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Human chorionic gonadotropin patterns after a single dose of methotrexate for ectopic pregnancy
European Journal of Obstetrics & Gynecology and Reproductive Biology 100 (2002) 227–230
Human chorionic gonadotropin patterns after a single dose of methotrexate for ectopic pregnancy Andrea Natalea,*, Mauro Busaccaa, Massimo Candiania, Luciano Grufta, Stefano Izzoa, Irene Felicettab, Mario Vignalia a
II Department of Obstetrics and Gynecology, Centro Universitario di Chirurgia Endoscopica e Sperimentazione Clinica (CUCESC), University of Milan, Milan, Italy b Laboratory of Clinical Chemistry and Endocrinology, Istituti Clinici di Perfezionamento, Milan, Italy Received 12 December 2000; accepted 2 July 2001
Abstract Objective: The great variability in human chorionic gonadotropin (HCG) levels after a single dose of methotrexate (MTX) for ectopic pregnancy makes it difficult to predict treatment failure. We describe different patterns of HCG levels. Study design: Fifty patients were injected i.m. with 50 mg/m2 of MTX for an ectopic pregnancy. Venous blood samples for HCG detection were obtained on the day of treatment (day 0), day 3 and day 7 and weekly until values were undetectable. Patients were classified as: group 1, persistent pathology (n ¼ 11); group 2, complete resolution with a decrease of HCG levels at day 3 (n ¼ 30); group 3, complete resolution after a rise of HCG values at day 3 (n ¼ 9). Statistical analysis was performed using the Mann–Whitney non-parametric test with 95% confidence intervals. Results: Values of day 0 were similar for all the groups. HCG levels of group 3 decreased rapidly after day 3 and at day 7 they were significantly different from levels of group 1. Differences in HCG levels between groups 2 and 3 became indistinguishable from day 21. Conclusion: The observation of patients undergoing resolution after an initial increase of HCG levels justify an expectant management for 1 week in clinically stable patients. The strategy to separate HCG curves in patients undergoing resolution may shed light on the different clinical responses to therapy for ectopic pregnancies. However, the phenomenon of the immediate rise of HCG should be better investigated. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Ectopic pregnancy; Methotrexate; HCG
1. Introduction As a consequence of the current widespread availability of early diagnosis of ectopic pregnancy, medical treatment assumes an important role for the treatment of this condition. Specifically, the management with a systemic single dose methotrexate (MTX) has shown promising results [1–5], since it is associated with high rate of resolutions and almost no side-effects, although as with every conservative treatment, it may expose to the persistence of trophoblastic tissue. Cases of tubal rupture or hemoperitoneum after MTX treatment have been described [3,4]; in this context, early detection of persistences can be relevant to avoid this complication. Therefore, a correct short-term follow up after medical therapy is aimed to identify persistences as soon
*
Corresponding author. Tel.: þ39-2-57-99-23-43; fax: þ39-2-55-19-05-32. E-mail address: [email protected] (A. Natale).
as possible and to prevent potential complications. To this aim, the human chorionic gonadotropin (HCG) has been identified as an accurate marker of trophoblastic tissue vitality and, in clinical practice, has been widely used to reveal persistences. An early rising of HCG title has been observed is 50–70% of cases subjected to medical therapy, although it has not always been associated to a clinically relevant persistence of trophoblastic tissue [2,6,7]. The phenomenon has not been clearly described yet, but an accurate interpretation of the issue is necessary in order to identify real persistences that need further therapy to avoid serious consequences from cases undergoing resolution. The purpose of this prospective study is to illustrate different patterns of HCG values after a single dose of methotrexate for ectopic pregnancy, with a particular attention to those cases that demonstrated an initial rise of the HCG curve before resolution. These cases are the most difficult to manage and, therefore, a prompt interpretation of different HCG curves is indeed of clinical relevance.
0301-2115/02/$ – see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 0 1 - 2 1 1 5 ( 0 1 ) 0 0 4 8 0 - 8
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A. Natale et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 100 (2002) 227–230
2. Materials and methods Fifty cases of ectopic pregnancy were treated i.m. with a single dose of 50 mg/m2 MTX at the II Department of Obstetrics and Gynecology of the University of Milan (Italy). Inclusion criteria were: (1) a certain diagnosis of ectopic pregnancy (extrauterine u.s. visualization of gestational sac, persistent or rising HCG values > 1500 mIU/ml without intrauterine evidence of pregnancy, persistent or rising HCG values < 1500 mIU/ml without histologic evidence of intrauterine villi); (2) exclusion of an intrauterine or tubal spontaneous abortion; (3) the absence of any sign of tubal rupture; (3) the absence of embryonic cardiac activity; (4) HCG levels < 4000 mIU/ml; (5) u.s. diameter < 4 cm; (6) the clinically well-being of the patient; (7) her consensus for treatment. The possibility for an accurate monitoring was also considered. Patients were not considered for MTX therapy if they had hepatic dysfunction, blood dyscrasia or renal disease. Patients were discharged within 3 h from treatment. In all the patients, no relevant side-effects were observed. Blood samples for HCG detection were obtained on the day the therapy was administered (day 0) and on day 3, day 7, and day 14 after MTX administration and, thereafter, once a week until values were completely undetectable. Serum HCG was detected by the electrochemiluminescence immunoassay (ECLIA) which is based on a sandwich antibody principle (Elecsys 1010/2010 Systems, Elecsys HCG Immunoassay, Roche). The interassay and intraassay coefficients of variation were 5.8 and 4.5%, respectively. Persistences were identified when precipitation of clinical parameters (i.e. acute pelvic pain or signs of tubal rupture, hemoperitoneum or intratubal cardiac activity) required surgical intervention (persistences with clinical relevance or clinical persistences) or when HCG values did not decrease more than 20% of the previous measurement within 1 week from treatment (persistences without clinical relevance or biochemical persistences).
For analysis, patients were classified as group 1 when they underwent persistence of the pathology, group 2 when they had a complete resolution with a rapid decrease of HCG levels at day 3, and group 3 when they underwent a complete resolution after a rise of HCG values at day 3. HCG clearance curves were obtained and studied as real values and as percentage of the concentration of day 0 (initial value). Statistical analysis was performed using the Mann– Whitney non-parametric test with 95% confidence intervals. Data are presented as means S:E.
3. Results A complete resolution of the pathology was obtained in 39 cases (78%) (groups 2 and 3). All the patients had an uneventful post-treatment period and resulted completely negative at HCG determination within 42 days (range: 7–42 days; mean: 20.4 days). Persistences (group 1) were observed in 11 cases (22%). Six of them consisted of clinical persistences (12%) and the remaining five cases (10%) consisted of biochemical persistences (Table 1). Initial HCG mean levels were not statistically different between the three groups (mean: 1238.4 mIU/ml for group 1; 1073.4 mIU/ml for group 2; 795.7 mIU/ml for group 3). However, a great variability in HCG values was observed for group 1. This was due to three specific cases in which persistence was clinically demonstrated, although HCG levels on day 3 had decreased slightly from day 0. Among patients who underwent resolution of the pathology, 30 (group 2, 60% of all patients, 76.9% of all resolutions) showed an immediate decrease of HCG values within day 3 after treatment. In nine cases (group 3, 18% of all patients, 23.1% of all resolutions), a marked increase compared to day 0 value was recorded on day 3, but a rapid decrease (>20% of day 3 value) was recorded after 4 days and an uneventful complete resolution was observed within 1 month after treatment. Indeed, HCG levels of group 3, both
Table 1 Persistences following a single dose of MTXa Gestational age (weeks)
Initial HCG (mIU/ml)
Second treatment
5 7 6 6 10 7 7 6 7 5 7
502 718 2202 1980 169 2400 1200 1130 1815 830 676
LPS for acute pelvic pain LPS for acute pelvic pain LPS for acute pelvic pain LPS for u.s. evidence of ectopic cardiac activity LPS for tubal rupture LPS for acute hemoperitoneum LPS (the patient refused a second dose of MTX)b Second dose of MTX and then a conservative LPSb Expectant management Expectant management Expectant management
a
Persistences following a single dose of MTX (group 1: 11 patients) divided as clinical and biochemical persistences; gestational age and HCG levels at day 0 are indicated. b Clinically stable patients.
A. Natale et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 100 (2002) 227–230
analyzed as real values or percentage decrease of the day 0 sample, remained higher than those of group 2 on day 7 and day 14, but on day 21, HCG levels were identical for both groups of patients. In terms of time for resolution, for both groups of patients, mean values for HCG resulted in less than 5 mIU/ml at day 21 and no difference was observed between the number of days required for resolution for group 2 (range: 7–42 days; mean: 19.5 days) as compared to those for group 3 (range: 14–28 days; mean: 22.7 days). An immediate rise of HCG levels could represent a clinical dilemma. Indeed, the necessity to distinguish real from only apparent persistences lead us to compare HCG curves related to group 1 to those of group 3. At day 3,
Fig. 1. HCG value profiles in patients treated with 50 mg/m2 MTX i.m. for ectopic pregnancy. Day 0 represents the day on which the therapy was administered. Data for patients undergoing persistence of trophoblastic tissue (group 1) were compared to those for patients undergoing resolution with an immediate decrease of the hormonal parameter (group 2) and to those for patients undergoing resolution with an increase of HCG levels at day 3 (group 3). (a) HCG real values; (b) levels of HCG as a percentage of day 0 measurement. Statistical significance, when present, is indicated as follows: () significantly different vs. correspondent group 2 values (P < 0:01); () significantly different vs. correspondent group 3 values (P < 0:05).
229
clearance titers of HCG levels in group 1 were not significantly different from those in group 3; furthermore, when data were analyzed as percentage of day 0 value, group 3 patients showed a higher increase than group 1 (þ43.4 versus þ15.1%). In contrast, at day 7, as a consequence of the rapid decrease of HCG levels in group 3, values became significantly lower in group 3 in comparison to group 1. HCG profiles are illustrated in Fig. 1.
4. Comment In recent years, the effective role of the conservative surgical treatment for ectopic pregnancy has been controversial when compared to the non-conservative approach: on one hand, it was thought to give better results in terms of future pregnancies; on the other hand, the risk of persistences and a higher recurrence rate have limited its utilization. In selected patients, medical treatment constitutes a safe and effective alternative to surgical conservative treatment. Persistence of trophoblastic tissue is considered the failure of the various therapies for ectopic pregnancy, either surgical or medical. To our knowledge, only one case of persistence has been described after salpingectomy [8]; on the contrary, persistence should be considered as a possible failure of every conservative procedure. It has been reported that medical treatment by MTX is followed by 10–15% of cases undergoing persistence requiring a surgical intervention; thus, a prompt and correct interpretation of biochemical parameters could lead to early diagnosis of persistence and might lower the surgical treatment rate. Therefore, HCG curves are important for monitoring patients treated conservatively and they are universally considered as an accurate marker for the identification of persistences. After salpingostomy, HCG levels rapidly decrease to less than 10% of the initial value after 12 days [7,9]; moreover, the patterns are similar to those obtained after salpingectomy [10–12]. Therefore, in most cases, postsurgical HCG levels might discriminate persistences from resolutions in a very short time [13]. In contrast, after medical therapy, HCG levels show a high variability and within the first days after treatment, it remains complicated to separate resolutions from persistences. Specifically, this is due to the phenomenon of the rapid increase in HCG values that occurs in a certain percentage of cases undergoing resolution. Indeed, several authors noted a transient rise of HCG within the first few days after MTX treatment. Groutz et al. [6] observed the rising of HCG values for at least 2 days after laparoscopic local injection of MTX in 70% of patients. Saraj et al. [7] reported an initial increase between day 0 and day 4 after a single dose of 1 mg/kg MTX. Finally, Stovall and Ling [2] noted that 86% of patients had a transient increase of serum HCG between day 1 and day 4 after the treatment. In keeping with these reports, the present study showed an initial increase of HCG
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levels at day 3 in 23.1% of patients that underwent resolution. The fact that this study did not take into consideration HCG levels obtained in the very first days from treatment might explain the lower percentage when compared to other published series. To better clarify the post-treatment patterns of biochemical parameters, the present retrospective study evaluated three different curves of HCG values: curves related to group 1 patients illustrated persistences, while those related to groups 2 and 3 patients illustrated two different modes of resolution: cases in which HCG levels immediately decreased after the medical treatment for the former, and cases in which HCG levels initially increased for the latter. While HCG levels for group 2 patients were immediately different from those of persistences, values related to group 3 patients may be misinterpreted. Indeed, only 47% of patients that showed an increase of HCG titers on day 3 showed to have real persistences. This suggests that in clinically stable patients, an expectant management is indicated until a week from treatment. It is still to be clarified why an initial increase of HCG titers can be observed before a complete resolution and why it is present only in specific patients. Some hypotheses have addressed the interpretation of this issue. (1) The long halflife (36 h) of HCG must be considered for an initial lag time in serum HCG clearance. (2) It is possible, but not unequivocally demonstrated yet, that the initial response of the trophoblast to the cytotoxic effect of methotrexate is the release of additional HCG into the circulation. (3) MTX is a folic acid analogue, an antimetabolite that interferes with the synthesis of DNA by inhibiting the action of dihydrofolate reductase: it interrupts the synthesis of the purine nucleotide thymidilate and the amino acids serine and methionine. This results in a cytotoxic effect on trophoblastic tissue. It is possible that, although MTX is arresting mitosis in cytotrophoblasts, the syncytotrophoblastic mass still may be increasing and producing HCG [14]. (4) The metabolism of folinic acid in different patients might influence the effect of MTX. This is supported by findings by Hajenius et al. [15] who observed that in two groups of patients treated with multiple-dose MTX, different protocols of folinic acid administration determined different patterns of HCG curves. In conclusion, the results of the present study support the following observations: (1) 23.1% of patients undergoing resolution for ectopic pregnancy show an immediate increase of HCG values within day 3 after a single dose of MTX; according to the literature, this issue justify that in clinically stable patients, an expectant management is indicated until a week from treatment; (2) at day 21 after the medical treatment, HCG values are similar for all patients undergoing resolution; thus, when it occurs, the rapid rise of HCG levels is associated with a rapid decrease after day 3. The strategy to separate HCG curves in patients undergoing resolution may shed light on the different clinical
responses to therapy for ectopic pregnancies. However, the phenomenon of the immediate rise of HCG after a single dose of MTX for ectopic pregnancy should be better investigated. Biological studies on this topic are also needed.
Acknowledgements The authors thank Dr. Paola Vigano` for her help and support in the preparation of this manuscript. Also, the authors thank Dr. Darren R. Link for his linguistic support. References [1] Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for the treatment of ectopic pregnancy. Obstet Gynecol 1991;77:754– 5. [2] Stovall TG, Ling FW. Single-dose methotrexate: an expanded clinical trial. Am J Obstet Gynecol 1993;168:1759–62. [3] Glock JL, Johnson JV, Brumsted JR. Efficacy and safety of singledose methotrexate in the treatment of ectopic pregnancy. Fertil Steril 1994;62(4):716–21. [4] Hajenius PJ, Engelsbel S, Mol BWJ, et al. Randomised trial of systemic methotrexate versus laparoscopic salpingostomy in tubal pregnancy. Lancet 1997;350:774–9. [5] Lipscomb GH, Bran D, Ling FW. Analysis of three hundred fifteen ectopic pregnancies treated with single-dose methotrexate. Am J Obstet Gynecol 1998;178:1354–8. [6] Groutz A, Luxman D, Cohen JR, et al. Rising HCG titers following laparoscopic injection of methotrexate into unruptured, viable tubal pregnancies. Br J Obstet Gynaecol 1993;100:287–8. [7] Saraj AJ, Wilkox JG, Najambadi S. Resolution of hormonal markers of ectopic gestation: a randomized trial comparing single-dose intramuscular methotrexate with salpingostomy. Obstet Gynecol 1998;92:989–94. [8] Giambelli F, Gruft L, Busacca M, et al. Increasing bHCG levels after laparoscopic salpingectomy for tubal pregnancy. J Gynecol Surg 1998;14:133–5. [9] Vermesh M, Silva PD, Sauer MV, et al. Persistent ectopic gestation: patterns of circulating b-chorionic gonadotropin and progesterone and management options. Fertil Steril 1988;50:584–8. [10] Hajenius PJ, Mol BWJ, Ankum WM, et al. Clearance curves of serum human chorionic gonadotropin for the diagnosis of persistent trophoblast. Hum Reprod 1995;10:683–7. [11] Busacca M, Gruft L, Giambelli F, et al. Clinical usefulness of monitoring bHCG levels after laparoscopic treatment for tubal pregnancy. J Gynecol Surg 1996;12:99–103. [12] Giambelli F, Candiani M, Natale A, et al. Laparoscopic treatment of ectopic pregnancy: analysis of 114 consecutive cases. It J Obstet Gynecol 1996;8:5–9. [13] Spandorfer SD, Sawin SW, Benjamin I, et al. Postoperative day 1 serum human chorionic gonadotropin level as predictor of persistent ectopic pregnancy after conservative surgical management. Fertil Steril 1997;68:430–4. [14] De Loja JA, Stewart-Akers AM, Crenin MD. Effects of methotrexate on trophoblast proliferation and local immune response. Hum Reprod 1998;13(4):1063–9. [15] Hajenius PJ, Voigt RR, Engelsbel S, et al. Serum human chorionic gonadotropin clearance curves in patients with interstitial pregnancy treated with systemic methotrexate. Fertil Steril 1996;66(5): 723– 8.
Human chorionic gonadotropin patterns after a single dose of methotrexate for ectopic pregnancy Andrea Natalea,*, Mauro Busaccaa, Massimo Candiania, Luciano Grufta, Stefano Izzoa, Irene Felicettab, Mario Vignalia a
II Department of Obstetrics and Gynecology, Centro Universitario di Chirurgia Endoscopica e Sperimentazione Clinica (CUCESC), University of Milan, Milan, Italy b Laboratory of Clinical Chemistry and Endocrinology, Istituti Clinici di Perfezionamento, Milan, Italy Received 12 December 2000; accepted 2 July 2001
Abstract Objective: The great variability in human chorionic gonadotropin (HCG) levels after a single dose of methotrexate (MTX) for ectopic pregnancy makes it difficult to predict treatment failure. We describe different patterns of HCG levels. Study design: Fifty patients were injected i.m. with 50 mg/m2 of MTX for an ectopic pregnancy. Venous blood samples for HCG detection were obtained on the day of treatment (day 0), day 3 and day 7 and weekly until values were undetectable. Patients were classified as: group 1, persistent pathology (n ¼ 11); group 2, complete resolution with a decrease of HCG levels at day 3 (n ¼ 30); group 3, complete resolution after a rise of HCG values at day 3 (n ¼ 9). Statistical analysis was performed using the Mann–Whitney non-parametric test with 95% confidence intervals. Results: Values of day 0 were similar for all the groups. HCG levels of group 3 decreased rapidly after day 3 and at day 7 they were significantly different from levels of group 1. Differences in HCG levels between groups 2 and 3 became indistinguishable from day 21. Conclusion: The observation of patients undergoing resolution after an initial increase of HCG levels justify an expectant management for 1 week in clinically stable patients. The strategy to separate HCG curves in patients undergoing resolution may shed light on the different clinical responses to therapy for ectopic pregnancies. However, the phenomenon of the immediate rise of HCG should be better investigated. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Ectopic pregnancy; Methotrexate; HCG
1. Introduction As a consequence of the current widespread availability of early diagnosis of ectopic pregnancy, medical treatment assumes an important role for the treatment of this condition. Specifically, the management with a systemic single dose methotrexate (MTX) has shown promising results [1–5], since it is associated with high rate of resolutions and almost no side-effects, although as with every conservative treatment, it may expose to the persistence of trophoblastic tissue. Cases of tubal rupture or hemoperitoneum after MTX treatment have been described [3,4]; in this context, early detection of persistences can be relevant to avoid this complication. Therefore, a correct short-term follow up after medical therapy is aimed to identify persistences as soon
*
Corresponding author. Tel.: þ39-2-57-99-23-43; fax: þ39-2-55-19-05-32. E-mail address: [email protected] (A. Natale).
as possible and to prevent potential complications. To this aim, the human chorionic gonadotropin (HCG) has been identified as an accurate marker of trophoblastic tissue vitality and, in clinical practice, has been widely used to reveal persistences. An early rising of HCG title has been observed is 50–70% of cases subjected to medical therapy, although it has not always been associated to a clinically relevant persistence of trophoblastic tissue [2,6,7]. The phenomenon has not been clearly described yet, but an accurate interpretation of the issue is necessary in order to identify real persistences that need further therapy to avoid serious consequences from cases undergoing resolution. The purpose of this prospective study is to illustrate different patterns of HCG values after a single dose of methotrexate for ectopic pregnancy, with a particular attention to those cases that demonstrated an initial rise of the HCG curve before resolution. These cases are the most difficult to manage and, therefore, a prompt interpretation of different HCG curves is indeed of clinical relevance.
0301-2115/02/$ – see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 0 1 - 2 1 1 5 ( 0 1 ) 0 0 4 8 0 - 8
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A. Natale et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 100 (2002) 227–230
2. Materials and methods Fifty cases of ectopic pregnancy were treated i.m. with a single dose of 50 mg/m2 MTX at the II Department of Obstetrics and Gynecology of the University of Milan (Italy). Inclusion criteria were: (1) a certain diagnosis of ectopic pregnancy (extrauterine u.s. visualization of gestational sac, persistent or rising HCG values > 1500 mIU/ml without intrauterine evidence of pregnancy, persistent or rising HCG values < 1500 mIU/ml without histologic evidence of intrauterine villi); (2) exclusion of an intrauterine or tubal spontaneous abortion; (3) the absence of any sign of tubal rupture; (3) the absence of embryonic cardiac activity; (4) HCG levels < 4000 mIU/ml; (5) u.s. diameter < 4 cm; (6) the clinically well-being of the patient; (7) her consensus for treatment. The possibility for an accurate monitoring was also considered. Patients were not considered for MTX therapy if they had hepatic dysfunction, blood dyscrasia or renal disease. Patients were discharged within 3 h from treatment. In all the patients, no relevant side-effects were observed. Blood samples for HCG detection were obtained on the day the therapy was administered (day 0) and on day 3, day 7, and day 14 after MTX administration and, thereafter, once a week until values were completely undetectable. Serum HCG was detected by the electrochemiluminescence immunoassay (ECLIA) which is based on a sandwich antibody principle (Elecsys 1010/2010 Systems, Elecsys HCG Immunoassay, Roche). The interassay and intraassay coefficients of variation were 5.8 and 4.5%, respectively. Persistences were identified when precipitation of clinical parameters (i.e. acute pelvic pain or signs of tubal rupture, hemoperitoneum or intratubal cardiac activity) required surgical intervention (persistences with clinical relevance or clinical persistences) or when HCG values did not decrease more than 20% of the previous measurement within 1 week from treatment (persistences without clinical relevance or biochemical persistences).
For analysis, patients were classified as group 1 when they underwent persistence of the pathology, group 2 when they had a complete resolution with a rapid decrease of HCG levels at day 3, and group 3 when they underwent a complete resolution after a rise of HCG values at day 3. HCG clearance curves were obtained and studied as real values and as percentage of the concentration of day 0 (initial value). Statistical analysis was performed using the Mann– Whitney non-parametric test with 95% confidence intervals. Data are presented as means S:E.
3. Results A complete resolution of the pathology was obtained in 39 cases (78%) (groups 2 and 3). All the patients had an uneventful post-treatment period and resulted completely negative at HCG determination within 42 days (range: 7–42 days; mean: 20.4 days). Persistences (group 1) were observed in 11 cases (22%). Six of them consisted of clinical persistences (12%) and the remaining five cases (10%) consisted of biochemical persistences (Table 1). Initial HCG mean levels were not statistically different between the three groups (mean: 1238.4 mIU/ml for group 1; 1073.4 mIU/ml for group 2; 795.7 mIU/ml for group 3). However, a great variability in HCG values was observed for group 1. This was due to three specific cases in which persistence was clinically demonstrated, although HCG levels on day 3 had decreased slightly from day 0. Among patients who underwent resolution of the pathology, 30 (group 2, 60% of all patients, 76.9% of all resolutions) showed an immediate decrease of HCG values within day 3 after treatment. In nine cases (group 3, 18% of all patients, 23.1% of all resolutions), a marked increase compared to day 0 value was recorded on day 3, but a rapid decrease (>20% of day 3 value) was recorded after 4 days and an uneventful complete resolution was observed within 1 month after treatment. Indeed, HCG levels of group 3, both
Table 1 Persistences following a single dose of MTXa Gestational age (weeks)
Initial HCG (mIU/ml)
Second treatment
5 7 6 6 10 7 7 6 7 5 7
502 718 2202 1980 169 2400 1200 1130 1815 830 676
LPS for acute pelvic pain LPS for acute pelvic pain LPS for acute pelvic pain LPS for u.s. evidence of ectopic cardiac activity LPS for tubal rupture LPS for acute hemoperitoneum LPS (the patient refused a second dose of MTX)b Second dose of MTX and then a conservative LPSb Expectant management Expectant management Expectant management
a
Persistences following a single dose of MTX (group 1: 11 patients) divided as clinical and biochemical persistences; gestational age and HCG levels at day 0 are indicated. b Clinically stable patients.
A. Natale et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 100 (2002) 227–230
analyzed as real values or percentage decrease of the day 0 sample, remained higher than those of group 2 on day 7 and day 14, but on day 21, HCG levels were identical for both groups of patients. In terms of time for resolution, for both groups of patients, mean values for HCG resulted in less than 5 mIU/ml at day 21 and no difference was observed between the number of days required for resolution for group 2 (range: 7–42 days; mean: 19.5 days) as compared to those for group 3 (range: 14–28 days; mean: 22.7 days). An immediate rise of HCG levels could represent a clinical dilemma. Indeed, the necessity to distinguish real from only apparent persistences lead us to compare HCG curves related to group 1 to those of group 3. At day 3,
Fig. 1. HCG value profiles in patients treated with 50 mg/m2 MTX i.m. for ectopic pregnancy. Day 0 represents the day on which the therapy was administered. Data for patients undergoing persistence of trophoblastic tissue (group 1) were compared to those for patients undergoing resolution with an immediate decrease of the hormonal parameter (group 2) and to those for patients undergoing resolution with an increase of HCG levels at day 3 (group 3). (a) HCG real values; (b) levels of HCG as a percentage of day 0 measurement. Statistical significance, when present, is indicated as follows: () significantly different vs. correspondent group 2 values (P < 0:01); () significantly different vs. correspondent group 3 values (P < 0:05).
229
clearance titers of HCG levels in group 1 were not significantly different from those in group 3; furthermore, when data were analyzed as percentage of day 0 value, group 3 patients showed a higher increase than group 1 (þ43.4 versus þ15.1%). In contrast, at day 7, as a consequence of the rapid decrease of HCG levels in group 3, values became significantly lower in group 3 in comparison to group 1. HCG profiles are illustrated in Fig. 1.
4. Comment In recent years, the effective role of the conservative surgical treatment for ectopic pregnancy has been controversial when compared to the non-conservative approach: on one hand, it was thought to give better results in terms of future pregnancies; on the other hand, the risk of persistences and a higher recurrence rate have limited its utilization. In selected patients, medical treatment constitutes a safe and effective alternative to surgical conservative treatment. Persistence of trophoblastic tissue is considered the failure of the various therapies for ectopic pregnancy, either surgical or medical. To our knowledge, only one case of persistence has been described after salpingectomy [8]; on the contrary, persistence should be considered as a possible failure of every conservative procedure. It has been reported that medical treatment by MTX is followed by 10–15% of cases undergoing persistence requiring a surgical intervention; thus, a prompt and correct interpretation of biochemical parameters could lead to early diagnosis of persistence and might lower the surgical treatment rate. Therefore, HCG curves are important for monitoring patients treated conservatively and they are universally considered as an accurate marker for the identification of persistences. After salpingostomy, HCG levels rapidly decrease to less than 10% of the initial value after 12 days [7,9]; moreover, the patterns are similar to those obtained after salpingectomy [10–12]. Therefore, in most cases, postsurgical HCG levels might discriminate persistences from resolutions in a very short time [13]. In contrast, after medical therapy, HCG levels show a high variability and within the first days after treatment, it remains complicated to separate resolutions from persistences. Specifically, this is due to the phenomenon of the rapid increase in HCG values that occurs in a certain percentage of cases undergoing resolution. Indeed, several authors noted a transient rise of HCG within the first few days after MTX treatment. Groutz et al. [6] observed the rising of HCG values for at least 2 days after laparoscopic local injection of MTX in 70% of patients. Saraj et al. [7] reported an initial increase between day 0 and day 4 after a single dose of 1 mg/kg MTX. Finally, Stovall and Ling [2] noted that 86% of patients had a transient increase of serum HCG between day 1 and day 4 after the treatment. In keeping with these reports, the present study showed an initial increase of HCG
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levels at day 3 in 23.1% of patients that underwent resolution. The fact that this study did not take into consideration HCG levels obtained in the very first days from treatment might explain the lower percentage when compared to other published series. To better clarify the post-treatment patterns of biochemical parameters, the present retrospective study evaluated three different curves of HCG values: curves related to group 1 patients illustrated persistences, while those related to groups 2 and 3 patients illustrated two different modes of resolution: cases in which HCG levels immediately decreased after the medical treatment for the former, and cases in which HCG levels initially increased for the latter. While HCG levels for group 2 patients were immediately different from those of persistences, values related to group 3 patients may be misinterpreted. Indeed, only 47% of patients that showed an increase of HCG titers on day 3 showed to have real persistences. This suggests that in clinically stable patients, an expectant management is indicated until a week from treatment. It is still to be clarified why an initial increase of HCG titers can be observed before a complete resolution and why it is present only in specific patients. Some hypotheses have addressed the interpretation of this issue. (1) The long halflife (36 h) of HCG must be considered for an initial lag time in serum HCG clearance. (2) It is possible, but not unequivocally demonstrated yet, that the initial response of the trophoblast to the cytotoxic effect of methotrexate is the release of additional HCG into the circulation. (3) MTX is a folic acid analogue, an antimetabolite that interferes with the synthesis of DNA by inhibiting the action of dihydrofolate reductase: it interrupts the synthesis of the purine nucleotide thymidilate and the amino acids serine and methionine. This results in a cytotoxic effect on trophoblastic tissue. It is possible that, although MTX is arresting mitosis in cytotrophoblasts, the syncytotrophoblastic mass still may be increasing and producing HCG [14]. (4) The metabolism of folinic acid in different patients might influence the effect of MTX. This is supported by findings by Hajenius et al. [15] who observed that in two groups of patients treated with multiple-dose MTX, different protocols of folinic acid administration determined different patterns of HCG curves. In conclusion, the results of the present study support the following observations: (1) 23.1% of patients undergoing resolution for ectopic pregnancy show an immediate increase of HCG values within day 3 after a single dose of MTX; according to the literature, this issue justify that in clinically stable patients, an expectant management is indicated until a week from treatment; (2) at day 21 after the medical treatment, HCG values are similar for all patients undergoing resolution; thus, when it occurs, the rapid rise of HCG levels is associated with a rapid decrease after day 3. The strategy to separate HCG curves in patients undergoing resolution may shed light on the different clinical
responses to therapy for ectopic pregnancies. However, the phenomenon of the immediate rise of HCG after a single dose of MTX for ectopic pregnancy should be better investigated. Biological studies on this topic are also needed.
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