Department of Obstetrics and Gynaecology, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, China
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Abstract |
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Key words: cervical priming/misoprostol/oestrogen/postmenopausal women
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Introduction |
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Difficulty in negotiating through the cervical os is not uncommon. The procedure may be abandoned even when it is performed under general anaesthesia. Cervical injuries, uterine perforation, creation of a false tract or haemorrhage may occur. Unfortunately, data concerning the effectiveness of cervical priming agent in postmenopausal women are lacking. This is of particular importance, especially if office hysteroscopy is to be used.
The synthetic prostaglandin E1 analogue misoprostol (Cytotec; Searle, High Wycombe, UK) has been used successfully in the management of peptic ulcer. It is an effective cervical priming agent prior to suction evacuation (Ngai et al., 1995; Ngai et al., 1999
). A previous study showed that it was also effective in pre-menopausal non-pregnant patients (Ngai et al., 1997
). It is safe, well tolerated and inexpensive. As data for the use of this drug in postmenopasal women were lacking, a randomized study was performed to investigate the cervical priming effect of misoprostol in this group.
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Materials and methods |
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Women were randomized into two groups: group 1, placebo (vitamin B6); group 2, 400 µg of oral misoprostol. The randomization schedule was produced as described by Meinert (Meinert, 1986). The tablets were put into a plastic bag labelled with subject number according to the randomization schedule at the pharmacy in Queen Mary Hospital.
Women who were recruited underwent a full medical, obstetrical and gynaecological history and physical examination. Subjects were admitted 1 day before the operation. The oral tablet (either misoprostol or vitamin B6) was given 12 h before the operation. All hysteroscopy and endometrial sampling was carried out under general anaesthesia by one of the two investigators (S.W.N or Y.M.C). The randomization schedule was unknown to the surgeon. A cervical tonometer (West of Scotland Health Board, Department of Clinical Physics and Bioengineering, UK) was used to measure the peak force required to enter the cervical os with successive dilators from 26 mm. The resistance of cervix to dilatation was objectively assessed using a series of tapered dilators attached to a force-sensing handle as described previously (El-Rafaey et al., 1994). Baseline dilatation was defined as the first dilator, which required a peak force >5 N to enter the internal os. The cumulative force required to dilate the cervix was calculated by summing the peak forces produced by each dilator up to 6 mm. Other parameters that were assessed during operation included the pre-operative side-effects and the complications during the procedure. The blood loss during the operation was assessed by subjective visual assessment. After hysteroscopy, women were observed for a further 6 h. The blood pressure and pulse rate were measured hourly. These observations were only recorded on the data forms if complications occurred. All women were followed up 6 weeks later.
The calculation of the sample size was based on the following assumptions: (i) type 1 error of 0.05 and power of 0.8 were acceptable and (ii) it was assumed that the baseline cervical dilatation was 1 mm in the postmenopausal women and a change of 2 mm in baseline dilatation would be significant in clinical management. The ideal sample size in each group was calculated as 17, and to allow for ~10% of the data being unusable, the number in each group was set at 19. Therefore, the total sample size was 38.
The characteristics of the subjects, the indication for dilatation and curettage, the incidence of side-effects and the baseline cervical dilatation between the two groups were compared. The difference in discontinuous variables was analysed by 2 test and Fisher's exact test. The difference of continuous variables was analysed by the Student's t-test for normally distributed data and MannWhitney U-tests for skewed data.
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Results |
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Patients' characteristics are shown in Table I. The median age of subjects in the misoprostol group was significantly lower than that of the placebo group (55.6 versus 66.9 years, P = 0.01). In the placebo group, the patients' ages ranged from 47 to 86 years whereas in the misoprostol group, they ranged from 49 to 67 years. Other demographic parameters, including body weight, height and body mass index, were comparable between the two groups. Operative findings are summarized in Table II
. The mean baseline cervical dilatation was similar between the two groups (4.2 mm in misoprostol group versus 4.4 mm in placebo group). Cumulative force required for the procedure was also comparable (27.7 N in misoprostol group versus 21.8 N in placebo group).
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Discussion |
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We have previously demonstrated that 400 µg oral misoprostol, when given 12 h prior to hysteroscopy, reduced cervical resistance significantly when compared with placebo (Ngai et al., 1997). In that study, subjects suffered from infertility and were admitted for laparoscopy and hysteroscopy.
In the present study, using the same dosage and route of administration as our prior study (Ngai et al., 1997), we failed to demonstrate any beneficial effect. The only difference between the two studies was that we recruited postmenopausal women in this study, whereas women of reproductive age were recruited in the previous study. Endogenous oestrogen may be essential for the cervical priming induced by prostaglandin, and therefore women in a hypo-oestrogenic state would show no response to prostaglandins.
This theory is supported by findings from laboratory and animal studies on cervical priming. The final, rapid cervical softening that occurs just before the onset of labour corresponds to the connective tissue remodelling characterized by an increased turnover of both collagen and proteoglycans (Norman et al., 1993). Several hormones, such as prostaglandins, gonadal steroids and relaxin, are involved in the process. Administration of oestrogen promotes, and of progesterone at high concentrations inhibits, neutrophil migration into rodent uterine tissue (Stites and Siiteri, 1983
). Human studies have further demonstrated that there is an upregulation of gene expression as well as protein concentrations of interleukin-8, interleukin-6 and granulocyte colony-stimulating factor during the final cervical priming process, which is similar to an inflammatory process (Sennstrom et al., 2000
). The effect of hormones on cervical priming may be related to the regulation of pro-inflammatory cytokines.
Our knowledge of the molecular basis for the ripening of the human cervix has increased substantially since the pioneering reports by Danforth 40 years ago (Danforth, 1960). Expanded knowledge of the biochemistry and ultrastructure of the human cervix will most likely be of practical importance in the near future. Further laboratory basic research on the local concentration, action and interaction of gonadal steroids and prostaglandins, and their effects on collagenase and non-collagenolytic proteases in the cervical ripening process are awaited to confirm or refute the speculation stated above.
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Acknowledgements |
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Notes |
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References |
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Danforth, D.N., Buckingham, J.C. and Roddick, J.W. (1960) Connective tissue changes in the pregnant cervix during pregnancy and labor. Am. J. Obstet. Gynecol., 80, 939.[ISI][Medline]
El-Rafaey H., Calder, L., Wheatley, D.N. and Templeton, A. (1994) Cervical priming with prostaglandin E1 analogues, misoprostol and gemeprost. Lancet, 343, 12071209.[ISI][Medline]
Meinert, C.L. (1986) Randomization and the mechanics of treatment masking. In Meinert, C.L. and Tonaseia, S. (eds), Clinical Trials, Design, Conduct and Analysis. Oxford University Press, New York, Oxford, pp. 90112.
Ngai, S.W., Tang, O.S. and Lao, T. (1995) Oral misoprostol versus placebo for cervical dilatation before vacuum aspiration in first trimester pregnancy. Hum. Reprod., 5, 12201222.
Ngai, S.W., To, W.K., Lao, T. and Ho, P.C. (1996) Cervical priming with oral misoprostol in pre-labour rupture of membranes at term. Obstet. Gynecol., 87, 923926.
Ngai, S.W., Chan, Y.M. and Liu, K.L. (1997) Oral misoprostol for cervical priming in non-pregnant women. Hum. Reprod., 5, 12201222.
Ngai, S.W., Chan, Y.M., Tang, O.S. and Ho, P.C. (1999) The use of misoprostol for pre-operative cervical dilatation prior to vacuum aspiration: a randomized trial. Hum. Reprod., 14, 21392142.
Norman, M., Ekman, G. and Malmstrom, A. (1993) Prostaglandin E2 induced ripening of the human cervix involves changes in the proteoglycan metabolism. Obstet. Gynecol., 82, 10131020.[Abstract]
Sennstrom, M.B., Ekman, G., Thorsson, W.G. et al. (2000) Human cervical ripening, an inflammatory process mediated by cytokines. Mol. Hum. Reprod., 6, 375381.
Stites, D.P. and Siiteri, P.K. (1983) Steroids as immunosuppressants in pregnancy. Immunol. Rev., 75, 117138.[ISI][Medline]
Submitted on November 22, 2000; accepted on March 22, 2001.