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 Marys 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
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Abstract |
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Key words: early pregnancy failure/expectant management/first trimester miscarriage/medical management/vaginal misoprostol
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Introduction |
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Expectant management of first trimester miscarriage has been compared with ERPC since 1995 with varying results (Nielsen and Hahlin, 1995; Chipchase and James, 1997
; Hurd et al., 1997
; Jurkovic et al., 1998
). Nielsen and Hahlin (1995
) showed that expectant management had a 79% success rate whereas Jurkovic et al. (1998
) 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., 1993). Nielsen et al. (1999
), 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., 1999
) to 95% (Henshaw et al., 1993
).
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., 1997; Zalanyi, 1998
; Autry et al., 1999
; Demetroulis et al., 2001
). However, data from randomized controlled trials are limited and a total of 55 patients only have been assigned to vaginal misoprostol (Ngai et al., 2001
; Wood and Brain, 2002
). The ideal dose of misoprostol has not been established with side-effect rates varying from 4 to 73% (Ngai et al., 2001
; Wood and Brain, 2002
). The results of expectant management also need to be reproduced in other settings following the reports of Nielsen et al. (1999
) and Chipchase and James (1997
).
We therefore designed a prospective randomized, double-blind, placebo-controlled trial to determine whether medical management using vaginal misoprostol is superior to expectant management.
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Materials and methods |
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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 crownrump 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 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 hCG. If the
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 2-test or Fishers exact test as appropriate. Students t-test was performed for continuous variables.
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Results |
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Discussion |
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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., 2002). Luise et al. (2002
) 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. (1998) 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. (1999
). 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. (2001) and Wood and Brain (2002
) 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 (2002
), 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., 1993). Mifepristone, an antiprogestin, increases the uterine response to misoprostol in women with live pregnancies undergoing legal abortion (Norman et al., 1991
). However, the addition of mifepristone to misoprostol has not improved the success rate of misoprostol used alone in managing miscarriage (Nielsen et al., 1999
; Demetroulis et al., 2001
). This is most likely due to the abnormally low progesterone levels associated with a failing pregnancy (Ledger et al., 1994
).
A review by Ankum et al. (2001) 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., 2001
; Wood and Brain, 2002
). 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., 1999
). 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., 2003
). 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., 1995
). 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., 1997
).
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 costbenefit 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., 2001).
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.
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Acknowledgements |
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References |
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Submitted on June 20, 2003; accepted on September 23, 2003.