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ORIGINAL RESEARCH |
From the Department of Woman and Child Health, Division for Obstetrics and Gynecology, Karolinska Hospital, Stockholm, Sweden; and the Department of Cell Biology, University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, Stratford, New Jersey.
Address reprint requests to: K. Gemzell Danielsson, MD, PhD Department of Woman and Child Health Division for Obstetrics & Gynecology Karolinska Hospital S-171 76, Stockholm Sweden
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Abstract |
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Methods: Thirty women with a normal intrauterine pregnancy between 8 and 11 weeks’ gestation who requested termination of pregnancy were given either 0.2 mg (orally n = 5; vaginally n = 6) or 0.4 mg (orally n = 10; vaginally n = 9) of misoprostol. Intrauterine pressure was recorded using a Grass polygraph connected to a pressure transducer 30 minutes before misoprostol was given and for 4 hours thereafter. At the end of the recording, suction curettage was performed. Blood samples were obtained at 0, 0.5, 1, 2, 4, and 6 hours for measurement of misoprostol, which was assayed by high-pressure liquid chromatography–mass spectrometry.
Results: In all patients, the first effect was an increase in uterine tonus. After 0.4 mg of misoprostol administered orally, uterine tonus started to increase after a mean (± standard deviation) time of 7.8 ± 3.0 minutes and reached its maximum after 25.5 ± 5.0 minutes. The corresponding times after vaginal administration were 20.9 ± 5.3 minutes and 46.3 ± 20.7 minutes, respectively. The initial increase in tonus was also more pronounced after oral than after vaginal administration. After vaginal administration, all patients developed uterine contractions; the activity, measured in Montevideo units, increased continuously during the observation period. This was not the case after oral administration. Plasma levels of misoprostol were measured in 18 patients. The highest levels were found 30 minutes after oral treatment and 1–2 hours after vaginal administration.
Conclusion: The long-lasting and continuously increasing uterine contractility after vaginal administration can be explained only in part by a direct effect of misoprostol. The longer period of elevated plasma levels of misoprostol may also have initiated the prolonged events leading to increased uterine contractility.
Misoprostol (Cytotec; Searle AG, Chicago, IL) is a commercially available prostaglandin E1 (PGE1) analogue used to decrease the ulcerogenic effect of nonsteroidal anti-inflammatory drugs. It is administered orally, and the dose normally used is 0.4–0.8 mg/day. The protective effect on the gastric mucosa is dependent on many factors, such as increased production of gastric mucus and secretion of bicarbonate in the duodenum.
In early pregnancy, the effect on uterine contractility after oral administration is limited, and abortion was induced in only 5% of the women studied.1 The effect of misoprostol is, however, enhanced after pretreatment with the antiprogestin mifepristone (Roussel Uclaf, Paris, France). Several studies have shown that the combination of mifepristone and misoprostol is a highly effective medical method to terminate pregnancy, at least up to 49 days of amenorrhea.2–4
More recent data have been published showing that vaginal administration of oral tablets of misoprostol in very low doses (50–200 µg) is sufficient to induce second-trimester abortion5 and to induce labor at or near term.6–8 In a randomized study, vaginal administration was more effective than oral administration of misoprostol for this purpose.9 Vaginal misoprostol has also been used with methotrexate for termination of early pregnancy.10
Misoprostol has several advantages over the other PGs currently used for termination of pregnancy or labor induction. It is supplied in tablet form, does not require refrigeration, and is considerably cheaper.
In a study by Zieman et al,11 the absorption kinetics of misoprostol were compared between oral administration and vaginal treatment. However, no studies have been performed comparing the degree of absorption and the effect on uterine contractility after vaginal administration of misoprostol and after oral treatment. Furthermore, the apparent difference in clinical effect after oral and vaginal administration has not been explained. The aims of this study were to determine plasma levels and the effects on uterine tonus and contractility after oral and vaginal administration of misoprostol in women in the first trimester of pregnancy.
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Materials and Methods |
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Twelve and 20 women were randomized using numbered, sealed envelopes to receive 0.2 mg or 0.4 mg of misoprostol, respectively, by the oral or vaginal route. One woman randomized to 0.2 mg orally and one woman randomized to 0.4 mg vaginally were excluded because of technical problems at the recording. Degree of pain after misoprostol treatment was evaluated subjectively by the women, and time and intensity were recorded.
Intrauterine pressure was recorded using a Grass polygraph (Grass Instruments Co., Quincy, MA) connected to a pressure transducer (Millar Microtip PC-771; Millar Instruments Inc., Houston, TX). The transducer was inserted extra-amniotically through the cervical canal into the upper part of the uterus with its tip 1–2 cm from the fundus and was secured in position by a suture on the cervix, placed without anesthesia. The women remained in a supine position during the entire recording session. Intrauterine pressure was monitored for 30 minutes before misoprostol was given and for 4 hours thereafter. At the end of the recording period, the pregnancy was terminated by suction curettage.
Intrauterine tonus and uterine activity, expressed in mmHg and Montevideo units,12 respectively, were calculated before and at 10-minute intervals after misoprostol administration in each subject. Blood samples (10 mL) were obtained at 0, 0.5, 1, 2, 4, and 6 hours in heparinized vials and were centrifuged. We added d3-misoprostol10 to each sample and kept the plasma frozen at -80 C until analyzed.
Stock solutions of misoprostol acid were prepared in acetonitrile, and adequate dilutions were made to solutions containing 40, 20, 10, 2, and 0.4 ng/mL using the same solvent. Solutions kept at 4 C under nitrogen were stable for more than a month. The internal standard solution of d3-misoprostol acid was prepared in acetonitrile at a concentration of 1500 ng/mL.
At analysis, the plasma was thawed to room temperature and 2 mL of each sample was transferred to a 25-mL plastic extraction vial. The samples were homogenized with a Vortex mixer (Fisher Scientific, Springfield, NJ) before the addition of 4 mL of a 1:1 mixture of ethyl acetate and toluene. After 15 seconds of homogenization, 0.1 mL of a 10% aqueous solution of phosphoric acid was added, and the resulting suspension was vortexed for an additional 30 seconds. Then the sample was centrifuged for 10 minutes at 3500 rpm and 10 C. The upper organic layer was transferred to a 20-mL scintillation vial and to the residue, 4 mL more of the ethyl acetate–toluene mixture was added and vortexed again for 30 seconds. After centrifugation, the upper layer was combined with the first one, and the clear solution was evaporated under vacuum in a Speed Vac system (Model SC110A; Savant Instruments, Farmingdale, NY). The residue was reconstituted in 0.5 mL of acetonitrile-water 25:75 and filtered through a syringe filter to a high-pressure liquid chromatography autoinjector vial.
The column used was a Hewlett Packard ODS-Hypersil C18 (79916OD-552), 5 µm, 100 x 2.1 mm in an HPLC Hewlett Packard HP1090 Series II with PV5 SDS (Solvent Delivery System). The detector was a Hewlett Packard Electrospray model HP-59987A with the atmospheric pressure ionization chamber coupled to mass spectrometer model HP-5989B MS Engine (Hewlett Packard, Palo Alto, CA) and Autosampler Hewlett Packard HP1090 Series II. Control and data analysis was made using MS ChemStation (DOS series) software in a Hewlett Packard Vectra XM2 4/100i computer.
The injector volume was 200 µL and the flow rate was 0.25 mL/minute. The compound was eluted using solvent A (0.1% formic acid in acetonitrile) and solvent B (0.1% formic acid in water) through a gradient program, starting with 25% solvent A and 75% solvent B and ending with 80% solvent A and 20% solvent B.
The electrospray operating variables were adjusted daily with a tuning solution of 50 µg/mL of misoprostol acid in acetonitrile maintained at 4 C in a closed container under nitrogen. The ions monitored and dwell time for each transition are given in Table 1
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2) linear regression was applied to the area of misoprostol acid compared with the amount of misoprostol acid injected. A calibration curve with a correction factor of 0.9975 (n = 6) was obtained. Fifty microliters of misoprostol acid stock solution was added to the plasma samples taken before treatment. Sample extraction as described produced a calibration curve with a correction factor of 0.9975. Comparing the mean area of internal standard in the nonplasma calibration curve, a recovery of 80% was determined. The sensitivity of the method was 10 pg/mL.
We tested the statistical significance of the differences between means using t tests or analyses of variance.13 A sample size of ten subjects for the higher dose was chosen to be able to detect a 35% difference in the primary response measure (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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. All patients but one were at 9–11 weeks’ gestation. Before administration of misoprostol, there was negligible uterine activity, and the mean (± standard error) uterine tonus (all four groups combined) was 13.6 ± 0.9 mmHg.
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, Figure 1). However, after vaginal treatment, tonus remained at a higher level for a longer time.
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). However, there was no significant difference between the effects of 0.2 mg and 0.4 mg of misoprostol when given by the same route of administration.
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, misoprostol was absorbed faster after oral administration, whereas detectable plasma levels lasted longer after vaginal treatment. The plasma levels were highest 30 minutes after oral administration and 1–2 hours after vaginal treatment.
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It is noteworthy, although not part of this study, that all patients had a dilated cervical canal at the time of surgery. In the patients treated vaginally, remainders of the tablets were found at the preoperative vaginal washing.
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Discussion |
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Although only a limited number of blood samples could be analyzed from each patient, it was obvious that the increase in plasma levels of misoprostol after vaginal administration was slower than that after oral treatment. Our results are similar to those reported recently by Zieman et al.11 These authors found a maximum plasma concentration at 34 minutes after oral dosing and at 80 minutes after vaginal administration of 0.4 mg of misoprostol, as well as a prolonged serum concentration after vaginal treatment. The absolute values of misoprostol acid in plasma reported in their study were of the same magnitude as the values obtained in the present one. Furthermore, the bioavailability of vaginally administered misoprostol was three times higher than that of orally administered misoprostol when calculated by area under the curve. Unfortunately, the limited number of samples in our study did not allow any corresponding calculation.
The half-life of misoprostol is about 30 minutes, and because there is no reason to believe that this differs depending on the route of administration, the difference observed in plasma levels most likely represents a difference in the rate of absorption. Because the misoprostol tablets are not prepared for vaginal use and local factors that may have an influence are not characterized, one might have expected larger interpatient variations in plasma levels after vaginal administration than were demonstrated in the present study and in that of Zieman et al.11 However, similar results have been published for PGE2 tablets prepared for labor induction, and these were also found to be very effective after vaginal administration.
The introduction of a catheter into the uterine cavity could increase uterine activity by itself through the release of endogenous PGs. Because the recordings were performed in the same way in all patients, there is no reason to believe that the recording method would influence the outcome of the study. The effect of oral administration of misoprostol on the uterus—an increase in uterine tonus—was similar to that reported by Norman et al1 and is the typical response seen with other PG analogues when administered during early pregnancy.14,15 It is only after repeated treatment that regular uterine contractions appear. The effect of vaginal administration of misoprostol on uterine contractility is initially similar to that after oral administration: an increase in uterine tonus, which after 1–2 hours is followed by an increase in uterine contractility, lasting at least up to 4 hours after the start of treatment. One explanation can be that prolonged stimulation of the myometrium due to the slower absorption of misoprostol is able to overcome the so-called progesterone block, which otherwise prevents the myometrium from regular activity. Clinical data support the finding that vaginal administration of misoprostol has a unique capacity to induce a long-lasting stimulation of uterine contractility. A single dose (as small as 0.2 mg) of misoprostol was sufficient to induce second-trimester abortion in most patients.16
In combination with mifepristone, orally administered misoprostol seems less effective than vaginal administration of gemeprost (Cervagem; Rhône-Poulenc Rorer, Helsingborg, Sweden), especially in gestations after 49 days of amenorrhea.3,4 In contrast, it was shown recently that when given by the vaginal route, misoprostol was as effective as gemeprost.17 Vaginal administration also seems more effective than oral administration for labor induction.9
Vaginal administration of misoprostol has a strong ripening effect on the cervix, most evident at term pregnancy,17 and seems in this respect to be more effective than the intracervical application of PGE2 7 Bugalho et al6 noted that in many women, advanced cervical dilatation appeared to occur before the onset of typical labor pain. A possible explanation for the long-lasting stimulatory effect after vaginal administration of misoprostol found in the present study could therefore be the effect on the cervix, which initiates the physiologic events leading to increased uterine contractility.
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Footnotes |
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Received February 2, 1998. Received in revised form June 29, 1998. Accepted July 17, 1998.
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References |
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2. Aubeny E, Baulieu EE. Activité contragestive de l’association au RU 486 d’une prostaglandin active par voie orale. C R Acad Sci (Paris) 1991;312:539–45.
3. McKinley C, Thong KJ, Baird DT. The effect of dose of mifepristone and gestation on efficacy of medical abortion with mifepristone and misoprostol. Hum Reprod 1993;8:1502–5.
4. Baird DT, Sukcharven N, Thong KJ. Randomized trial of misoprostol and Cervagem in combination with a reduced dose of mifepristone for induction of labour. Hum Reprod 1995;10:1521–7.
5. Jain KJ, Mishell DR. A comparison of intravaginal misoprostol with prostaglandin E2 for termination of second trimester pregnancy. N Engl J Med 1994;331:290–3.
6. Bugalho A, Bique C, Machungo F, Faundes A. Low-dose vaginal misoprostol for induction of labor with a live fetus. Int J Gynaecol Obstet 1995;49:149–55.[Medline]
7. Wing DA, Rakall A, Jones MM, Goodwin TM, Paul RH. Misoprostol: An effective agent for cervical ripening and labor induction. Am J Obstet Gynecol 1995;172:1811–6.[Medline]
8. Kadanali S, Kücüközkan T, Zor N, Kumtepe Y. Comparison of labor induction with misoprostol vs oxytocin/prostaglandin E2 in term pregnancy. Int J Gynaecol Obstet 1996;55:99–104.[Medline]
9. Toppozada MK, Anwar MYM, Hassan HA, El-Gazaerly WS. Oral or vaginal misoprostol for induction of labor. Int J Gynaecol Obstet 1997;56:135–9.[Medline]
10. Creinin MD, Vittinghoff E, Galbraith S, Klaisle C. A randomized trial comparing misoprostol three and ten days after methotrexate for early abortion. Am J Obstet Gynecol 1995;173:1578–84.[Medline]
11. Zieman M, Fong SK, Benowitz NL, Banskter D, Darney PD. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90:88–92.[Abstract]
12. Caldeyro-Barcia R, Poseiro JJ. Oxytocin and contractility of the human pregnant uterus. Ann N Y Acad Sci 1959;75:813–30.
13. Snedecor GW, Cochran WG. Statistical methods. 6th ed. Ames, Iowa: State University Press, 1973.
14. Bygdeman M, Swahn ML. Progesterone receptor blockage. Effect on uterine contractility in early pregnancy. Contraception 1985;32: 45–51.[Medline]
15. Swahn ML, Bygdeman M. The effect of the antiprogestin RU 486 on uterine contractility and sensitivity to prostaglandin and oxytocin. Br J Obstet Gynaecol 1988;95:126–34.[Medline]
16. Bugalho A, Bique C, Almeida L, Faundes A. The effectiveness of intravaginal misoprostol (Cytotec) in inducing abortion after eleven weeks of pregnancy. Stud Fam Plann 1993;24:319–23.[Medline]
17. El-Refaey H, Templeton AA. Early induction of abortion by a combination of mifepristone and misoprostol by the vaginal route. Contraception 1993;49:111–4.
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