1 Department of Obstetrics and Gynaecology, National University of Singapore, Singapore 119074 and 2 Department of Obstetrics and Gynaecology, St Georges Hospital Medical School, London SW17 0RE, UK.
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Introduction |
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We read with interest the study by Tang and colleagues on the pharmacokinetics of misoprostol administered by various routes for first trimester abortion (Tang et al., 2002a). The authors reported that the sublingual and oral routes resulted in significantly higher serum peak concentrations of misoprostol acid compared with the vaginal route, with significantly shorter times to peak concentration. These findings agree with earlier pharmacokinetics studies (Zieman et al., 1997
; Gemzell Danielsson et al., 1999
), which also reported that oral misoprostol produced an earlier onset of action and greater initial increase in uterine tonus compared with vaginal misoprostol, mirroring the higher initial plasma levels of misoprostol acid achieved by the oral route. Tang and colleagues subsequent paper (Tang et al., 2002b
) reported that 600 µg sublingual misoprostol 3 hourly was very effective and quick in inducing first trimester abortions, but also produced very high incidences of fever (72%) and chills (82%). Previous studies (Tang et al., 1999
; Wong et al., 2000
) using 3 hourly repeated doses of 400800 µg vaginal misoprostol for abortion did not document such high rates of these side-effects.
We have previously published results that suggest that oral doses of misoprostol >400 µg are more likely to cause shivering and fever (Chong et al., 2001). We would now like to suggest another reason for the high rate of side-effects with sublingual misoprostol by reporting our experience using an oral solution of misoprostol in pregnant women. In a prospective open-label study, we measured uterine activity using intrauterine pressure catheters in 40 women treated with 400 µg misoprostol after normal vaginal delivery. The misoprostol was administered as an aqueous solution orally, or as tablets orally, rectally or vaginally (10 women in each group). We found that misoprostol given as an aqueous oral solution had a significantly quicker onset of action compared with misoprostol given as tablets orally, rectally or vaginally. The uterotonic effect produced by oral solution misoprostol was also significantly greater in the first 30 min after administration compared with the other routes.
Unfortunately, the women given aqueous solutions of misoprostol also had a very high incidence of shivering (50%) and increase in temperature to >38°C (90%). Both of these side-effects were significantly more common than in the other groups. Women who received oral solution misoprostol also had significantly higher maximum body temperatures. Only two women given tablets orally, and one rectally, experienced pyrexia. Women given misoprostol vaginally did not experience any side-effects. Our findings correlate well with those of Tang and colleagues two recent papers.
We hypothesized that the increased side-effects were due to the higher peak plasma concentrations of misoprostol acid achieved with oral solution misoprostol. It is probable that high plasma concentrations of misoprostol acid, besides acting on uterine receptors to produce contractions, also act on receptors elsewhere that are primed by the pregnancy state to result in disturbed thermoregulation.
We therefore warn that, while misoprostol administered sublingually or as an oral solution may be better absorbed and produce a faster and greater uterotonic effect, it may also result in greater side-effects than when given vaginally or rectally. Although the women in Tang and colleagues pilot study (Tang et al., 2002b) found the side-effects of fever and chills acceptable, these side-effects may not be so benign if sublingual misoprostol is given in the wrong dose or repeated too often. Severe hyperthermia is a potential danger when high doses of misoprostol are administered to pregnant women (Chong et al., 1997
).
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Notes |
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References |
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Chong, Y.S., Chua, S., El-Refaey, H., Choo, W.L., Chanrachakul, B., Tai, B.C., Rodeck, C. and Arulkumaran, S. (2001) Postpartum intrauterine pressure studies of the uterotonic effect of oral misoprostol and intramuscular syntometrine. Br. J. Obstet. Gynaecol., 108, 4147.[ISI]
Gemzell Danielsson, K.G., Marions, L., Rodriguez, A., Spur, B.W., Wong, P.Y.K. and Bygdeman, M. (1999) Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet. Gynecol., 93, 275280.
Tang, O.S., Wong, K.S., Tang, L.C. and Ho, P.C. (1999) Pilot study on the use of repeated doses of misoprostol in termination of pregnancy at less than 9 weeks of gestation. Adv. Contracept., 15, 211216.[ISI][Medline]
Tang, O.S., Schweer, H., Seyberth, H.W., Lee, S.W.H. and Ho, P.C. (2002a) Pharmacokinetics of different routes of administration of misoprostol. Hum. Reprod., 17, 332336.
Tang, O.S., Miao, B.Y., Lee, S.W.H. and Ho, P.C. (2002b) Pilot study on the use of repeated doses of sublingual misoprostol in termination of pregnancy up to 12 weeks gestation: efficacy and acceptability. Hum. Reprod., 17, 654658.
Wong, S.K., Ngai, C.S., Yeo, E.L., Tang, L.C. and Ho, P.C. (2000) A comparison of two regimens of intravaginal misoprostol for termination of second trimester pregnancy: a randomized comparative trial. Hum. Reprod., 15, 709712.
Zieman, M., Fong, S.K., Benowitz, N.L., Banskter, D. and Darney, P.D. (1997) Absorption kinetics of misoprostol with oral or vaginal administration. Obstet. Gynecol., 90, 8892.