A randomized trial to compare the use of sublingual misoprostol with or without an additional 1 week course for the management of first trimester silent miscarriage

Abstract

BACKGROUND: This randomized controlled trial compared the use of sublingual misoprostol with or without an additional 1 week course of sublingual misoprostol for the medical management of silent miscarriage. METHODS: A total of 180 women who had silent miscarriage (<13 weeks) was given 600 µg of misoprostol every 3 h for a maximum of three doses. These women were randomized into two groups: (i) no extended course of misoprostol or (ii) an extended course of sublingual misoprostol 400 µg daily for 1 week. The primary outcome measure was complete miscarriage rate. RESULTS: The success rates for complete miscarriage were similar in both groups (group 1: 92.2%; 95% CI: 86.1–97.5% and group 2: 93.2%; 95% CI: 84.6–96.8%). There were no serious complications. The incidence of diarrhoea was higher (P < 0.01) in the group with an extended course of sublingual misoprostol. Other side-effects were similar. CONCLUSION: Sublingual misoprostol is useful for the management of silent miscarriage. An additional 1 week course of sublingual misoprostol did not improve the success rate or shorten the duration of vaginal bleeding. Instead, it increased the incidence of diarrhoea.

Introduction

Miscarriage occurs in 15% of all first trimester pregnancies (Laferia, 1986). Surgical evacuation of the uterus used to be the standard management. It is a quick procedure and the success rate is very high. However, surgical evacuation may be associated with complications, e.g. infection, perforation of the uterus or Asherman’s syndrome. Although the incidences of these complications were low, the future fertility of the women may be jeopardized. Recently, expectant management and medical management using a prostaglandin analogue were being investigated as an alternative management. The incidence of complete miscarriage after expectant management is variable and depends on the duration of observation (Nielsen and Hahlin, 1995; Jurkovic et al., 1998). Expectant management may be useful in selected patients but the unpredictable success rate makes it unacceptable to some patients as a routine method of management. Reports from the literature have shown that the success rate ranged from 25–85%. The reported success rates were higher in the studies that included women with incomplete miscarriage (Nielsen and Hahlin, 1995; Hurd et al., 1997; Jurkovic et al., 1998; Nielsen et al., 1999; Ngai et al., 2001). Medical management may be a better alternative for some women.

Medical management is being used increasingly as an alternative for management of miscarriage. Many studies have been performed to investigate the best regimens of prostaglandin analogues with or without mifepristone. The best regimen is yet to be determined. However, it is likely to involve the use of misoprostol without mifepristone. Mifepristone is expensive and not available in all countries. There is some evidence to show that the addition of mifepristone does not improve the success rate of medical management of silent miscarriage (Gronlund et al., 2002). Misoprostol is the prostaglandin analogue of choice as it is cheap and easily available. Various routes of administration of misoprostol, including oral, vaginal and sublingual, have been studied for termination of pregnancy in the first trimester (El-Refaey et al., 1995; Tang et al., 2002a,b, 2003a). A pharmacokinetic study has shown that sublingual misoprostol has the highest bioavailability and the shortest time to the peak concentration among the three different routes of administration (Tang et al., 2002c). Recently, a study comparing the use of sublingual against vaginal misoprostol in the management of silent miscarriage has shown that the success rates (87.5%) were similar for both routes of administration (Tang et al., 2003b). Sublingual misoprostol is convenient to administer and is the route of choice of some women who find vaginal administration unacceptable.

It is the objective of this randomized trial to investigate whether the addition of an extended 1 week course of sublingual misoprostol can improve the success rate of medical management and shorten the duration of vaginal bleeding after miscarriage.

Materials and methods

Women with a diagnosis of first trimester spontaneous miscarriage <13 weeks of gestation were recruited. An ultrasound examination was performed for all women to confirm the diagnosis of silent miscarriage (Bernard and Cooperberg, 1985): (i) intrauterine gestational sac with a mean sac diameter of ≥2 cm without a fetal pole; (ii) presence of a fetal pole with no cardiac pulsation; (iii) the gestational sac was <2 cm with no interval growth or persistent absence of fetal cardiac pulsation on rescanning 7–10 days later. Incomplete miscarriage was excluded. The study protocol was approved by the Ethics Committee, Faculty of Medicine, University of Hong Kong. Each woman gave her informed consent prior to randomization.

The study was carried out from July, 2002 to January, 2004. Eligible women were randomized according to computer-generated random numbers into two groups. Women in both groups received 600 mg misoprostol sublingually every 3 h for a maximum of three doses (day 1). Additionally, women in group 2 also received 400 mg misoprostol sublingually daily for a further week (day 2–8). This was an open randomized study and both the subjects and the investigators knew the treatment that the women had received. The women were instructed by the investigator to put the three tablets of misoprostol under the tongue themselves. They were not allowed any food or drink for the next 20 min to allow complete dissolution of the tablets. The blood pressure, pulse rate and side-effects were recorded every hour and the body temperature was recorded every 3 h. Oral or parenteral analgesic was given if the women complained of severe pain. The women were asked to inform the nurse when they passed any tissue at the hospital and they were given a bottle with formalin to collect any tissue passed at home. The tissue was sent for histological confirmation.The woman was discharged after completion of the course of misoprostol if there was no heavy vaginal bleeding and she was not in pain. Women in group 2 were given 400 mg misoprostol to be taken daily at home starting from day 2 of the study. Emergency surgical evacuation was carried outif the blood loss or abdominal pain was uncontrolled. All the women were asked to use barrier method for contraception if necessary. The outcome of the study was assessed on day 9. A transvaginal ultrasound examination of the pelvis was performed. Surgical evacuation was done if a gestational sac was still present or if there was significant amount of products of conception in the uterus together with clinical evidence of heavy vaginal bleeding. Otherwise, the amount of bleeding was monitored and the woman was asked to come back on day 43 for the bleeding pattern and return of menstruation. The outcome of treatment was classified as complete miscarriage if surgical evacuation was not required.

The primary outcome measure was the complete miscarriage rate. The incidence of side-effects, duration of vaginal bleeding and the change in haemoglobin level were also studied. Differences in continuous variables will be analysed with Student’s t-test for normally distributed data and the Mann–Whitney U-test for skewed data. Differences in discontinuous variables will be analysed by χ²-test and the Fisher exact test as appropriate.

The difference in complete miscarriage rate was used to calculate the sample size required. According to the previous studies, the use of this regimen of sublingual misoprostol without an extended course would achieve a complete miscarriage rate of 87.5% (Tang et al., 2003b). The use of an extended course of misoprostol would be considered superior if it could achieve a complete miscarriage rate of 97.5%. A sample size of 90 in each group gave 80% power in detecting a difference of 10% in complete miscarriage rate with an alpha of 0.05.

Results

Two hundred and six women with a diagnosis of silent miscarriage were screened (Figure 1). Twelve women did not want to join the study since they preferred surgical method. Eight women passed the products of conception before treatment was started and six women had other medical problems and did not satisfy the inclusion criteria. One hundred and eighty women met the inclusion criteria and agreed to participate (Figure 1). The demographic characteristics of these 180 women who underwent medical management of miscarriage are shown in Table I. There was no significant difference between the two groups with respect to the age, weight, height and gestational age. The complete miscarriage rate was 92.2% (95% CI: 86.1–97.5%) for group 1 and 93.3% (95% CI: 84.6–96.8%) for group 2. There was no significant difference between the two groups (Table II). Three subjects, two from group 1 and one from group 2, did not come back for follow-up on day 43. One subject from group 1 passed the tissue on the day of misoprostol; an ultrasound examination on day 9 showed incomplete miscarriage and she did not come back on day 43. The other subject from group 1 did not pass any tissue on the day of misoprostol and she did not come back on day 9. The subject from group 2 did not pass any tissue on the day of misoprostol; an ultrasound examination on day 9 showed incomplete miscarriage and she did not return on day 43 for follow-up. The median induction–miscarriage intervals and duration of vaginal bleeding after the miscarriage were similar in both groups. There was no significant change in the haemoglobin level before and after miscarriage in both groups. The side-effect profiles are shown in Table III. The incidence of diarrhoea was significantly higher in group 2 from day 2 to day 9. No serious complications occurred.

Discussion

Misoprostol has been used orally and vaginally for medical abortion and management of miscarriage (El-Refaey et al., 1995; Chung et al., 1997; Ngai et al., 2001). Most studies have shown that the vaginal route of administration is more effective and gives a higher complete miscarriage rate. However, the oral route is more convenient and acceptable (Ho et al., 1997). This is especially true for regimens using misoprostol alone because repeated administrations are required. Apart from the oral and vaginal routes, it has been shown that misoprostol can be taken sublingually. A pharmacological study also showed that sublingual misoprostol gave the shortest time to peak serum concentration and greatest systemic bioavailability (Tang et al., 2002c). This means that sublingual misoprostol may have the most potent and quickest onset of action compared to the other routes of administration. It has been shown that sublingual misoprostol is as effective as vaginal misoprostol for the management of silent miscarriage. The success rate of a regimen using 600 mg misoprostol every 3 h for up to three doses was 87.5% and it was the same for both vaginal and sublingual routes (Tang et al., 2003b). Other regimens using a single daily dose of 400–800 mg of misoprostol have also been studied. These regimens required the women to come back daily for ultrasonography to decide on the need for repeating the dose of misoprostol. The reported success rate for silent miscarriage ranged from 70 to 86% with regimens using single daily dose of misoprostol (Dementroulis et al., 2001; Ngai et al., 2001; Gronlund et al., 2002; Bagratee et al., 2004). The need for an intense daily visit and ultrasound examination for 2–3 days after misoprostol may be inconvenient for the women and may increase the workload of the clinic if this is used as a routine method of management of silent miscarriage. The ideal medical regimen of management of silent miscarriage would be one that can be finished within a short and defined period of time. The clinically acceptable success rate should be ∼90%, as in medical abortion. This is especially true for the management of miscarriage since expectant management may already result in a success rate of up to 50% (Jurkovic et al., 1998; Ngai et al., 2001). Regimes with a success rate of <85% may not be useful for clinical practice as extra manpower and resources are required for following up the women in order to identify the failure cases. In addition, a prolonged period of treatment and follow-up may not be acceptable to women who already have to undergo the stress of miscarriage.

Our previous study using 600 mg sublingual misoprostol every 3 h for three doses has shown that the success rate was 87.5% (Tang et al., 2003b). The current study actually confirmed the previous findings. The success rate of the current study (>90%) was better than that of the previous one. This might be due to statistical variation but it was more likely to be the consequence of an increase in confidence of the subjects and the medical staff in this regimen of medical management. It was also shown in the previous study that many of the subjects required surgical evacuation because of incomplete miscarriage. It was proposed that women who did not respond to the course of misoprostol on the first day might respond to an extended course in the subsequent week. However, the results of this study showed that the success rates of both regimens were similar. It seemed that adding another week of misoprostol did not improve the overall success rate but it would increase the incidence of diarrhoea. The incidences of other side-effects were similar and comparable to our previous study using similar repeated doses of misoprostol sublingually or vaginally (Tang et al., 2003b).

In conclusion, medical management using repeated doses of misoprostol is effective for the management of silent miscarriage. An additional 1 week course of misoprostol does not improve the clinical outcomes.

Acknowledgement

The work described in this paper was supported by a grant from the Committee on Research and Conference Grants of The University of Hong Kong of the Hong Kong Special Administrative Region, China.

References