Hum. Reprod. Advance Access originally published online on April 7, 2004
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Human Reproduction, Vol. 19, No. 5, 1101-1104,
May 2004
© 2004 European Society of Human Reproduction and Embryology
A randomized study comparing the use of sublingual to vaginal misoprostol for pre-operative cervical priming prior to surgical termination of pregnancy in the first trimester
Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
1 To whom correspondence should be addressed at: 6/F, Professorial Block, Department of Obstetrics and Gynaecology, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR. China. e-mail: ostang{at}graduate.hku.hk
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Abstract |
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BACKGROUND: Misoprostol is an effective agent for pre-operative cervical priming before surgical termination of pregnancy in the first trimester. Previous studies have shown that both oral and vaginal routes are equally effective for such a purpose. This study aimed to compare a new route of sublingual administration to the vaginal route of administration for pre-operative cervical priming in first trimester surgical abortion. METHODS: Eighty women with gestational age <12 weeks were randomized by a computer-generated model to receive 400 µg of misoprostol either sublingually or vaginally 3 h prior to vacuum aspiration. The primary outcome measure was the degree of cervical dilatation, and secondary outcomes included the force required to dilate the cervix from 3 to 8 mm, intra-operative blood loss and incidence of pre-operative side-effects. RESULTS: There was no significant difference in the baseline cervical dilatation (sublingual: 7.6 ± 1.3 mm; vaginal: 7.7 ± 0.73 mm), cumulative force required to dilate the cervix from 3 to 8 mm (sublingual: 9.0 ± 9.8 N; vaginal: 6.6 ± 5.4 N) and total blood loss (sublingual: 52.1 ± 20.2 ml; vaginal: 48.3 ± 12.3 ml). Pre-operative side-effects were also similar. CONCLUSIONS: Both sublingual and vaginal misoprostol are effective in cervical priming before surgical termination of pregnancy in the first trimester. Sublingual misoprostol has the advantage of being more convenient to administer and may be more suitable for day surgery.
Key words: cervical priming/misoprostol/sublingual/vaginal
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Introduction |
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Surgical evacuation is currently the standard management for termination of pregnancies in the first trimester in many parts of the world. It is considered to be safe and effective with a success rate of >95% (Child et al., 2001
). However, it is associated with major morbidity in 
1% of women and minor morbidity in 10% (Royal College of General Practitioners and the Royal College of Obstetricians and Gynaecologists, 1985). A more recent study of 170 000 first trimester abortions carried out in New York City, USA reported that <0.1% of the women experienced serious complication requiring hospitalization (Hakim-Elahi et al, 1990). It might appear that the incidence of severe morbidity has decreased recently in some of the countries in the developed world. Another more recent study, however, showed that the incidences of uterine perforation, blood transfusion and pelvic infection were 0.24, 0.97 and 1.69% respectively. The seniority of the surgeon was found to affect the outcome of the surgical evacuation (Child et al., 2001). Therefore the incidences of complications vary in different centres. The picture in the less developed countries is less clear. Although rare, the complications associated with surgical evacuation can affect the reproductive health of a substantial number of women, especially taking into consideration that 
40–50x106 abortions are performed annually (World Health Organization, 2003). And many of these abortions are done in areas where facilities and expertise are lacking. The procedure of vacuum aspiration is associated with complications such as excessive haemorrhage, incomplete abortion, cervical tear and uterine perforation. The risk is increased when difficulty is encountered during cervical dilatation at vacuum aspiration, especially in nulliparous patients. Various methods have been used for cervical priming before vacuum aspiration including laminaria tent, mifepristone and prostaglandin analogues. Nowadays, vacuum aspiration is often performed as day-patient surgery. Laminaria tent has to be inserted for 12 h and mifepristone has to be taken for 36–48 h to have adequate cervical priming effect. Therefore they are less convenient for day-patients. Prostaglandin analogues are the cervical priming agents of choice and misoprostol has been studied for this purpose (El-Refaey et al., 1994; Ngai et al., 1995, 1996). Both vaginal and oral administration were found to be useful (Ngai et al., 1999). It was found that 400 µg misoprostol given 3 h before the procedure was the optimal dose for vaginal application (Fong et al., 1998; Singh et al., 1998; 1999a,b). However, oral administration is more convenient. It can avoid a vaginal examination in a busy day-patient surgery admission clinic and is more acceptable to women (Ho et al., 1997). Recently, it has been shown that oral administration of 400 µg misoprostol 3 h before the vacuum aspiration is as effective as a similar regimen of vaginal misoprostol (Ngai et al., 1999). However, administration of oral drug with water 3 h before operation may cause problems if the patient undergoes the operation under general anaesthesia.
We have studied a new route of sublingual administration of misoprostol in medical abortion recently (Tang et al., 2002b,c). Misoprostol is absorbed through the vaginal mucosa in vaginal administration. The buccal muscosa, being very vascular, should be able to serve the same purpose. The misoprostol tablet is very soluble in water and dissolves within 10–15 min when administered under the tongue. Sublingual administration of misoprostol avoids the first-pass effect via the liver as in oral administration. A pharmacokinetic study showed that sublingual misoprostol was absorbed as rapidly as oral misoprostol and more rapidly than vaginal misoprostol (Tang et al., 2002a). The peak serum concentration after sublingual misoprostol and the area under the curve was also significantly higher than those after oral or vaginal misoprostol. We have shown that sublingual misoprostol is effective in medical abortion and the management of miscarriage (Tang et al., 2002b,c, 2003). Sublingual misoprostol is convenient to use, avoids vaginal administration and avoids the ingestion of water before anaesthesia. It is the aim of this randomized study to compare the efficacy of sublingual with vaginal misoprostol for pre-operative cervical priming before surgical termination of pregnancy in the first trimester.
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Methods |
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A total of 80 pregnant nulliparous women with gestational age
12 weeks were recruited from among women requesting legal termination of pregnancy from September 2001 to September 2002 at Queen Mary Hospital in Hong Kong. The gestational age was established by a reliable menstrual history and confirmed by a physical examination or ultrasound examination when necessary. The study was approved by the ethics committee of the Faculty of Medicine, University of Hong Kong. All subjects gave informed consent after the study was explained. Criteria for inclusion were a normal general and gynaecological history and physical examination. Subjects were excluded if they were taking long-term medication, had an intrauterine contraceptive device, were heavy smokers or allergic to misoprostol. The 80 women were allocated to the sublingual group and vaginal group by computer-generated random numbers produced and kept by the nurse. They were given misoprostol 400 µg either sublingually or vaginally 3 h before the scheduled operation. The randomization was unknown to the surgeon.
They were admitted to the hospital on the morning of the surgical evacuation. Vacuum aspiration was performed by a single operator (K.H.M.). The blood pressure, pulse rate, temperature and the side-effects were recorded before the operation. The operation was performed under conscious sedation. All subjects were given i.v. fentanyl 25 µg and midazolam 2 mg before the operation. A cervical tonometer (West of Scotland Health Board, Department of Clinical Physics and Bio-engineeing, UK) was used to measure the peak force required to enter the cervical os with successive dilators from 3 to 8 mm. It consisted of a series of tapered dilators attached to a force-sensing handle as described by Hazem et al. (1994). The force required to dilate the cervix was then recorded by the tonometer via a force transducer. The resistance of the cervix to dilatation was objectively assessed when the cervix was dilated using the series of tapered dilators from 3 to 8 mm. Baseline dilatation was defined as the first dilator requiring a peak force of 3 Newton (N) to enter the internal os. Force <3 N was considered to be negligible and this would define the dilatation achieved by misoprostol alone. The cumulative force required to dilate the cervix was calculated by adding the peak force needed for each dilator up to 8 mm. Vacuum aspiration was performed by a Karman curette after the cervix was adequately dilated. The intra-operative blood loss was measured as the volume of the uterine aspirate after sieving away the products of conception. The women were observed for 3 h before discharge from the hospital.
The primary outcome measure was the pre-operative cervical dilatation and was used to calculate the sample size required. The cumulative force required to dilate the cervix from 3 to 8 mm, the intra-operative blood loss and side-effects were also compared. A previous study using similar doses of vaginal misoprostol showed that the baseline dilatation was 7.2 mm and the SD was 1.4 mm (Ngai et al., 1999). A difference of 1 mm in baseline dilatation is considered as clinically significant. Therefore, a sample size of 36 in each arm will have a power of 0.8 at the 5% significance level to detect such a difference in baseline dilatation. Assuming that 10% of the subjects’ data cannot be used for analysis, the total number of subjects required is 40.
SPSS 10.0 for Windows Statistical Package was used for statistical analysis. Differences in continuous variables were analysed with Student’s t-test for normally distributed data and the Mann–Whitney U-test for skewed data. Differences in discontinuous variables were analysed by 
2-test and the Fisher exact test as appropriate. P (two-tailed) < 0.05 was considered statistically significant.
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Results |
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A total of 109 women who requested termination of pregnancy were interviewed during the study period. Six women did not meet the inclusion criteria because the gestation was found to be >12 weeks. Seventeen women did not want to join because they were worried about the effectiveness and side-effects of sublingual misoprostol. Two women changed their minds and wanted to keep the pregnancy after admission. Two women had their operation re-scheduled to another date and they were not recruited. Eighty women were eligible and agreed to participate in the study (Figure 1). There was no difference in the demographic characteristics between the two groups of women (Table I). The findings at operation are summarized in Table II. There was no significant difference in the baseline cervical dilatation between the two groups. The median dilatation for both groups was 8 mm. There was also no difference between the two groups of women in the force required to dilate the cervix from 3 to 8 mm. The blood loss was also comparable between the two groups. Side-effects were similar in the two groups of women (Table III). Nausea was the commonest gastrointestinal side-effect. Vomiting and diarrhoea were uncommon. Most women complained of abdominal pain and some of them started to bleed before the operation. None of them passed the product of conception before the operation. No significant complication was reported in these 80 women.
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Discussion |
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Surgical abortion using vacuum aspiration is still the standard method for termination of pregnancy in the first trimester in many parts of the world. Cervical priming has been shown to result in a shorter operation time, less blood loss and easier mechanical dilatation (Bugalho et al., 1994
; El-Refaey et al., 1994; Ngai et al., 1999) and these may reduce the incidence of complications associated with surgical abortion including cervical injury, uterine perforation, haemorrhage and incomplete abortion (Grimes et al., 1979, 1984). Although the major complication rate has been shown to be as low as 0.1% in one study (Hakim-Elahi et al., 1990), it does not mean that it is not a significant clinical problem when we take into consideration that there are 40–50x106 abortions occurring annually (World Health Organization, 2003). Women who undergo this minor procedure do not expect and will not accept the major complications that may affect their fertility or long-term reproductive potential. Moreover, many of these abortions are performed in the developing countries where the procedure is done by trained health-workers or midwives. Therefore, there is a need to discover methods that can decrease the difficulties and complications of this particular operation.
Pharmacological agents have the advantage over osmotic dilators as cervical priming agents since the former does not require a trained medical personnel to administer. Mifepristone and prostaglandin E1 analogues are effective cervical priming agents (El-Refaey et al., 1994; Ngai et al., 1996). However, mifepristone is expensive, not available in many countries and has the disadvantage of requiring 36–48 h for adequate cervical priming effect. Therefore, prostaglandin E1 analogue is usually the drug of choice. It takes a few hours for its action and is convenient for surgical abortion performed as a day case. Misoprostol is the drug of choice although it is not licensed for this purpose since it is cheap and stable at room temperature. A randomized controlled trial has shown that both misoprostol and gemeprost are effective cervical priming agents in the first trimester. However, misoprostol was associated with fewer gastrointestinal side-effects (Henry et al., 1999).
Various routes of administration of misoprostol have been used for cervical priming in the first trimester. Both oral and vaginal routes were shown to be equally effective when given 3 h before the vacuum aspiration (Ngai et al., 1999). However, both the oral and vaginal routes have drawbacks. Some women found vaginal administration of drug inconvenient and unacceptable (Ho et al., 1997) and it is more convenient to give a drug by mouth in a day surgery setting. At the same time, it is better to avoid oral intake of fluid before operation, especially if this is done under general anaesthesia. Sublingual misoprostol can avoid the uncomfortable vaginal application and oral intake of fluid before operation. Its clinical effectiveness in cervical priming was proven to be the same as vaginal misoprostol in this study.
Vaginal bleeding and abdominal pain were the commonest side-effects after misoprostol. These side-effects are undesirable because it may affect the acceptability of the method. Severe abdominal pain and heavy bleeding may warrant an emergency vacuum aspiration before the scheduled time. Sometimes the woman may pass the products of conception before the operation. Additional manpower may be required to handle these situations and this may affect the smooth running of the day surgery schedule. In this study, very few women complained of heavy bleeding or severe abdominal pain and none of the women passed the product of conception, which illustrated that both regimens are good for the purpose of cervical priming before first trimester surgical termination of pregnancy in a day surgery setting.
In conclusion, both sublingual and vaginal misoprostol are effective routes of administration for cervical priming prior to surgical termination of pregnancy in the first trimester. Sublingual misoprostol has the advantage of being more convenient to administer and may be more suitable for day surgery.
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Acknowledgements |
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The work reported 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.
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Submitted on September 29, 2003; resubmitted on November 25, 2003; accepted on December 2, 2003.
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