1 Department of Obstetrics and Gynecology, PoissySaint Germain Hospital, University VersaillesSt Quentin, 2 Department of Biostatistics, Saint Louis Hospital, University Paris VII, Assistance PubliqueHôpitaux de Paris, 3 Department of Obstetrics and Gynecology, Antoine Béclère Hospital, Clamart, 4 Department of Obstetrics and Gynecology, C.M.C.O. Schiltighein, 5 Department of Obstetrics and Gynecology, C.H.R.U. Tours, 6 Department of Obstetrics and Gynecology, Hôtel Dieu Hospital, Rennes, 7 Department of Obstetrics and Gynecology, Jeanne de Flandre Hospital, Lille, 8 Department of Obstetrics and Gynecology, Paul Gelle Hospital, Roubaix, 9 Department of Obstetrics and Gynecology, Annecy Hospital, and 10 Department of Obstetrics and Gynecology, Evreux Hospital, France
11 To whom correspondence should be addressed at: Centre hospitalier PoissySaint Germain, Rue du Champ Gaillard, 78303 Poissy Cedex, France. e-mail: prozenberg{at}chi-poissy-st-germain.fr
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Abstract |
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Key words: ectopic pregnancy/medical treatment/methotrexate/mifepristone/randomized controlled trial
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Introduction |
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However, these studies were based on small sample sizes, and the only randomized trial was not double-blind. Therefore, we underwent a prospective multicentre, double-blind, randomized trial with an appropriate number of patients in order to compare the efficacy and tolerance of the combined methotrexatemifepristone to those of methotrexateplacebo for the medical treatment of ectopic pregnancy.
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Materials and methods |
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The diagnosis of ectopic pregnancy was made by using a non-laparoscopic algorithm combining quantitative -hCG serum level, transvaginal ultrasonogram showing no intrauterine gestational sac, and any adnexal mass, and curettage failing to retrieve trophoblastic villi. Patients with serum
-hCG level
1500 mIU/ml and no intrauterine sac seen by ultrasonography were not subjected to curettage, nor were those with gestational cardiac activity by ultrasonography in the ectopic pregnancy. Patients with serum
-hCG level <1500 mIU/ml and <50% increase over 48 h underwent a curettage. Patients with serum
-hCG level <1500 mIU/ml which decreased after 48 h did not receive any treatment and were followed up until
-hCG levels were undetectable.
Inclusion criteria were: stable haemodynamics without active bleeding or evidence of haemoperitoneum, an unruptured mass, an ectopic pregnancy with gestational cardiac activity, serum -hCG level
1500 mIU/ml and no intrauterine sac seen by ultrasonography, serum
-hCG level <1500 mIU/ml and a persistent abnormal increase in this level (<50% increase over 48 h) and no trophoblastic villi found in curettage, living within 1 h drive from the hospital (maximal route of 1 h), not living alone, patient agreeing to serial follow-up, no contraindications to methotrexate or mifepristone and signed written informed consent.
Exclusion criteria were: age <18 years, a decrease in serum -hCG level or presence of trophoblastic villi following curettage; initial
-hCG level <1500 mIU/ml which decreased further after 48 h; hepatic (serum aminotransferase concentrations >2-fold the normal level), renal (serum creatinine concentration >1.5 mg/dl), or haematological dysfunction (leukopenia <2000/ml, thrombocytopenia <100 000/ml), suprarenal gland dysfunction, active pulmonary disease, peptic ulcer disease, overt or biological evidence of immunodeficiency, known sensitivity to methotrexate or mifepristone.
Blood type, Rh, and antibody screening were performed on all patients. Those who were Rh negative were given Rh immunoglobulin (300 µg) at inclusion. Finally, a serum progesterone level was measured at inclusion.
Randomization, based on a computer-generated list and balanced in blocks of variable size, stratified by centre, was carried out with sealed, opaque envelopes, stored in the pharmacy of each hospital. The envelope was opened immediately before the allocated treatment was administered.
All patients received a single i.m. injection of 50 mg/m2 of body surface of methotrexate, and a single oral dose of mifepristone (600 mg) or placebo according to randomization.
Women were discharged home following treatment. They were reviewed at day 4 and day 7 on an outpatient basis. All women had serial serum -hCG, hepatic and renal function tests and full blood counts on each visit. If
-hCG levels dropped by >15% between days 4 and 7, the women were then reviewed weekly until serum
-hCG concentrations fell to <10 mIU/ml. If the decrease was <15% between days 4 and 7, a second injection of methotrexate (50 mg/m2) was given i.m. In these cases,
-hCG levels were also checked on days 11 and 14. A repeated dose of methotrexate was also given if gestational cardiac activity was still present on day 7 after the first or the subsequent dose of methotrexate.
Patients were instructed to refrain from alcohol and intercourse and to avoid vitamin preparations containing folic acid until complete resolution of the ectopic pregnancy, and to use either oral contraceptive pills or barrier contraception for 3 months after treatment completion.
Women were asked about side-effects and complaints on each visit. These were recorded on data sheets. Repeat transvaginal scanning was performed to rule out rupture of ectopic pregnancy if the patient presented increasing abdominal pain. When gestational cardiac activity was seen at treatment initiation, transvaginal scanning was performed on alternate days until cardiac activity disappeared. Repeated clinical pelvic examinations were not performed in any patients to avoid the potential of iatrogenic tubal rupture after treatment initiation.
Patients were admitted in hospital if transient and isolated pelvic pain appeared or worsened. Laparoscopic treatment was indicated if the -hCG level had not decreased sufficiently after day 14 and if pelvic pain was not controlled by non-opiate analgesics or if signs of internal haemorrhage developed.
The primary outcome was the success rate of the medical treatment, defined by the absence of indication for surgical intervention before serum -hCG levels were below 10 mIU/ml irrespective of the number of injections of methotrexate.
The secondary outcomes were: (i) efficacy criteria: indications for surgical intervention, surgical modalities, need for a second dose of methotrexate, number of days in hospital, time-interval from randomization to fall in -hCG levels to <10 mIU/ml; (ii) safety and tolerance criteria: gastritis, stomatitis, reversible alopecia, increase in serum aminotransferase concentrations, severe neutropenia or thrombocytopenia.
Computation of sample size, stopping rules
Assuming a success rate of 80% in the methotrexate group, it was computed that 158 patients had to be enrolled in each group to demonstrate a benefit of 15% in the methotrexatemifepristone group (i.e. a success rate of
95%), controlling for a type I error of 5% and a power of 90% (two-sided test). Nevertheless, owing to the uncertainties of the benefit associated with methotrexatemifepristone treatment, the protocol had planned the schedule of inspections ahead, with computation of stopping rule based on the triangular test (Whitehead, 1992
). Briefly, the triangular test consisted of drawing stopping boundaries on the plot of the difference in efficacy (Z) against its precision (V), which complied with type I error and power requirements. Following inclusion of each group of 60 patients, all available data on the patient responses were gathered together, and current values of Z and V were computed. If the computed point lay between the boundaries, then the trial was continued until the next inspection. If it lay outside the stopping boundaries, then the trial was stopped (Figure 1).
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Estimation of treatment success was defined by the ratio of observed successes to the total number of randomized patients, with computation of relative risk (RR) and 95% confidence interval (95% CI). Regression logistic models allowed to search for prognostic covariates, estimating the strength of the association between covariates and outcome by odds ratio (OR) of success with 95% confidence interval (95% CI). Such a modelling approach also allowed us to: (i) explore the shape of the influence of continuous covariates on success rate, using smoothing (spline) functions, and (ii) test for treatment by centre interaction. Finally, Gail and Simon (1985) tests for quantitative interaction between randomization and either
-hCG or progesterone levels were carried out.
Statistical analysis was performed using SAS 8.2 (SAS Inc., USA) and Splus2000 (MathSoft Inc, USA) software packages. All tests were two-sided, with P 0.05 considered statistically significant.
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Results |
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Among the 212 randomized women, 113 (53.3%) were included in the methotrexatemifepristone group and 99 (46.7%) in the methotrexateplacebo group. Table I shows the initial characteristics of these 212 women according to the randomization group.
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The overall success rate of medical treatment was 77.1% (162/210). There was no significant difference between the methotrexatemifepristone and the methotrexateplacebo groups: 79.6% (90/113) versus 74.2% (72/97) respectively [RR (95% CI): 1.07 (0.921.25), P = 0.41 (non-significant) by Fishers exact test]; the results remained similar when assuming that the two patients lost to follow-up in the methotrexateplacebo group could have been successfully treated [RR (95% CI): 1.065 (0.921.23), P = 0.42, non-significant or not (RR (95%CI): 1.095 (0.941.27), P = 0.26, non-significant]. No evidence of treatment by centre interaction was found (P = 0.36, non-significant).
Predictive factors for the main outcome measure (i.e. treatment success) were studied, on the basis of logistic models, overall and according to treatment group (Table II). Only serum -hCG levels at inclusion were significantly related to the outcome (P < 0.0001), whatever the randomized group, while progesterone levels were only related to the outcome in the methotrexateplacebo group (P = 0.01). To obtained further insight in these relationships, we estimated the shape of the influence for
-hCG and progesterone levels measured at baseline on the risk of success, using smoothing functions. As displayed in Figure 3, the assumption of log linearity of the effect of serum
-hCG levels was checked: the higher the level of
-hCG, the lower the probability of success. On the other hand, Figure 3 shows a non-linear effect for progesterone levels: risk of success falls with increasing progesterone level, up to a value of
1015 ng/ml, and then rises after 15 ng/ml. The threshold of 10 ng/ml was chosen on the basis of a non-parametric estimate of the effect of progesterone on the risk of success, and this value roughly corresponds to the change in slope observed on the curve.
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Discussion |
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Overall, the efficacy of methotrexate was not increased by the adjunct of mifepristone. The effect of methotrexate decreased linearly when serum -hCG levels increased. We chose as threshold the value of 1500 mIU/ml for serum
-hCG level which is near the median value of our population, to assess interaction between
-hCG levels and the effect of treatment: the addition of mifepristone did not improve the success rate of methotrexate irrespective of
-hCG concentrations (Table III).
However, there was significant quantitative interaction of mifepristone effect and serum progesterone levels, illustrating the heterogeneity in treatment effect according to baseline progesterone levels: actually, in women with progesterone level 10 ng/ml the addition of methotrexate to mifepristone improved the success rate, whereas in those with progesterone level <10 ng/ml there was no difference in outcome between randomized groups.
High serum progesterone concentrations reflect an important activity of the corpus luteum and are associated with an ectopic conceptus that is likely to be developing and growing. Indeed, in ectopic pregnancies, high baseline level of progesterone is predictive of failure of medical treatment by the methotrexate only (Ransom et al., 1994; Corsan et al., 1995
). Thus, the additional therapeutic efficacy of mifepristone could be due to a luteolytic effect (Somell et al., 1990
; Telleria et al., 2001
) particularly useful in the case of active corpus luteum.
Furthermore, Paris et al. (1986) observed marked trophoblastic necrosis at histological examination of the tissue samples from ectopic pregnancies when mifepristone was given. Therefore, mifepristone might facilitate this necrosis by a drop in the progesterone concentration.
Finally, it is also likely that in poorly active ectopic pregnancies, i.e. when serum -hCG level is <1500 mIU/ml, the great efficacy of methotrexate (90.6% in our study) probably masks the potential benefit due to a luteolytic effect of mifepristone even in the case of a very active corpus luteum.
Nonetheless, these conclusions must be guarded in view of the absence of initial stratification by progesterone levels which led to this post-hoc analysis. Furthermore, serum progesterone levels are not widely used clinically and were indeed omitted; these data are therefore missing from one half of the cases although it was part of the study protocol.
In our study, the need for a second injection was not considered as a criterion of failure because the optimal dose of methotrexate is unknown. Furthermore, the absence of indication for surgical intervention is a more relevant outcome in clinical practice. Finally, this same primary outcome was also used in a prior randomized trial (Fernandez et al., 1998) comparing methotrexate treatment to laparoscopic salpingotomy for conservative management of ectopic pregnancy.
Our results are different from those first published. In Perdu et al. (1998), the combination of mifepristone and methotrexate significantly increased the risk of success in the medical treatment of ectopic pregnancy. However, the patients treated by a combination of methotrexate and mifepristone were historically compared with a group which received only methotrexate. The combination of methotrexate and mifepristone was therefore used at a time when medical management was better understood and standardized; this might have overestimated the effect of the combined treatment, since surgery (notably, for persistent pain) was likely to be offered less often in this group.
In a randomized, controlled trial (Gazvani et al., 1998), ectopic pregnancy resolved faster in women who were given the combination of methotrexate and mifepristone as compared with those who were given methotrexate alone. Several drawbacks of this trial might be kept in mind, that limit the interpretation of the study results: (i) this trial was not a double-blind study; and (ii) the small sample size (25 in each arm) was not based on pre-specified power calculations.
The overall efficacy of medical treatment is less important than that previously reported in the largest series (Stovall et al., 1993; Lipscomb et al., 1998
). Several explanations are plausible. (i) Our multicentre clinical trial included both university teaching hospitals and general hospitals. Some investigators were thus possibly less trained in medical management and might have indicated surgery more often in the absence of a rapid favourable evolution whereas the previous three published studies were performed in the same single centre. However, our results are comparable with several others reporting lower success rates (Ransom et al., 1994
; Corsan et al., 1995
; Hajenius et al., 1997
). (ii) Patients with a serum
-hCG level <1500 mIU/ml that decreased after 48 h were not included in our trial. Thus, we only treated ectopic pregnancies that were clearly developing, although other studies included ectopic pregnancies with abnormal decrease of serum
-hCG levels to <1500 mIU/ml. This definitely applies to Korhonen et al. (1996
) who found that spontaneous resolution occurred in 77% of the cases when the median baseline hCG level was low. (iii) Although the combined use of sonography and serum
-hCG measurements improves the diagnosis of ectopic pregnancies, the limitations are also documented (Ankum et al., 1993
; Fernandez et al., 1998
). Among patients with low
-hCG plasma levels, a spontaneous abortion can be mistaken for an ectopic pregnancy. This is less likely when
-hCG level increases abnormally than when it decreases. Thus, the lower efficacy of medical treatment in our study might be the also consequence of a reduction in the false positive rate in the diagnosis of ectopic pregnancy.
In summary, there was a lack of statistically significant advantage in response rates for the combination of mifepristone and methotrexate over methotrexateplacebo, at the 5% level. By contrast, the observed treatment by serum progesterone level interaction suggests that this combination could be reserved to ectopic pregnancies with high levels of progesterone. This should be assessed in a randomized clinical trial in this particular population.
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Acknowledgements |
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Appendix |
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FOOTNOTES |
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References |
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Submitted on November 21, 2002; resubmitted on March 12, 2003; accepted on May 9, 2003.