Ultrasound-guided injection of methotrexate versus laparoscopic salpingotomy in ectopic pregnancy*

Transcription

1 FERTILITY AND STERILITY Copyright 1995 American Society for Reproductive Medicine Vol. 63, No. I, January 1995 Printed on acid-free paper in U. S. A. Ultrasound-guided injection of methotrexate versus laparoscopic salpingotomy in ectopic pregnancy* Herve Fernandez, M.D.t Sylvie Pauthier, M.D. Severin Doumerc, M.D. Christophe Lelaidier, M.D. Fran9ois Olivennes, M.D. Yves Ville, M.D. Rene Frydman, M.D. Department of Obstetrics and Gynecology, H6pital Antoine Beclere, Clamart, France Objective: To compare local injection of methotrexate (MTX) under sonographic control to laparoscopic salpingotomy for conservative management of ectopic pregnancy (EP). Design: Prospective randomized study. Patients: Forty patients were randomized into two groups using a random number table. Inclusion criteria were an EP visualized by ultrasound with a pretherapeutic score,; 13 as assessed by six criteria graded from 1 to 3: gestational age, hcg level, P level, abdominal pain, volume of the hemoperitoneum, and diameter of the hematosalpinx. Interventions: Group 1 patients injected transvaginally with 1 mg/kg MTX into the EP without anesthesia versus group 2 patients undergoing laparoscopic salpingotomy. Main Outcome Measures: Postoperative hospital stay, decrease of hcg levels, success rate. Results: The success rates, defined by hcg levels returned to normal ( <10 miu /ml [conversion factor to SI units, 1.00]), were 19 of 20 in both groups. Medical treatment was associated significantly with shorter postoperative stay (24 versus 46 hours) and a higher initial hcg level Human chorionic gonadotropin returned to normal more quickly after laparoscopic treatment (14 versus 28 days). Conclusions: In selected cases of EP with a pretherapeutic score,; 13, MTX treatment appeared to be as safe and efficient as was conservative treatment by laparoscopy. Fertil Steril 1995;63:25-9 Key Words: Ectopic pregnancy, laparoscopy, methotrexate The concordant development of hcg measurements using radioimmunologic, immunoradiometric, and immunoenzymatic methods and high resolution sonography using vaginal probes has allowed early diagnosis of ectopic pregnancy (EP). Thus, EP often is discovered before any clinical symp- Received November 5, 1993; revised and accepted August 19, * Presented at the conjoint Meeting of The American Fertility Society and the Canadian Fertility and Andrology Society, Montreal, Quebec, Canada, October 11 to 14, t Reprint requests: Herve Fernandez, M.D., Hopital Antoine Beclere, Department of Obstetrics and Gynecology, 157, rue de Ia Porte de Trivaux, Clamart cedex, France (FAX: ), toms have occurred. Linear salpingotomy by laparoscopy remains the treatment of choice for tubal pregnancy (1) and represents a significant advance over laparotomy in terms of duration of hospitalization, delay of recovery, and health service costs (2, 3). During the past 10 years, many series have reported the results of conservative medical treatment in EP. Methotrexate (MTX) administration included IM or IV injection of one to four doses (4-8), oral administration (9), or local injection under laparoscopic or sonographic control (10-14). Although no randomization could be done with laparoscopic surgery, MTX failure rates were similar to those previously reported in laparoscopic surgery series (1, 15). Moreover, follow-up and reproductive outcomes were similar in both conservative treat- Vol. 63, No. 1, January 1995 Fernandez et al. Medical treatment or salpingotomy 25

2 ments (1, 8, 14-17). We aimed to compare two conservative treatments of tubal pregnancies either by laparoscopic salpingotomy or by transvaginal injection of MTX under sonographic control in a prospective randomized study. MATERIALS AND METHODS Institutional review board approval of the study and informed written consent were obtained. Between September 1, 1992 and October 1, 1993, all patients with EP were evaluated according to a pretherapeutic score for the medical treatment (18). This score is based on six criteria graded on a scale from 1 to 3: gestational age, hcg level, P level, abdominal pain, volume of the hemoperitoneum, and diameter of the hematosalpinx as assessed by ultrasound (US). Previous studies (14, 18) demonstrated that with a score s 13 the success rate was >90%. Patients with a score s 13 were included in the trial. Among 70 EPs diagnosed during this period, 40 (57%) were entered into the study. Thirty patients were excluded for various reasons, e.g., no visualization of EP (n = 7), score > 13 (n = 10), suspicion of ruptured tubal pregnancies (n = 11), liver or kidney diseases and/or abnormal laboratory parameters with elevated liver enzymes or neutropenia that contraindicated MTX treatment (n = 2). No eligible patient opted against inclusion. The patients then were included into two groups, using a random number table. Twenty patients (group 1) were treated with a single dose of MTX. This procedure was realized without anesthesia, under vaginal sonographic control, with an 18- gauge needle inserted into a needle introducer. Penetration and aspiration of the ectopic sac was followed by an injection of 1 mg/kg MTX into the sac. Twenty patients (group 2) were treated by laparoscopy using a triple-puncture technique with three 5-mm trocar and a 10-mm nonoperative laparoscope connected to a video camera. A linear salpingotomy was performed on the surface of the antimesoalpinx proximal portion of the EP, and an aquapurator was used to flush the tube once the ectopic sac was removed. Patients in group 1 were monitored on an outpatient basis unless they lived too far from the hospital or when the procedure was performed after 4 P.M. (n = 10). Patients in group 2 were hospitalized for 2 days as usual in France, according to the French Health Service. Patients were followed up by telephone after each hcg control. All patients were aware of the possibility of treatment failure, as defined by the persistence of a high hcg levels and/or by the onset of abdominal pain. In these cases patients were managed by laparoscopy or by an additional injection of intramuscular MTX in group 2. Human chorionic gonadotropin levels (International Reference Preparation) were required (RIA gnost-hcg; Behring, Marburg, Germany) on days 2, 5, and 10 after the procedure and weekly until normalization (<10 miu/ml [conversion factor to SI unit, 1.00]). Liver function tests and red and white cell counts were obtained on day 10. Characteristics and risk factors of EP were assessed for each patient (19): age, parity, gravidity, smoking habits, history of tubal surgery and ofep, history of pelvic inflammatory disease, pregnancy starting while contraception was being used, history of infertility, use of infertility drugs, and presence of cardiac activity in the EP diagnosed by transvaginal US. Neither vaginal scan nor pelvic examination was repeated to avoid an iatrogenic tubal rupture. Human chorionic gonadotropin level normalization was compared with normal range (14-20). Hysterosalpingography (HSG) was programmed in patients 2 months after the return of the first menstrual period. Patients were seen or contacted by telephone regularly to update the fertility and obstetric history. Patient characteristics are expressed as means ± SD. Parameters in the two groups were compared by Student's t-test and by the x 2 test modified by Yates, as appropriate. RESULTS Demographics and characteristics (Table 1) were similar in both groups. Table 2 shows characteristics of the tubal pregnancies in both groups. Treatment failed in one case in each group. In group 1, a laparoscopy was performed on day 5 because of the occurrence of abdominal pain with an initial score at 13 and an hcg level at 5,900 miu/ml. A salpingotomy was required and the patient was pregnant again 3 months after surgery. One patient required IM MTX for a persistent EP in group 2. The initial hcg level was 880 miu /ml. In group 1, the initial hcg level was higher (P < 0.05) and the postoperative stay was shorter (P < 0.05). In group 2, the hcg median resolution time was shorter (P < 0.01). Treatment failure can be diagnosed early on the rate of decrease in hcg 26 Fernandez et al. Medical treatment or salpingotomy Fertility and Sterility

3 Table 1 Demographics and Characteristics of 40 Patients WithEPs Group 1 Group 2 (n = 20) (n = 20) Age (yr) 31.1 ± ± 3.9 (24 to 43)* (20 to 34)t Parity 0.5 ± ± 0.69 (0 to 3) (0 to 2)t Gravidity 1.67 ± ± 1.19 (0 to 4) (0 to 4)t Smoking 4 6 Infertility 11 7 Appendectomy 11 8 Past history EP and/or tubal surgery 7 6 Pelvic inflammatory disease 4 4 Induction of ovulation 5 6 Contraception failure 2 4 * Values are means ± SD with ranges in parentheses. t Not significant compared with group 1. levels. In group 1, mean number of blood samples for hcg measurements until return to normal, i.e., hcg level< 10 miu/ml, was 5 ± 1 (mean± SD) whereas it was 3 ± 0. 7 after surgery in group 2. Three EPs with cardiac activity and scores ~ 13 were treated successfully (respectively, one in group 1 and two in group 2). The postoperative course was uneventful with no side effects or septic complications in either group. Thirty-five patients had HSG after successful treatment. Thirty-one had a patent tube on the same side as the EP (two patients with tubal damage observed in each group with 1 to 2 em diameter defect in the ampullary region). To date, 30 wished to become pregnant again and 20 had a follow-up period of >6 months, among which 8 achieved an intrauterine pregnancy (IUP; 6 in group 1 and 2 in group 2). One recurrent EP has been observed in group 2 treated by laparoscopy. DISCUSSION Our findings suggest that a similar success rate defined by return to hcg < 10 miu/ml can be obtained with local MTX under US guidance when compared with laparoscopic linear salpingotomy. Currently, most cases of tubal EP are diagnosed by US examination and MTX can be administered at the same time that transvaginal US locates the ectopic sac. This procedure can be done on an outpatient basis without anesthesia or surgery. Good results were obtained with a single dose of MTX (8-14) and the site of injection in single-dose injection of MTX (locally or IM) could be relevant. Indeed, local aspiration allows emptying of the ectopic sac and permits histopathologic diagnosis of EP. Moreover, our finding about MTX kinetics clearly are in favor of the local injection (21). We observed in this study that area under the curve (AUC- oo) decreased more rapidly after injection in the gestational sac alone than after IM injection. This finding may be related to a decrease in bioavailability of MTX that links to trophoblastic cells. However, only a prospective randomized study could state clearly the rationale for local or IM injection. This finding was not included in the aim of the present study. The failure rate observed in this series after laparoscopic salpingotomy is similar to rates reported earlier (1, 22). Moreover, the pretherapeutic score Table 2 Clinical Laboratory, and Sonographic Findings in EPs Success (return to hcg <10 miu/ml)* Gestational age (d)t Scoret HCG preoperative (miu/ml)t Progesterone preoperative (ng/mlltll Hematosalpinx (mm)t Resolution time (d)t Postoperative stay (h)t Tubal patency (HSG) Patient desiring pregnancy with a follow-up >6 months Ongoing or a term pregnancy Recurrent EP Group 1 (n = 20) ± 10.0 (37 to 70) 10.4 ± 2.1 (7 to 13) 4,948 ± 7,682 (320 to 26,600) 10.8 ± 12.8 (0.5 to 38.6) 19.8 ± 9.9 (6 to 40) 28.8 ± 10.0 (13 to 47) 24 ± / Group 2 (n = 20) ± 10.5 (36 to 73)t 9.6 ± 1.8 (6 to 12)t 2,160.4 ± 1,756 (119 to 4,600) 4.9 ± 3.4 (1 to 11.5)t 16 ± 7.2 (5 to 31}t 13.6 ± 3. 7 (8 to 18)1f 46 ± / Day 0, day of MTX injection or laparoscopy. * Conversion factor to SI units, t Values are means ± SD with ranges in parentheses. t Not significantly different from group 1. Significantly different from group 1, P < II Conversion factor to SI units, f Significantly different from group 1, P < Vol. 63, No.1, January 1995 Fernandez et al. Medical treatment or salpingotomy 27

4 authorizes medical treatment with a low failure rate and defined a population that could really benefit from this atraumatic procedure, even with cardiac activity. Mottla et al. (23) reported a randomized trial comparing surgical laparoscopic treatment with medical treatment via laparoscopy. However, doses of MTX used were unusually low (12.5 mg) and the criteria used to judge treatment failure were unclear. The conclusions of this preliminary study were debated previously (24). For practical purposes, when an ectopic sac is found at laparoscopy, removal of the tube or of the trophoblast after linear salpingotomy should be done immediately. In these cases, IM MTX is indicated when there is persistent high serum hcg. In selected cases, as defined in our study, when the ectopic sac is visualized by US, local MTX treatment appears to be safe and efficient. In such cases, surgical treatment seldom is required except in cases of unusual abdominal pain with increasing of hematosalpinx at sonographic control or rising hcg level after additional IM MTX injection. However, it is very well known that patients receiving MTX treatment either locally or IM often experience increased abdominal pain on day 2 or 3 after puncture. In this series, the presence of cardiac activity was not considered as a contraindication when the score was :S;;13 and all patients were treated successfully. However, the presence of cardiac activity might represent a relative contraindication. Moreover, the low hcg levels observed in our trial in group 2 probably was due to chance in a small series. However, this should be debated in the interpretation of hcg decline after surgery or medical treatment. However, this difference could be pernicious only for medical treatment and cannot influence the results of our trial. Follow-up in this series was too short to determine the equivalence of reproductive performance. The overall rate of tubal patency observed on the post-treatment HSG was 88%. This is similar to that reported after nonsurgical management (7, 16, 17) or after surgical series (1). However, eight IUPs were obtained (six and two in groups 1 and 2, respectively) and previous studies after medical treatment (8, 14-17) found similar reproductive outcomes after conservative laparoscopic procedure. Moreover, prior history of infertility appears as the most significant parameter to predict fertility potential and outcome is not influenced by the choice of surgical procedures, either radical or conservative (25). Preliminary results of this prospective random- ized study confirm there is a place for a nonsurgical approach in the treatment of EP when the initial score is :S;;13, and this procedure is an efficient alternative to laparoscopic surgery. 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