1 Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki and 2 Department of Biomedicine, University of Helsinki, Helsinki, Finland
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Abstract |
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Key words: hCG/medical abortion/mifepristone/misoprostol/progesterone
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Introduction |
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The kinetics of the trophoblast-derived hormones hCG and progesterone have been evaluated previously when mifepristone was used alone for termination of early human pregnancy (Somell et al., 1990). Studies evaluating the kinetics of these hormones following a combination of mifepristone and gemeprost, another prostaglandin E1 analogue, showed that hCG values remain high until abortion occurs, and progesterone levels fall by 4 h after administration of gemeprost (Howell et al., 1989
; Olajide et al., 1989
). When mifepristone was used alone for pregnancy termination, the only predictor of success was a low pretreatment level of serum hCG (Birgerson and Odlind, 1988
).
In order to compare the efficacy of oral and vaginal administration of misoprostol after a single oral dose of 200 mg of mifepristone, and to investigate whether the efficacy could be improved by continuing oral misoprostol for a week, the World Health Organization (WHO) organized a double-blind randomized multicentre study (World Health Organization, manuscript submitted). Given the different patterns of uterine contractility following oral and vaginal misoprostol (Gemzell-Danielsson et al., 1999), we wanted to evaluate, along with the WHO medical abortion study, whether the route of misoprostol administration is related to the serum kinetics of trophoblast-derived hormones, namely hCG and progesterone. In addition, we sought to establish the relationships between these hormones and the levels of mifepristone.
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Materials and methods |
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The study was conducted at the Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, Helsinki, Finland, and approved by the local ethics committee. The subjects gave their informed consent prior to participation in the study.
In the efficacy study the women were randomized to one of three treatment arms. The treatment regimens are summarized in Table I. All women were given an oral dose of 200 mg mifepristone on day 0 of the study. On day 2 of the study (3648 h after the administration of mifepristone) group A (oral group) received 0.8 mg of misoprostol orally; groups B (vaginal plus continued oral misoprostol) and C (vaginal only group) received 0.8 mg of misoprostol vaginally. After administration of misoprostol, the women were observed for 3 h in the hospital. They were asked to note the time of expulsion of the fetal material.
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The subjects returned for follow-up visits 2 and 6 weeks after beginning the treatment. The final assessment of complete abortion was conducted at the 6-week visit.
Consecutive blood samples were collected five times; sample I just prior to administration of mifepristone, sample II on day 2, prior to administration of misoprostol, sample III on day 2, 3 h after misoprostol, sample IV on day 3, prior to the first home administration of misoprostol and sample V on day 14. The exact time of abortion was observed in 27 of the 34 women.
Hormone assays
The concentrations of hCG and progesterone in serum were measured in duplicate by time-resolved fluoroimmunoassays, using commercial kits (DELFIA), manufactured by Wallac Finland Oy, Turku, Finland. According to the manufacturer, the detection limit of the hCG assay was 0.5 IU/l and that of the progesterone assay 0.8 nmol/l. The calculated intra-assay coefficient of variation (CV) for hCG was 2.04.1%, and for progesterone 3.37.3%. The interassay CVs for hCG and progesterone were 3.24.6 and 2.710.1% respectively.
Serum mifepristone was quantitated by a specific radioimmunoassay after Chromosorb column chromatography (W-NAW-6080 Mesh; Sigma St. Louis, MO, USA), as described previously (Heikinheimo et al., 1986). The specific tracer, [6,73H]-RU 486, was provided by the Roussel-Uclaf Research Centre (Romainville, France), and the monoclonal antibody against mifepristone was a gift from Dr Fortune Kohen (Weizmann Institute, Israel). The quantitation limit of the assay, 0.36 pmol/l, is the lowest concentration on the standard curve that can be measured with acceptable precision (i.e. intra-assay CV
20%). The intra-assay CV (8.4%) was calculated from duplicate samples in one representative assay. The inter-assay CV was calculated from serum pools run in each assay and varied between 10.313.6%.
The initial individual t1/2 values of serum hCG were calculated by assessing the serum concentration versus time data measured on days 2 and 3 in linear regression and dividing the natural logarithm of two by the slope.
Statistical methods
Differences between the groups were assessed by analysis of variance. The Kruskal-Wallis test was used as appropriate. Analysis of variance for repeated measures was used to analyse the longitudinal changes in concentrations. Correlations between variables were assessed by calculating Spearman's coefficient of correlation. These analyses were performed by using SPSS 8.0 for Windows. Statistical significance was defined as P < 0.05.
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Results |
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The concentrations of hCG continued to increase after administration of mifepristone until day 2, prior to administration of misoprostol (Figure 1). After administration of misoprostol, a clear decline, 18.8 ± 2.0% (mean ± SD) (P
0.001), was noted in hCG levels at 3 h. On the following day, hCG levels had fallen by 70.5 ± 8.8% (P
0.001) from the peak level. The trend in the change was similar in all treatment groups, and there was no difference in the percentage decrease in hCG levels when the groups receiving oral and vaginal misoprostol were compared. In addition, the percentage decline in hCG levels within the first 3 or 24 h did not correlate with the peak hCG level measured prior to misoprostol administration. The half-life of serum hCG varied between 13.8 ± 3.0 and 16.3 ± 6.2 h (mean ± SD) in the different treatment groups, the mean (± SD) figure being 14.6 (± 4.1) h.
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By day 14, the serum concentrations of hCG had declined by 99.4 ± 1.0% (mean ± SD). Three subjects had concentrations above 1000 IU/l, one of these was the only failure (hCG 3560 IU/l) we had in our study. One subject had an even higher hCG value, 4210 IU/l, but she was found to have aborted completely by the 6-week follow-up visit.
The concentrations of progesterone continued to increase after administration of mifepristone until day 2 (Figure 2). Three hours after administration of misoprostol a clear decline, 31.8 ± 10.8% (mean ± SD) (P < 0.001) was noted in serum progesterone levels. On the following day, progesterone concentrations had fallen by 61.3 ± 16.3% (mean ± SD) (P < 0.001) from the peak level. The trend in the decline was similar in all treatment groups. The percentage decline in progesterone concentrations within the first 3 or 24 h did not correlate with the peak levels of progesterone measured on day 2.
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Serum levels of mifepristone decreased by 47.6 ± 20.2% (mean ± SD) from day 2 to day 3 (Figure 3). A weak negative correlation, although not statistically significant, was found between serum mifepristone concentrations measured prior to administration of misoprostol on day 2, and the time taken to abort (r = 0.35, P = 0.1).
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Discussion |
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There is also a suggestion that the clinical efficacy might be ameliorated by extending the duration of misoprostol treatment (Tang et al., 1998). Given the high efficacy of the mifepristone-misoprostol combination, it is clear that possibly improved clinical efficacy can only be shown in large-scale randomized clinical trials. Along with the WHO study evaluating the clinical effect of the route and duration of misoprostol administration (World Health Organization, manuscript submitted), we evaluated the kinetics of hCG and progesterone in response to mifepristone in combination with oral and vaginal misoprostol. We hypothesized that potentially different kinetics of trophoblast-derived hormones might aid in optimization of the regimens used in medical termination of pregnancy.
Ashok et al. summarized extensive experience from a single centre where a combination of 200 mg of mifepristone followed by 0.8 mg vaginally administered misoprostol was used: in their study the median inductionabortion interval was 255 min (Ashok et al., 1998). In the present study, the median time to abortion varied between 210 and 380 min in the different groups (Table II
). Thus the clinical courses were well in line with experience reported previously.
Serum levels of hCG behaved as expected and followed the well characterized clinical course of medical termination of pregnancy (Spitz et al., 1998). Despite mifepristone administration serum hCG concentrations continued to increase up to day 2 (Figure 1
), this finding being in line with previous studies in which mifepristone in combination with gemeprost was used (Olajide et al., 1989
). However, following administration of misoprostol, the levels of hCG declined rapidly, and a decrease of 70.5 ± 8.8% (mean ± SD) was evident in 24 h. The decline in hCG was similar in all three groups. When groups B and C, who received similar vaginal misoprostol up to day 3, were combined, no difference between the groups receiving oral or vaginal misoprostol emerged. It thus appears that the initial misoprostol dose starts a cascade leading to a progressive fall in hCG. The levels of hCG had declined by 99.4 ± 1.0% (mean ± SD) by 14 days following administration of mifepristone. The decline was similar in all groups; thus extended administration of misoprostol offered no benefit as judged by the kinetics of hCG.
Earlier in-vitro data (Das et al., 1987) suggested that the trophoblast itself might be the target of the inhibitory effect of mifepristone on placental hCG and progesterone secretion. However, the increase in serum levels of hCG up to 2 days following mifepristone administration suggests that the trophoblast is not the target of mifepristone action in vivo. Even though a direct action(s) of misoprostol on trophoblast function cannot be ruled out, it appears that the fall in hCG levels following misoprostol administration is most likely to be secondary to the abruption of the placenta due to rapidly enhanced uterine contractility (Swahn and Bygdeman, 1988).
Following surgical termination of pregnancy the initial half-life of hCG is 15 h (Lähteenmäki, 1978
). In the present study the initial t1/2 of serum hCG was similar in the different treatment groups, the mean value being 14.6 h. Thus in terms of the initial elimination of hCG, medical termination of pregnancy does not differ from surgical evacuation of the uterus.
The absolute level of hCG still exceeded 1000 IU/l in three cases on day 14. Two were eventually judged to have had a successful termination of pregnancy whereas one was eventually managed surgically due to continued vaginal bleeding. The drop in the level of serum hCG has recently been proposed as a means to monitor the clinical outcome of medical abortion (Walker et al., 2001). However, on the basis of these three cases, a complete clinical abortion is possible despite elevated levels of hCG observed at 2 weeks following mifepristone-misoprostol treatment.
The kinetics of serum progesterone were similar to those of hCG, and the levels of progesterone first declined after administration of misoprostol (Figure 2). The effect of misoprostol on serum progesterone might be due to its actions on trophoblast and/or corpus luteum function. The luteolytic effects of prostaglandins are well-characterized (Ottander et al., 1999
). However, the decline in progesterone levels during the first 3 or 24 h was similar regardless of the peak progesterone level measured on day 2. In addition, the decline in progesterone concentrations from day 2 to day 3 correlated significantly with the decrease in serum hCG levels. We therefore hypothesize that the decline in progesterone concentrations is due to abruption of the placenta and the fall in hCG levels.
When mifepristone is used alone for pregnancy termination the only predictor of successful outcome is a low pretreatment level of serum hCG (Birgerson and Odlind, 1988). In the present study, with a limited number of subjects and high efficacy of the mifepristone-misoprostol combination, the correlation between the pretreatment hCG level and the final outcome could not be evaluated. Similarly, a non-significant correlation was found between the peak hCG level and the time taken to abort. However, the percentage decline in serum hCG levels from days 2 to 3 was inversely and significantly (r = 0.39, P < 0.05) correlated with the time taken to abort. No correlation was found between the percentage decline in serum progesterone levels and the time taken to abort.
The kinetics of serum mifepristone behaved much as expected, on the basis of our previous studies (Heikinheimo et al., 1990). According to its t1/2 of
25 h, serum levels of mifepristone decreased to about one half between days 2 and 3. As expected, the serum levels of mifepristone were similar in the different treatment groups. When the peak level of mifepristone measured on day 2 was correlated with the time taken to abort, only a weak, statistically non-significant correlation emerged. When an attempt was made to correlate the peak levels of mifepristone measured on day 2 with the declines of serum hCG and progesterone concentrations, no correlations were found.
In conclusion, the expulsion of fetal material following misoprostol administration in the course of medical termination of pregnancy results in a rapid decline in serum hCG and progesterone levels. The decrease in serum hCG levels correlated inversely with the time taken to abort. The decline in hCG and progesterone concentrations was similar following oral and vaginal misoprostol administration. In addition, extended oral administration of misoprostol did not enhance the disappearance of hCG or progesterone. Thus, in the present study, the previously shown enhanced uterine contractility (Gemzell-Danielsson et al., 1999) and clinical efficacy associated with vaginally administered misoprostol (El-Refaey et al., 1995
) was not reflected in the serum kinetics of hCG or progesterone.
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Acknowledgements |
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Notes |
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References |
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Submitted on April 8, 2002; accepted on May 23, 2002.