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).