A randomized controlled trial comparing medical and expectant management of first trimester miscarriage

J.S. Bagratee1,4, V. Khullar2, L. Regan2, J. Moodley1,3 and H. Kagoro3

1 Department of Obstetrics and Gynaecology, Nelson R.Mandela School of Medicine, University of Natal, Durban, South Africa, 2 Department of Reproductive Science and Medicine, Imperial College and St Mary’s Hospital, London, UK and 3 Medical Research Council, Durban, South Africa

4 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Nelson R.Mandela School of Medicine, Private Bag 7, Congella, 4013, South Africa. e-mail: bagrateej1{at}nu.ac.za


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: We aimed to determine whether outpatient treatment of miscarriage with vaginal misoprostol is more effective than expectant management in reducing the need for surgical evacuation of retained products of conception (ERPC). METHODS: Of 131 eligible women with first trimester miscarriage, 104 agreed to randomization to either 600 µg misoprostol or placebo intravaginally. They were assessed the following day and administered a second dose of their allocated treatment if miscarriage was not complete. Those not successful after two doses were seen on day 7, and, if miscarriage was not complete, an ERPC was performed. RESULTS: The success rate of medical management was 88.5% (46/52) compared with 44.2% (23/52) for expectant management. There was no significant difference in success rate (100 versus 85.7%) in women treated with an incomplete miscarriage. Women with early pregnancy failure had a success rate of 87% with misoprostol compared with 29% with expectant management [odds ratio (OR) 15.96; 95% confidence interval (CI) 5.26, 48.37]. The complete miscarriage rate was achieved quicker in the medical group than the expectant group by day 1 (32.7 versus 5.8%) and by day 2 (73.1 versus 13.5%) of treatment. There were no differences in side-effects, bleeding duration, analgesia use, pain score and satisfaction with treatment. Women in the expectant group made more outpatient visits (5.06 versus 4.44%; OR = –0.62, 95% CI –1.04, –0.19). More women in the medical group (90.4 versus 73.1%; OR 1.26, 95% CI 1.05, 1.50) would elect the same treatment in the future. CONCLUSIONS: Medical management using 600 µg misoprostol vaginally is more effective than expectant management of early pregnancy failure. Misoprostol did not increase the side-effect profile and patient acceptability was superior to expectant management.

Key words: early pregnancy failure/expectant management/first trimester miscarriage/medical management/vaginal misoprostol


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Miscarriage is the most common complication of pregnancy, occurring in 10–20% of clinically recognized pregnancies (Warburton and Fraser, 1964Go; Regan et al., 1989Go; Alberman, 1992Go). The standard management of miscarriage for >50 years has been surgical evacuation of the retained products of conception (ERPC) because of the fear of haemorrhage and sepsis secondary to illegal abortion (Hartman, 1953Go). However, ERPC is associated with risks of anaesthesia, haemorrhage, infection, cervical trauma, uterine perforation and intrauterine adhesions. Four to 10% of women are treated with antibiotics for infection and this may predispose patients to secondary infertility, pelvic pain and an increased risk of ectopic pregnancy (Chung et al., 1982Go). The advent and widespread use of antibiotics, improved general health of women, easy access to health services, the early diagnosis of miscarriage by ultrasound and the legalization of abortion have resulted in investigators studying non-surgical methods for the treatment of miscarriage.

Expectant management of first trimester miscarriage has been compared with ERPC since 1995 with varying results (Nielsen and Hahlin, 1995Go; Chipchase and James, 1997Go; Hurd et al., 1997Go; Jurkovic et al., 1998Go). Nielsen and Hahlin (1995Go) showed that expectant management had a 79% success rate whereas Jurkovic et al. (1998Go) found a 25% success rate with follow-up up to 6 weeks. Furthermore, only 38% of patients in the latter study accepted a trial of expectant management, suggesting that the uncertainty as to when complete miscarriage will occur may be stressful to patients.

Active management using medical treatment on an outpatient basis seems to be an acceptable alternative. Mifepristone, an antiprogesterone, and misoprostol have been found to be effective for the management of medical abortion (Peyron et al., 1993Go). Nielsen et al. (1999Go), however, did not find a significant difference in avoiding curettage when comparing mifepristone plus oral misoprostol (82%) with expectant management (76%). Misoprostol used alone via the oral route has achieved success rates of 47% (Chung et al., 1999Go) to 95% (Henshaw et al., 1993Go).

Vaginal administration of misoprostol, used in four trials (total of 82 patients), has been associated with success rates of between 82 and 89% (Creinin et al., 1997Go; Zalanyi, 1998Go; Autry et al., 1999Go; Demetroulis et al., 2001Go). However, data from randomized controlled trials are limited and a total of 55 patients only have been assigned to vaginal misoprostol (Ngai et al., 2001Go; Wood and Brain, 2002Go). The ideal dose of misoprostol has not been established with side-effect rates varying from 4 to 73% (Ngai et al., 2001Go; Wood and Brain, 2002Go). The results of expectant management also need to be reproduced in other settings following the reports of Nielsen et al. (1999Go) and Chipchase and James (1997Go).

We therefore designed a prospective randomized, double-blind, placebo-controlled trial to determine whether medical management using vaginal misoprostol is superior to expectant management.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Participants
All women presenting to the Early Pregnancy Assessment Unit (EPAU) at St Mary’s Hospital, London, UK, from August 2001 to March 2002 with spontaneous incomplete miscarriage and early pregnancy failure up to 13 weeks gestation were invited to participate in the trial. Local Ethical Committee approval was obtained and all participants gave informed consent.

Diagnosis of incomplete miscarriage was made when there was a history of passage of tissue and/or blood and confirmed by transvaginal ultrasound (6.5 MHz transducer: Kretz, Austria) identifying heterogeneous material in the uterine cavity with an endometrial thickness of >15 mm. Early pregnancy failure was diagnosed when clinical examination revealed a closed cervical os and ultrasound confirmed either an intact gestational sac of >20 mm diameter with no visible embryonic pole (anembryonic) or an intrauterine gestation with an embryo of crown–rump length >5 mm without heart pulsations. Symptomatic and asymptomatic miscarriages were differentiated by the presence or absence of vaginal bleeding.

Women with complete miscarriage as assessed by endometrial thickness of ≤15 mm on transvaginal ultrasound, fever (>37.5°C), haemoglobin <10 g/dl, contraindication to prostaglandin therapy (asthma, hypertension, glaucoma, mitral stenosis), and excessive bleeding requiring emergency ERPC were excluded.

Sample size calculation
The required sample size was based on improving the success rate of 70% with expectant management to 95% with the use of vaginal misoprostol. A trial with a power of 90% and an {alpha} of 0.05 would require a sample of 96 women.

Randomization
Randomization of 104 women was carried out by computer-based allocation of each study number to either misoprostol (medical treatment) or placebo for the expectant management arm. Three misoprostol or placebo tablets were placed in each of two small envelopes and sealed. These small envelopes were then placed in consecutively numbered larger envelopes according to the random schedule and sealed by staff not involved in the study.

Protocol
Following informed consent, the sealed envelopes were opened and consecutively enrolled women had their allocated treatment of either 3x200 µg misoprostol or 3 placebo tablets placed in the posterior fornix of the vagina by the doctor or nurse in the EPAU. Neither the investigator nor the women knew the treatment administered. Baseline haemoglobin and white cell count were obtained and Rhesus-negative women received anti-D immunoprophylaxis. Paracetamol with codeine was prescribed for pain and they were provided with telephone numbers to contact a doctor if necessary. All women attended for speculum and bimanual examination, and ultrasound the next day (day 1). Those women diagnosed as complete miscarriage were discharged with follow-up in 14 days time. The remaining women had a second dose of their allocated treatment and were seen the next day (day 2). Women not successful by day 2 were asked to return on day 7 and if miscarriage was not complete, were scheduled for an ERPC in theatre. All women scheduled for ERPC had their surgery performed as day cases.

All women in the study were seen 14 days later after the diagnosis of complete miscarriage or the procedure of ERPC for signs of bleeding, pain and infection. They had repeat full blood counts and serum {beta}hCG. If the {beta}hCG was >20 IU, patients were seen weekly till a negative result of <20 IU. A questionnaire, including visual analogue scales, was used to assess the severity of pain, and the satisfaction of treatment.

The primary outcome measure was complete miscarriage without ERPC by day 7. The secondary outcome measures included the number of doses of misoprostol, duration of bleeding, incidence of pelvic inflammatory disease, incidence of nausea, diarrhoea and vomiting, the severity of pain, the use of analgesia, satisfaction with treatment and their future choice.

Statistical analysis was performed using Statistical Package for Social Sciences. Comparisons of groups were made using {chi}2-test or Fisher’s exact test as appropriate. Student’s t-test was performed for continuous variables.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Of 131 eligible women, 104 agreed to randomization, 12 elected to have an ERPC, eight expectant management and seven elected to have medical management. In women electing ERPC, all were successful without any complications at their 2 week check-up. Six of the seven women having medical management had complete miscarriages and four of the eight women electing expectant management were successful after follow-up lasting up to 28 days. None of these women experienced complications and remained well at their follow-up visit. The 104 women randomized to the trial attended the scheduled visits as per protocol and completed the trial (Figure 1). They were well matched for demographic and clinical data, and there was no significant difference in the distribution of incomplete miscarriage and early pregnancy failure (Table I).



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Figure 1. Flow diagram showing participants through each stage of trial.

 

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Table I. Baseline characteristics in the misoprostol (medical) and placebo (expectant) groups
 
The overall success rate of medical management was 88.5% compared with 44.2% for expectant management (Table II). There was no difference in those with incomplete miscarriage, with all seven women in the misoprostol group and 86% (12/14) in the expectant group having successful outcomes. In contrast, patients with a diagnosis of early pregnancy failure had a success rate of 86.7% (39/45) with misoprostol compared with 28.9% (11/38) with expectant management [odds ratio (OR) 15.96, 95% confidence interval (CI) 5.26–48.37].


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Table II. Outcome measures of misoprostol (medical) versus placebo (expectant) treatment
 
The presence of vaginal bleeding before treatment significantly increased the success rate in patients undergoing expectant treatment by 59% (23/39) but did not alter the overall success rate significantly in patients having misoprostol: 91.4% (32/35) versus 82.4% (14/17). Significantly more women with early pregnancy failure and bleeding had successful outcome with misoprostol (89.7%) compared with 44% with expectant management (Table II). The complete miscarriage rate was achieved more quickly in the medical group than the expectant group by day 1 (32.7 versus 5.8%) and by day 2 (73.1 versus 13.5%) of treatment (Figure 2).



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Figure 2. Cumulative miscarriage rates.

 
The secondary outcome measures and follow-up assessment are presented in Table III. One woman having medical management developed endometritis. She developed fever and pelvic tenderness after the second dose of misoprostol. Blood cultures were negative and she responded rapidly to antibiotics. The number of women requiring analgesia, the duration of analgesia use and the duration of sick leave were comparable between groups; however, women receiving misoprostol made fewer outpatient visits. There was no significant difference in the incidence of nausea, vomiting and diarrhoea between groups. No women required blood transfusions. The haemoglobin concentrations and white cell counts were similar between groups at their follow-up visit 2 weeks later. The severity of pain and satisfaction with treatment was not significantly different between the groups. Significantly more women in the misoprostol group (90.4%) than in the expectant group (73.1%) would elect to have the same treatment rather than ERPC if they were to sustain a miscarriage in the future (OR 1.26; 95% CI 1.05–1.50).


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Table III. Secondary outcome measures assessed at the follow-up visit in women having misoprostol (medical) and expectant (placebo) treatment
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This double-blind, randomized, controlled trial demonstrates the efficacy and safety of outpatient medical management of early pregnancy failure. The use of up to two doses of 600 µg misoprostol intravaginally with follow-up for 1 week reduced the need for ERPC by 90%, when compared with expectant management; RR = 0.1 (95% CI, 0.04–0.28). In addition, the complete miscarriage rate was achieved quicker in the medical group than the expectant group with one-third successful after 1 day and just less than three-quarters successful after 48 h following therapy.

There was no difference in outcome with either modality of management in patients with incomplete miscarriage, though our numbers were small. Some women may prefer to allow the natural process of expectant management to complete their miscarriage. This is a satisfactory option in cases of incomplete miscarriage rather than in situations of early pregnancy failures; however, 10% of women will still require an ERPC after 4 weeks of observation (Luise et al., 2002Go). Luise et al. (2002Go) followed up 221 women who chose expectant management of incomplete miscarriage and the cumulative success rates at 1, 2, 3 and 4 weeks were 54, 83, 89 and 91% respectively. Thus it is important that women are counselled appropriately regarding prolonged follow-up, repeated weekly hospital visits and the need for surgical intervention in those that fail to successfully evacuate the uterus in this time frame. The uncertainty as to when complete miscarriage will occur and the emotional trauma of carrying a non-viable pregnancy for a prolonged period may be stressful to some women. Medical treatment with an equivalent success rate and obviating the risks of surgery may be acceptable to this group of women with incomplete miscarriage.

Expectant management does not appear to be an attractive option in women experiencing an early pregnancy failure as borne out in this study. Jurkovic et al. (1998Go) also questioned the efficacy of expectant management after finding a success rate of 25% in women with early pregnancy failure followed up for 6 weeks. The presence of vaginal bleeding influences the success rate of women with early pregnancy failure having expectant management. In the absence of vaginal bleeding, none of the patients in this study had a complete miscarriage after 1 week of observation, whereas in those with vaginal bleeding, 44% were successful. This is similar to the success rate of 54% achieved in symptomatic early pregnancy failure by Schwarzler et al. (1999Go). In contrast, outpatient medical management using misoprostol was found to be superior to expectant management. Of note, the presence of vaginal bleeding in patients with early pregnancy failure having medical treatment did not significantly alter the success rate (89.7 versus 81.3%).

The 86.7% success rate in women with early pregnancy failure having misoprostol compares favourably with the only two randomized controlled trials in the literature. Both Ngai et al. (2001Go) and Wood and Brain (2002Go) allocated 25 women each to receive vaginal misoprostol and obtained an 80% success rate. The earlier study used 400 µg misoprostol on days 1, 3 and 5 and followed up patients for 2 weeks prior to ERPC. The latter study used up to two 800 µg doses on days 1 and 2 and reported an 80% success rate after 48 h. In comparison with the study by Wood and Brain (2002Go), we used up to two 600 µg doses and obtained a success rate of 73.1% after 48 h which improved to 88.5% by 1 week. This demonstrates that a combination of medical and expectant management improves the success rate in early pregnancy failure. The allowing of a period of time of 1 week in our study was highly acceptable. In all, 104 out of 131 eligible women were prepared to undergo medical or expectant management for this finite period, knowing full well that they would have an ERPC after 1 week if spontaneous resolution had not occurred. This removed anxiety and uncertainty as regards the resolution of their pregnancy loss. The time taken to have a complete miscarriage with both medical and expectant management is valuable information when counselling women on their options for treatment. Though over three-quarters of the women receiving misoprostol were successful after 48 h, the onset of bleeding resulted in a further 15% being successful by the end of 1 week. The question arises as to whether the use of repeated daily doses of misoprostol for ≥3 days will further improve the success rate. Confirmation of whether prolonged medical treatment is of value will require further study. However, one has to balance this against patient acceptability, cost and whether further doses of misoprostol on an already primed cervix will enhance uterine contractility without increasing gastrointestinal side-effects.

Medical treatment using mifepristone and misoprostol in legal abortion has been shown to evacuate the uterus safely and effectively without resort to surgical curettage (Peyron et al., 1993Go). Mifepristone, an antiprogestin, increases the uterine response to misoprostol in women with live pregnancies undergoing legal abortion (Norman et al., 1991Go). However, the addition of mifepristone to misoprostol has not improved the success rate of misoprostol used alone in managing miscarriage (Nielsen et al., 1999Go; Demetroulis et al., 2001Go). This is most likely due to the abnormally low progesterone levels associated with a failing pregnancy (Ledger et al., 1994Go).

A review by Ankum et al. (2001Go) found no advantage of medical management of miscarriage over expectant management. As medical management was found to be associated with up to a 50% incidence of gastrointestinal side-effects, these authors recommended that women with early pregnancy failure, including those without bleeding, should be offered a choice between expectant and surgical management following counselling. In our double-blind, randomized trial comparing medical and expectant management, we found no significant differences in gastrointestinal side-effects. Nausea was the most common side-effect, affecting about a third of patients in either group. In the other two randomized controlled trials, 26.6 and 4% of patients reported side-effects (Ngai et al., 2001Go; Wood and Brain, 2002Go). We found an incidence of diarrhoea of 21% in both groups, whereas in another study 45% of patients experienced diarrhoea while taking a regimen of three doses of 400 µg misoprostol 4 hourly (Chung et al., 1999Go). The use of sublingual misoprostol has been found to be just as effective as vaginal misoprostol, but the incidence of diarrhoea of >70% makes this route unattractive (Tang et al., 2003Go). It appears that our regimen of 600 µg vaginal misoprostol daily up to two doses was well tolerated by our patients with no increase in side-effects and no increase in pain as reported on visual analogue scales. Vaginal administration of misoprostol has been found to be more effective than the oral route and causes fewer gastrointestinal side-effects (El-Refaey et al., 1995Go). The pharmacokinetics of the vaginal route results in a lower peak concentration but a longer sustained blood level of misoprostol, thus producing fewer side-effects but a longer duration of action (Zieman et al., 1997Go).

There were no differences found in blood loss (day 14 haemoglobin), duration of bleeding, duration of convalescence, the number of patients taking analgesia and the duration of analgesia use between the groups studied. However, one complication of endometritis developed in a patient taking misoprostol. This clinical diagnosis was not confirmed on bacteriological culture, but the patient made a prompt recovery on parenteral antibiotics and remained well at her review 2 weeks following discharge from hospital. We did not perform a cost–benefit analysis; however, patients receiving medical treatment made significantly fewer outpatient hospital visits than women undergoing expectant management. This, together with the 90% reduction in surgical evacuation of the uterus, suggests that our medical management of early pregnancy failure is more cost-effective for health institutions than expectant management.

The introduction of any new management intervention must also convince health providers that, in addition to safety and tolerability, it must be acceptable to patients. We have found that our medical regimen is associated with a high degree of satisfaction that is comparable with expectant management. This was related to the high success rate of the regimen. Although women having expectant management had a lower success rate, the knowledge that they had to wait for a finite period of 1 week prior to ERPC must have contributed to the high satisfaction rating. In contrast, regarding their choice if they happened to sustain a miscarriage in the future, significantly more women would elect to have medical treatment than expectant management. A study of the psychological impact and satisfaction of misoprostol treatment and ERPC in 218 patients with miscarriage confirmed that misoprostol is psychologically safe and acceptable to patients (Lee et al., 2001Go).

In conclusion, we have shown that using misoprostol vaginally on an outpatient basis is an effective means of managing first trimester miscarriage; evacuating the uterus in >70% of cases within 2 days and reducing the need for surgery by >90% after 1 week of observation. Women are now able to make an informed choice on their options for therapy of early pregnancy failure. An implementation of this medical protocol is evidence-based and a cost-effective strategy that will benefit hospital budgets.


    Acknowledgements
 
The authors would like to thank Sister Beverley Birbeck, Ms Sarah Widner, and the nursing and medical staff who helped in the management of patients in the Early Pregnancy Assessment Unit at St Mary’s Hospital, UK.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on June 20, 2003; accepted on September 23, 2003.