Several internationally published papers
have confirmed the reliability and durability of the VAS scale18,20, as have many Iranian national publications
confirmed its durability with a correlation coefficient of R: 0.8821.
Statistical Analysis
The data attained in the present study were analyzed by descriptive and
inferential indices through a repeated measurement method and
utilization of a one-way ANOVA test and SPSS v.22. The Wilcoxon
signed-rank test was used to compare population mean ranks. Also, for
the comparison between the different groups, Chi-square and
independent-sample t-test were employed and a significance level was
considered when P-value was<0.05.
Ethical Considerations
Before entering the study, all the patients were informed about the
process and research objectives and were requested to fill in a written
consent form subjectively. Also, all of them were given referral letters
for rapid and unconditional hospitalization in case they witnessed any
severe complications during the outpatient treatment such as severe
bleeding, severe pain, nausea, and vomiting. All the study’s procedures
were conducted under the Declaration of Helsinki, and the medical files
of the patients were kept confidential. All the cost in this study was
bored by the research team and no additional costs were requested from
the patients. Fortunately, none of the patients in this study
experienced intolerable pain, severe hemorrhage, and other
complications. Additionally, all patients received a follow-up for
treatment control. This research was approved by the ethical committee
of Jahrom University of Medical Sciences issued with code No.:
IR.JUMS.REC.1396.143, and it was further registered in the Iranian
registry of clinical trials with code ID of IRCT20200122046221N1.
Results
Descriptive Findings
In the current study, among the 110 eligible patients, 90 patients were
evaluated and randomly allocated into three distinctive groups, each
consisting of 30 participants. The first, second, and third groups
received a dose of misoprostol,
misoprostol plus
methylergometrine, and misoprostol
plus oxytocin, respectively, and were thus named accordingly (Figure 1).