A prospective study on the effectiveness of a combination regime (Mifepristone and Misoprostol) in comparison with Misoprostol for missed abortion

Abstract

Introduction:

Misoprostol is widely used in the medical management of missed abortions. However, pretreatment with Mifepristone has shown to be effective but still not recommended to be used in missed abortions.

Aims and Objectives:

To compare the outcome of medically managed missed abortion or blighted ovum using combination regime (Mifepristone and Misoprostol) vs Misoprostol alone.

Materials and Methods:

It was a prospective single-centre study performed in the Department of Obstetrics and Gynaecology, HIMSR and HAHC hospital, New Delhi, over, for one year. All the patients with diagnosed missed abortions were randomized into two groups (Group A and Group B). Group A was given Mifepristone 200 mg orally followed by Misoprostol 800 microgram per vaginal. Group B was given Misoprostol 800 microgram per vaginal. All the patients were observed for 24 hours for the expulsion of products of conception following the given regime. Ethical approval was taken from the Institutional Ethical Committee.

Results:

Both groups were comparable in demographic characteristics. On applying Fisher’s exact test, it has been observed that the odds of nonexpulsion of the product of conception, time taken in expulsion, and surgical evacuation because of excessive bleeding were significantly higher in Group B (Misoprostol) compared with Group A (Mifepristone followed by Misoprostol). The cost-effective analysis showed that the cost is higher among Misoprostol Group B compared with combination drugs of Group A (Mifepristone + Misoprostol), but this result is not significant.

Conclusion:

Mifepristone can be considered before Misoprostol in missed abortions. This regime might decrease the need for surgical evacuation.

Introduction

Missed abortion is defined as the intrauterine death of the embryo or foetus that may go unrecognized without expulsion of the products of conception (POC). It constitutes approximately 15% of clinically diagnosed pregnancies. Women with a missed abortion may present late due to the lack of apparent symptoms, but this has decreased these days due to routine early scans for cardiac activity.[1] Transvaginal sonography (TVS) currently allows the close monitoring of the intrauterine cavity making the pregnancy failure to be reliably diagnosed at an earlier stage. Another advantage of TVS is that it facilitates monitoring of the response to medical management of early pregnancy failure, an emerged out alternative to surgical termination.[2]

In the past, surgical evacuation was considered as early as possible for the first-trimester missed abortion. This was firstly because of prompt treatment designed to prevent blood loss or infection and secondly due to patient-driven desire to end a nonviable pregnancy.[3] Along with the anaesthesia risk, surgical evacuation may have many complications. Nowadays, medical management is considered, which is effective, safe and acceptable.[4]

Medical termination of pregnancy (MTP) using a protocol that includes Mifepristone and Misoprostol was accepted into comprehensive practice. This drug regimen was consistently shown to be associated with high success rates of 90%-95%.[5] However, medical treatment of pregnancy failure (blighted ovum or missed abortion) has gained wide acceptance with the PGE1 analog that is Misoprostol. There are various advantages of this PGE1 analog that is Misoprostol like of being inexpensive, can be easily stored and readily available. The varied success rates (62%-88%) following the administration of this prostaglandin regime could be attributed to differences in the selection of patients, different dosing regimens and various routes of administration, follow-up period and definition of success.[6,7]

It is expected that the Mifepristone pretreatment may increase the success of treatment with PG, because it increases the uterine smooth muscle contractility. Protocols combining Mifepristone and PG analogs for the treating early pregnancy failure have been studied, showing a success rate ranging from 52% to 84%.[8,9]

Mifepristone is anti-progesterone, so it blocks the progesterone hormone necessary for continuation of pregnancy. That is why it is primarily used in medical termination of pregnancy. It was thought that in cases of missed abortion, already the process of continuation of pregnancy is halted, so Mifepristone is not needed. Only Misoprostol can have good effects for termination such pregnancies.

As Mifepristone is having other effects too like initiating uterine contractions (activity) and cervical ripening to some extent, it can also be used in missed abortion cases for the better effect of Misoprostol like we used in medical termination. Mifepristone is costlier than Misoprostol, but it is less costly as well as safe with minimal side effects in comparison with surgical evacuation. So, if any drug may decrease the chances of undergoing surgical method of termination of missed abortion, then it should be considered. That is why more studies should be performed on different dosage regimes of Mifepristone with or without Misoprostol in missed abortion cases.

Despite the available studies, there is no consensus on use of Mifepristone in the medical regimen for the treatment of missed abortion although it is being used in medical termination of pregnancy. Hence, different regimens of Misoprostol have been studied and used more or less successfully, and it is one of the most confusing aspects of the medical treatment of missed abortion. Keeping all this in mind, we have planned this study with the following aims and objectives.

1. To study the success of the regime in terms of complete expulsion following the administration of combined Mifepristone and Misoprostol with only Misoprostol in cases of missed abortion.

2. To study the cost-effectiveness following the administration of combined Mifepristone and Misoprostol with only Misoprostol in cases of missed abortion.

Materials and Methods

It is a prospective single-centre study performed in the Department of Obstetrics and Gynaecology, HIMSR, and HAHC hospital over, for one year. All patients whether coming to the outpatient department or gynaecology casualty with diagnosed missed abortions on ultrasound with or without early pregnancy complaints like pain or spotting with haemoglobin level >8.0 g/dL were included in the study. Patients with incomplete or complete abortion at the time of presentation, inevitable abortion (products of gestation bulging from the cervix), suspicion of an extra-uterine pregnancy, and patients with retained products of conceptions (RPOC) if they have taken pills on their own and with abnormal complete blood count tests, which was routinely obtained, were excluded. After fulfilling the inclusion criterion, the patients were randomized into two groups based on the days which they came, which means under which unit they were admitted.

Group A constitutes the patients who had come on Monday, Wednesday, Friday, and every 1^st, 3^rd, and 5^th Sunday. These patients were admitted under unit 1 and were given regime A. In regime A, Mifepristone 200 mg oral followed by Misoprostol 800 microgram per vaginal was given. Mifepristone was provided on an outpatient basis and the patient come after 48 hours for Misoprostol insertion following admission to the hospital. Group B constitutes the patients who had come on Tuesday, Thursday, Saturday, and every 2^nd and 4^th Sunday. These patients were admitted under unit 2 and were given regime B. In regime B, Misoprostol 800 microgram per vaginal was given. In both groups, Misoprostol was given after admission to the hospital.

All the patients were observed for 24 hours for the expulsion of products of conception following the given regime. The surgical evacuation was performed in case of excessive bleeding during observation for expulsion or no expulsion after 24 hours of observation. The standard procedure of surgical evacuation was followed. All women with Rh-negative blood type will be given anti-D intramuscularly. Following the evacuation, patients were discharged on the next day with an advice to return to the hospital for evaluation if they experienced significant bleeding, severe pain, or fever. The first follow-up visit was after two weeks if patients experience no complaints. At follow-up visit, a detailed clinical interview was asked, and all patients will undergo an ultrasound assessment of the uterine cavity.

The success of the regime was defined as no need for surgical intervention even after two weeks. The various outcomes measured were whether the patient was expelled completely, the time in which expulsion occurred, the need for surgical evacuation as well as indication of evacuation, cost-effectiveness in two groups, and any intervention performed after two weeks on follow-up visits. Data were collected in the predesigned Performa and entered into Excel sheets. Standard statistical analysis was performed. A P value of <0.05 was considered statistically significant.

Results

Over, for one year, the sample size in our study was 49 patients in each group, fulfilling the inclusion criterion. The demographic characteristics in terms of age, parity status, education level, or the presence of any comorbidity like diabetes, hypertension, etc., of both the groups were comparable, as shown in Table 1.

Table 1.

Demographic characteristics

	Groups		P (FE test)
	Group A (n=49) (Mife + Miso)	Group B (n=49) (Miso)
Age group
Up to 25 years	18	15
26-30	17	28	0.062
31-35	6	5
36-40	8	1
Parity status
1	37	35
2	9	10	0.912
>2	3	4
Education status
Illiterate	4	8
Primary	2	4	0.258
Middle	13	14
Secondary	13	11
Graduate and above	12	12
Comorbidity
Present	3	1	0.617
Absent	46	48

On comparing the two groups, it was observed that the odds of expulsion were significantly higher, 3.48 times, in Group A, which received pretreatment of Mifepristone along with Misoprostol, as compared to Group B, which received only Misoprostol. These data are shown in Table 2.

Table 2.

Comparison of the groups with regard to expulsion

Expelled	Groups		P (FE test)
	Group A (n=49) (Mife + Miso)	Group B (n=49) (Miso)
Yes	37	23	0.006 (s)
No	12	26
Total	49	49

On comparing the two drug groups about concerning the time to expel the POCs, it was observed that the odds of expulsion beyond 12 hours were the significantly higher, 3.07 times, in the group which received Misoprostol alone as compared to the group, which received the combination regime. That means significantly time taken for expulsion was less in Group A compared with Group B as shown in Table 3. Fifteen patients in Group A and 25 patients in Group B underwent surgical evacuation, and the rest of the patients were expelled without any intervention.

Table 3.

Comparison of the groups with regard to time to expel product of conception (POC)

Time to expel POC	Groups		P
	Group A (n=34) (Mife + Miso)	Group B (n=24) (Miso)
Within 12 h	24	13
>12 h	10	11	0.016 (s)
Total	34	24

On comparing the two drug groups with regard to evacuation in view of excessive bleeding, it was observed that the odds of evacuation required in view of bleeding were significantly higher, 2.69 times, in the group, which received Misoprostol alone as compared to the group which received the Mifepristone and Misoprostol both as shown in Table 4. On comparing the two drug groups, there was no significant difference with regard to evacuation in view of nonexpulsion of POC in the two groups.

Table 4.

Comparison of the groups with regard to evacuation in view of excessive bleeding

Evacuation in view of excessive bleeding	Groups		P
	Group A (n=49) (Mife + Miso)	Group B (n=49) (Miso)
Yes	10	20	0.028 (s)
No	39	29
Total	49	49

On comparing the cost incurred in the two comparison drug groups, it was observed that the mean cost was higher in the group, which was given Misoprostol alone as compared to the group, which received a combination of Mifepristone and Misoprostol; however, this difference in the cost was not significant as shown in Table 5.

Table 5.

Cost comparison in the two groups

Groups	Mean	SD	P (using Mann–Whitney U test)
Group A (Mifepristone + Misoprostol) (n=49)	911.29	868.17	0.176
Group B (Misoprostol group) (n=49)	1201.53	078.88

Complications were studied regarding excessive bleeding leading to shock, blood transfusion, uterine perforation, and infection. No complication was seen in either of the group.

Discussion

Missed abortion is one of the most common complications of early pregnancy. Its incidence is 12%-15% of clinically diagnosed pregnancies, and among these, 2%-6% of pregnancies may have documented foetal cardiac activity previously.[10] Recommendations on medical management of missed abortion are only on the use of Misoprostol and ACOG and NICE guidelines do not recommend Mifepristone prior to Misoprostol.[11,12] But various studies using this combination have shown a higher success rates.[13-15] Therefore, more trials are needed to compare the efficacy of Mifepristone followed by Misoprostol with Misoprostol alone.

In 2020, a multicentre, double-blind, placebo-controlled, randomized trial was performed between October 2017 to July 2019 in twenty-eight UK hospitals popularly known as MIFEMISO trail. A total of 711 women were randomly assigned in two groups. One set of women received combination of Mifepristone and Misoprostol (357 women) and other set received placebo and Misoprostol (354 women). Within 7 days, 59 (17%) of 348 women in the Mifepristone plus Misoprostol group did not pass the gestational sac spontaneously versus 82 (24%) of 348 women in the placebo plus Misoprostol group (P = 0·043). The surgical intervention was required in 62 (17%) of 355 women in the Mifepristone plus Misoprostol group versus 87 (25%) of 353 women in the placebo plus Misoprostol group (P = 0·021). Adverse events between the study groups were comparable.[14]

Schreiber et al. in their study in 2018 defined the successful treatment as the gestational sac expulsion with one dose of Misoprostol by the first follow-up visit with no additional intervention up to 30 days after treatment. Successful treatment occurred in 124 of 148 women (83.8%) in the Mifepristone-pretreatment group and in 100 of 149 women (67.1%) in the Misoprostol-alone group.[15]

Sinha et al. did a double-blind randomized placebo-controlled trial, which showed the significant success rate (no need for surgical evacuation) in study group (P = 0.009). They have found that the 88.7% in Group I (Mifepristone or study group) as compared to 57.8% in Group II (placebo or control group) were expelled completely following medical management. The need for surgical evacuation was significantly less in Group I compared to Group II (13.34 vs. 42.2%, P = 0.002).[16]

There were few studies that showed that the pretreatment with Mifepristone did not significantly decrease the need for surgical evacuation. Stockheim et al. did a survey in 2005, and they found that the need for surgical intervention was not statistically different: 65.5% in group I (Mifepristone combined with Misoprostol) versus 73.6% in group II (Misoprostol only). The most common reasons for surgical evacuation were retained products in both the groups.[17]

Annelise et al. in 2002 did a multicentre trial to compare the efficacy of two different medical treatment regimens with conventional surgical evacuation (SE) in women with missed abortion. The two different regimes used were as follows: Mifepristone 600 mg orally + Misoprostol 0.4 mg vaginally (Mf + Ms) or Misoprostol 0.4 mg vaginally (Ms). They have found that the retreatment with Mifepristone does not increase the success rate.

Regarding complications of medical management, most of the studies have not mentioned any increased side effects with either of the regime, which was comparable to our study. One case report described a fatal infection by Clostridium sordellii occurring in women treated with Mifepristone for termination of pregnancy.[18] But later in literature search, we have found no other studies showing any causal association between Mifepristone administration and this rare infection was proven.

In our study, there was significant expulsion following pretreatment with Mifepristone, which was comparable with other studies. The only difference was the number of days in which no intervention was needed to define the success of the regime. Although the present study is a single-centre study with a small sample size, more extensive studies are required in order to formulate this regime in guidelines.

Conclusion

Mifepristone can be considered prior to Misoprostol in missed abortions. This regime might decrease the need for surgical evacuation as well cost burden.

Key points to summarize

1. The odds of nonexpulsion of the product of conception, time taken in expulsion, and surgical evacuation in view of excessive bleeding were significantly higher in Mifepristone pretreatment group (Group B) than Misoprostol only Group A.

2. Although cost analysis did not show any significant difference, but the cost was lower in the Mifepristone pretreatment group.

Novel take home message

Mostly pretreatment with Mifepristone is not used in missed abortion cases, but it may decrease the time taken in expulsion or chances of having surgical management. This combined regime may also be more cost effective, but for this, more studies are needed involving large number of cases.

Ethical approval

Taken (HIMSR/IEC/015/2021).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.