Human Reproduction, Vol. 19, No. 1, 81-84,
January 2004
© 2004 European Society of Human Reproduction and Embryology
Effects of misoprostol on uterine contractility following different routes of administration
Department of Woman and Child Health, Division for Obstetrics and Gynaecology, Karolinska Institute/Hospital, S-171 76 Stockholm, Sweden
1 To whom correspondence should be addressed. e-mail: kristina.gemzell@kbh.ki.se
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Abstract |
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BACKGROUND: The effect of misoprostol administered by different routes on pregnant uterine contractility was investigated. METHODS: Thirty-two women with a pregnancy between 8 and 11 weeks of gestation requesting termination of pregnancy were recruited. Misoprostol was administered either orally (0.4 mg), vaginally (0.4 mg) or sublingually (0.2 or 0.4 mg) according to consecutive allocation. Intrauterine pressure was recorded using a Grass polygraph connected to a pressure transducer 30 min before misoprostol was given and for 4 h thereafter. At the end of the recording, suction curettage was performed. RESULTS: The first effect observed was an increase in uterine tonus, which occurred after a significantly shorter time following oral (7.8 min) and sublingual (10.7– 11.5 min) than after vaginal (19.4 min) treatment. The time to maximum tonus elevation was also significantly shorter (39.5, 47.1–51.7 and 62.2 min for the three groups respectively). Regular uterine contractions developed in all subjects following sublingual and vaginal administration but not after oral administration. The increase in uterine activity measured in Montevideo Units was significantly higher after 2 h and thereafter for sublingual and vaginal treatment than for oral misoprostol. CONCLUSIONS: Based on recording of uterine activity, sublingual misoprostol acts as rapidly as oral treatment, while development of contractions was similar to that seen following vaginal administration.
Key words: misoprostol/pregnancy/sublingual administration/uterine contractility
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Introduction |
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Misoprostol is a commercially available prostaglandin E1 (PGE1) analogue used to decrease the ulcerogenic effect of non-steroidal anti-inflammatory drugs. It is administered orally and the dose normally used is 0.4–0.8 mg/day.
In early pregnancy, the effect on uterine contractility after oral administration is limited. However, the effect of misoprostol is enhanced after pre-treatment with the antiprogestin, mifepristone (Norman et al., 1991
). The combination of mifepristone and oral misoprostol is a highly effective method to terminate pregnancy at least up to 49 days of amenorrhoea (Peyron et al., 1993) but less effective in more advanced pregnancy (McKinley et al., 1993). More recent clinical studies have shown that vaginal administration of misoprostol is more effective than oral treatment in combination with mifepristone to terminate early pregnancy (El-Refaey et al., 1995). The higher efficacy of vaginal in comparison with oral administration has also been demonstrated in second trimester pregnancy termination (Ho et al., 1997).
The reason for the higher efficacy of vaginal administration seems to be a longer duration of elevated plasma levels in comparison with oral administration, resulting in more regular and long-lasting increase in uterine contractility (Zieman et al., 1997; Gemzell Danielsson et al., 1999). The vaginal route of administration may not be acceptable to many women due to religious and social reasons. The degree of absorption also showed a pronounced individual variation (Gemzell Danielsson et al., 1999). It has recently been shown that sublingual administration could effectively terminate pregnancy and results in plasma concentrations of misoprostol which are significantly greater than following both oral and vaginal administration (Tang et al., 2001, 2002).
The aim of the present study was to compare the effect of oral, vaginal and sublingual administration of misoprostol on uterine contractility in women in the first trimester of pregnancy.
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Materials and methods |
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We studied 32 healthy women with a normal intrauterine pregnancy between 8 and 11 weeks gestation calculated from the last menstrual period who requested termination of pregnancy by vacuum aspiration and who did not have any signs of local infection. All women gave their written consent and the study was approved by the Karolinska Hospital ethics committee. All women received misoprostol (Cytotec®; Pharmacia, USA), either 0.4 mg orally, 0.4 mg vaginally or 0.2 or 0.4 mg sublingually (Table I).
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The women were recruited consecutively to each treatment group. Intrauterine pressure was recorded using a Grass polygraph (Grass Instruments, USA) connected to a pressure transducer (Millar Microtips PC-771; Miller Instruments, Inc., USA). The transducer was inserted extra-amniotically through the cervical canal up to the top of the uterine cavity and then withdrawn so that its tip was placed 1–2 cm from the fundus. The women remained in a supine position during the entire recording session. Intrauterine pressure was monitored for 30 min before misoprostol was given and 4 h thereafter. At the end of the recording session, the pregnancy was terminated by suction curettage.
Elevation of uterine tonus, above the resting level, in mmHg and uterine activity in Montevideo Units (Caldeyro-Barcia et al., 1959), were calculated before and for 10 min intervals after misoprostol administration in each subject.
t-Test was used for assessing the significance of differences between two means under assumption of normal distribution. For several means, one-way analysis of variance (ANOVA) was employed. In the latter case, appropriate comparisons of the means were calculated (Snedecor et al., 1973). The limit of significance was set at P < 0.05. A sample size of at least six subjects in each group was chosen to detect a 35% difference in the time to start of tonus elevation and time to maximum effect, assuming a coefficient of variance of 25%.
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Results |
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The clinical characteristics of the patients are shown in Table I. All women were at 8–11 weeks of gestation and mean parity was 1.7–2.2. (range 0–5). Before administration of misoprostol the mean uterine tonus for all groups was
15 mmHg. Independent of dose and route of administration, the first effect of misoprostol treatment was an increase in uterine tonus. However, this increase was more rapid and more pronounced following oral and sublingual treatment than following vaginal treatment. The mean time to increase in tonus was between 7.8 and 11.5 min for oral and sublingual treatment compared with 19.4 min for vaginal administration. The mean time to maximum tonus was also significantly shorter for oral and sublingual treatment compared to vaginal treatment (P < 0.01) (Tables II and III, Figure 1).
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After 1–2 h the tonus began to decrease and following vaginal and sublingual treatment regular uterine contractions developed slowly. This was not the case after oral treatment. In five out of 10 women no contractions developed. Following vaginal administration, uterine activity continued to increase during the entire recording period, whereas for sublingual administration of 0.4 mg misoprostol uterine contractility tended to decrease during the last hour (Figure 2, Table IV).
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pooled sublingual groups (0.2 and 0.4 mg).
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A significant difference in uterine activity measured in Montevideo Units between 0.4 mg misoprostol administered sublingually and oral administration of the same dose was found 90 min after start of treatment. At 165 and 190 min the difference was significant when oral treatment was compared with both doses of sublingual misoprostol. Uterine activity following vaginal treatment was also significantly higher in comparison with oral treatment following 3 h and onwards. There was no significant difference between vaginal and sublingual treatment.
The only side-effect reported was abdominal pain. For women receiving oral treatment the pain was regarded as mild or moderate. Following vaginal treatment three women had strong abdominal pain and one received opioid analgesic. The same was true also for sublingual administration when the 0.4 mg dose was used.
One noteworthy finding, though incidental to the study, was that all patients had a dilated cervical canal at the time of vacuum aspiration.
In the patients who were treated vaginally, remaining parts of the tablets were found at the pre-operative vaginal washing which, however, did not seem to influence the effect on the uterus. Following sublingual administration the mean time needed for the tablets to dissolve was 16.3 min (0.2 mg) and 17.6 min (0.4 mg). In one woman in the 0.4 mg group this was not the case and the tablets remained unaffected after 3 h. In this woman there was no effect on uterine contractility. This patient was excluded from the calculation of uterine activity.
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Discussion |
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Treatment with 200–600 mg mifepristone followed 36–48 h later by oral administration of 0.4 mg misoprostol is the most commonly used medical method for termination of pregnancy up to 49 days following the first day of the last menstrual period (Norman et al., 1991
; Peyron et al., 1993). However, in more advanced pregnancies misoprostol has to be administered vaginally to avoid a decrease in efficacy (El-Refaey et al., 1995). The combination of 200 mg mifepristone and 0.8 mg misoprostol vaginally has been shown to be highly effective also when the duration of pregnancy is extended to 63 days of amenorrhoea (Ashok et al., 1998). The likely explanation for the higher efficacy of vaginal administration is the higher plasma levels which remain elevated for a longer period of time than following oral administration, resulting in a more intense and long-lasting stimulation of uterine contractility (Zieman et al., 1997; Gemzell Danielsson et al., 1999). However, vaginal administration as such may not be acceptable to all women. The aim of the present study was therefore to evaluate whether sublingual administration of misoprostol could be as effective as the vaginal route in stimulating uterine contractility. The background was the clinical and pharmacokinetic results recently published (Tang et al., 2001, 2002) showing that plasma levels of misoprostol were significantly higher following sublingual than following both oral and vaginal administration.
As indicated in Table II, the time from start of treatment to start of effect (increase in tonus) was the same following both oral and sublingual administration (between 7.8 and 11.5 min) but was significantly more prolonged following vaginal administration as established by one-way ANOVA. The time to maximum tonus elevation was also the same following oral and sublingual administration and significantly shorter than following vaginal administration of misoprostol. These results correspond well with the plasma levels reported by Tang et al. (2002), who found that the time to peak concentration of misoprostol in plasma was 26.0 and 27.5 min following sublingual and oral administration respectively, and between 72.0 and 75.0 min following vaginal administration. The increase in uterine tonus was most pronounced following sublingual administration of 0.4 mg misoprostol and significantly higher than that following oral administration of the same dose of misoprostol, which is also in accordance with the pharmacokinetic results (Tang et al., 2002).
The typical effect of a single oral administration of misoprostol is an increase in uterine tonus (Norman et al., 1991; Gemzell Danielsson et al., 1999). It is only following repeated treatment that regular uterine contractions appear. The effect of vaginal administration of misoprostol on uterine contractility is initially similar to that of oral administration; an increase in uterine tonus. However, after 1–2 h regular uterine contractions appear lasting at least up to 4 h after the start of treatment. The effect of sublingual administration was the same as following vaginal treatment and significantly more pronounced than after oral treatment as shown in Figure 2. One explanation can be that following both sublingual and vaginal treatment with misoprostol, the plasma levels of misoprostol are significantly elevated for a longer period of time than following oral treatment (Tang et al., 2002). It is possible that this prolonged duration of stimulation is able to overcome the so-called progesterone block which otherwise prevents the myometrium from regular activity. With sublingual administration of 0.4 mg misoprostol, uterine contractility tended to decrease at the end of the recording period. This is also in accordance with the pharmacokinetic data which demonstrated a more rapid decline in plasma levels following sublingual than following vaginal administration.
Both oral and vaginal administration of misoprostol is used to dilate the cervix prior to vacuum aspiration (Ngai et al., 1999). Although it was not the aim of the study, the outcome indicates that sublingual administration might be equally effective. In eight out of the 12 women treated by this route the cervical canal allowed the introduction of an 8 mm size vacuum curette without prior dilatation.
It may be concluded from the present study that sublingual administration of misoprostol with regard to effect on the uterus acts as rapid as oral administration and the effect on uterine contractility is similar to that following vaginal administration.
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Acknowledgements |
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We are grateful to Prof. P.C.Ho, Department of Obstetrics and Gynecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China who initiated the studies of sublingual administration of misoprostol and generously shared his ideas, and to Associate Professor S.Cekan for the statistical analyses. This investigation received financial support from the UNDP/UNFPA/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland.
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Submitted on June 3, 2003; accepted on August 17, 2003.
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