Comparison of sublingual, vaginal, and oral misoprostol in cervical ripening for first trimester abortion.

OBJECTIVES: To compare the effectiveness and tolerability of misoprostol as a cervical ripening agent in first trimester abortion through three different routes of administration before surgical evacuation (SE).
MATERIALS AND METHODS: It was a hospital based prospective randomized open labeled parallel study. A total of 150 randomly selected married women were divided in three groups for sublingual (S/L), vaginal and oral 400 μg of misoprostol single dose administration. The drug was administered 3-4 h before SE in the S/L and vaginal groups and 12 h before the procedure in the oral group. Efficacy was assessed on the basis of time taken for ripening, dilatation achieved, duration of the procedure, intra-operative blood loss, and pain score. The tolerability was noted on the basis of side effects.
RESULTS: The mean time taken for cervical ripening was less in sublingual administration (3.7±1.2 hr) as compared to the vaginal and oral routes. The S/L group had significant cervical dilatation (P<0.001) and the duration of SE was less as compared to the vaginal and oral routes. However, the mean intraoperative blood loss was more in sublingual as compared to the vaginal and oral groups. The intra-operative pain score of the S/L group was significantly lower (1.9±1.1, P<0.05) as compared to the vaginal (2.6±1.7) or oral route (3.3±1.7). Loose motions and nausea/vomiting were more with the S/L and oral routes while blood loss was more in the vaginal route.
CONCLUSION: Administration of misoprostol by the sublingual route is better than the oral and vaginal routes for cervical ripening.

RCT Entities:   Population Interventions Outcomes

Introduction

Cervical dilatation is a critical step in vacuum aspiration (VA) and the beneficial effects of pharmacological agents over mechanical cervical dilatation are well established.[1] Prostaglandins (PGs) have revolutionized the treatment of abortions.[2] Although misoprostol (PGE1) was first introduced as a gastric ulcer protective agent, it became popular for its effect on cervical ripening and other advantages like less cervical injuries, minimal intra operative blood loss, reduced requirement of general anesthetics, and availability in different dosage forms.[2] Comparative studies of sublingual (S/L), oral and vaginal[3-7] misoprostol for cervical ripening have been carried out in different parts of the world. However, the data are scanty in Indian patients.[8] Hence, the present study was carried out to compare the effectiveness of 400 μg of misoprostol through three different routes (vaginal, S/L, oral) for cervical ripening in first trimester abortion prior to VA. This study also evaluates other parameters like side effects, operative ease, and patient acceptability of various routes of administration.

Materials and Methods

Patients with the complaint of amenorrhea and bleeding per vagina were admitted with the provisional diagnosis of threatened, incomplete, or missed abortion. Ultrasonography confirmed the clinical diagnosis. A total of 150 patients with missed or incomplete abortion and blighted ovum were enlisted for the current study. Informed consent was taken and study was approved by Institutional Ethics Committee (IEC) under protocol Vide No. F/Minutes-BOPGS/Med/Acad/KU/510. Inclusion and exclusion criteria, treatment allocation and follow up of patients in the study are shown in Figure 1.

Figure 1

CONSORT statement of the study

Study Design and Conduct

It was a prospective randomized study carried out at Government Medical College and Lal Ded Maternity Hospital, Srinagar, over 1 year period. The patients were divided into three groups of 50 each. The patients and the attendants were explained about the procedure and informed consent was obtained. Baseline investigations including Hb, bleeding time, clotting time, platelet count, blood grouping, and kidney function tests, liver function tests, urine examination, HBAsg, and thyroid function test were carried out. Misoprostol dose was decided from the previous studies.[389]

Group A (S/L misoprostol): The patients were given 400 μg of S/L misoprostol and examined at 2 to 3 h interval for different parameters.

Group B (vaginal misoprostol): 400 μg of misoprostol (soaked in saline) was placed in posterior fornix and the effects were noted at 2-3 h interval.

Group C (Oral misoprostol): The patients were given 400 μg of misoprostol (self administered) orally 12 h prior to the procedure. The effects of the drug were noted after 10-12 h of administration.

All the three groups were assessed for efficacy on the basis of various parameters like cervical dilatation measured with maximum size of Hagar's dilator passed through the Cervical os without any resistance. Other parameters were intra-operative blood loss that was measured after sieving away the products and then subtracting the amount of liquor for the gestational age from the total aspirate, duration of the procedure, associated complication and the intra-operative pain score (based on a nominal scale of 0-10 with 0-3 as mild; 4-6 as moderate and 7-10 as severe pain requiring injectable analgesics). Before surgical evacuation the patients were asked about the side effects like abdominal pain graded from 0 to 3 (0 for no pain, 1 for mild pain, 2 for moderate pain that did not require analgesics and 3 for severe pain requiring treatment with analgesics), nausea, vomiting, shivering, and vaginal bleeding ranging from 0 to 3 (0 for no bleeding, 1 for minimal spotting, 2 for bleeding like menstrual flow, and 3 for severe bleeding).[9]

In all the three groups patients were discharged from the hospital 3-4 h after the completion of the procedure if all the parameters were normal and no complication observed.

Statistical Analysis

The data were recorded in mean ± SD. ANOVA followed by a multiple comparison (Kruskal Walli's) test was applied. F-value, degree of freedom, and P<0.05 were considered statistically significant. The chi-square test was applied wherever applicable. SPSS 15.0 statistical package was used for analyzing the data.

Results

The age and obstetric profile of the study population was comparable [Table 1]. A majority of the patients were diagnosed as incomplete abortion in the three groups, but the overall impact of this diagnosis over the study parameters was not of any statistical significance.

Table 1

Epidemiological and obstetric profile of study patients

Cervical ripening was significant in the S/L and vaginal routes as compared to the oral route (P<0.01) [Table 2;Figure 2]. The time taken for cervical ripening was less in S/L administration (3.7±1.2) as compared to the vaginal and oral routes of misoprostol administration [Figure 2]. The sublingual group had significant cervical dilatation (P <0.001) [Figure 3] and less time duration for surgery (P<0.05) [Figure 4] as compared to the vaginal and oral routes [Table 2]. However, intra-operative blood loss was more in the S/L group as compared to the vaginal and oral groups [Figure 5]. The mean intra-operative pain score of the sublingual group was significantly lower (P<0.05) as compared to the vaginal or the oral route [Table 2]. Abdominal pain was observed in all three groups while vaginal bleeding was more in the vaginal route, loose motion in the oral group and nausea, vomiting with gastrointestinal adverse effect was observed with the oral and sublingual routes of misoprostol.

Table 2

Comparisons of different parameters in patients administered 400 mcg of misoprostol by different routes

Figure 2

Cervical ripening in the studied subjects (n)

Figure 3

Dilation (mm) achieved with single dose in the studied subjects

Figure 4

Duration of procedure (min) in the studied subjects

Figure 5

Intra operative blood loss (ml) in the studied subjects

Discussion

Several studies have assessed the efficacy of prostaglandins (PGs) with or without mifepristone.[1011] It would be desirable to develop a regimen without mifepristone since it is expensive and not available in many countries.[12] Misoprostol is the PG of choice as it is cheap and stable at room temperature and available in different dosage forms.[13]

The present study observed that the cervical ripening effect and the mean time taken by misoprostol were favorable among the S/L group followed by the vaginal group [Figure 2]. The observed difference can be attributed to the different absorption kinetics and subsequent more systemic bioavailability with the S/L and vaginal routes than oral administration. Our results were consistent with the observations by Saxena et al.[8] and Tang et al.[14] However, the effects with the oral route were not as promising as observed in the earlier studies.

The mean intra-operative blood loss was less in the oral group, albeit it was higher than reported by Saxena et al.[8] The total duration of surgery was less in the S/L group that can be explained on the basis of the more cervical ripening and dilatation achieved in this group. These results are however different from those obtained by Saxena et al.[78]

Pain during operation in our study was found to be mild in case of S/L group with 18% of cases belonging to this group experiencing no pain while in other two groups, pain would range from mild to moderate in severity and the intra operative pain score was found to be significantly lower in case of S/L group than the other two study groups. Saxena et al. also found the significant difference with regard to this parameter.[8]

The observed side effects like abdominal pain, loose motions, vaginal bleeding, and nausea/vomiting were quite different from the earlier studies by Tang et al.[13] where the incidence was high which may be because of the higher and the frequent dosing used in the first study.[12] Vaginal bleeding in our study was more in the vaginal group than the other two groups, which could be attributed to the sustained peak plasma concentration in this route.

Ho et al.[15] in 1997 conducted a comparative study between oral and vaginal administration and concluded that oral administration is convenient and more acceptable to women and Ngai et al.[16] showed that oral administration of 400 μg of misoprostol 3 h before VA is as effective as a similar regimen of vaginal misoprostol. However, administration of oral drug with water 3 h before operation may cause problems especially if the patient requires general anesthesia for SE.[14] These, clinical studies have shown that the vaginal route is superior to oral misoprostol in termination of first trimester pregnancies. Sublingual misoprostol in medical termination of pregnancy has been studied.[15] The buccal mucosa being very vascular and misoprostol tablet being soluble in water dissolves within 10-15 min of administration.[14] This route is convenient to use, avoids vaginal administration and the ingestion of water before anesthesia (in case needed). A pilot study has shown that sublingual misoprostol with or without mifepristone is useful in first-trimester medical abortions.[13]

The present study has few limitations as it was not a placebo-controlled trial, the number of patients was relatively less, repeat dose versus single dose, and pharmacokinetic parameters while comparing three routes were not studied, which are highly warranted to establish the comparative results of the present study. It can be concluded that sublingual misoprostol is an effective and favorable cervical ripening agent for first trimester abortion as compared to vaginal and oral dosage forms.