Ectopic pregnancy is derived from the Greek word ektopos, meaning out of place. It is the result of a fault in human reproductive physiology that allows the conceptus to implant and mature outside the endometrial cavity, which ultimately ends in death of the fetus. Without early diagnosis and treatment, ectopic pregnancy can become a life-threatening situation. This abnormally implanted gestation grows and draws its blood supply from the site of abnormal implantation. As the gestation enlarges, it creates the potential for organ rupture because only the uterine cavity is designed to expand and accommodate fetal development. Ectopic pregnancy can lead to massive hemorrhage, infertility, or death 1.
Laparoscopic salpingotomy is a well-established treatment modality in patients with tubal pregnancy who desire to retain fertility. This procedure preserves the fallopian tube, thereby maintaining reproductive capacity 2,3. Another approach that preserves tubal integrity is medical treatment, in particular the systemic administration of methotrexate (MTX). As laparoscopy is no longer essential for diagnosis in patients with suspected ectopic pregnancy, MTX offers the option of completely nonsurgical management 4,5. Reviews summarizing uncontrolled studies have reported outcomes of systemic MTX treatment similar to those of laparoscopic salpingotomy with respect to success rate, homolateral tubal patency, and reproductive outcome 6–8. Because rupture of ectopic pregnancy after MTX treatment is possible 9–11, accessibility to healthcare facilities and patient compliance in the follow-up period are important factors to be considered. The decision to treat with MTX is further complicated by the lack of agreement on treatment criteria. All these issues need to be resolved in a prospective, randomized manner.
This study initiated a randomized prospective clinical trial comparing systemic MTX and laparoscopic salpingotomy in the treatment of tubal pregnancy.
Outcome measures were treatment success, tubal preservation, homolateral tubal patency, and fertility potential after each treatment protocol.
Patients and methods
This randomized prospective clinical trial was conducted between January 2010 and November 2011 in Tanta University Hospital. It was approved by the ethics committees of the university. Patients with a diagnosis of early undisturbed tubal ectopic pregnancy were invited to participate in this study. Ectopic pregnancy was diagnosed on the basis of a noninvasive strategy combining transvaginal sonography and measurement of serum human chorionic gonadotropin (HCG) 4,5. Exclusion criteria were disturbed ectopic pregnancy, evidence of significant internal hemorrhage, advanced ectopic pregnancy, fetal cardiac activity, sonographically detected interstitial, cervical, ovarian, or heterotopic pregnancy, and contraindications to systemic MTX, or laparoscopic surgery.
All eligible patients were informed about the possible complications and risk of failure of both treatments. Patients who gave written informed consent were randomly assigned to one of the two treatment modalities by means of a computer program.
In patients allocated for laparoscopic salpingotomy, laparoscopy was performed with the standard three-puncture technique under general anesthesia. A bipolar coagulation of the seromuscular tubal vessels, followed by a linear incision using a monopolar needle, was made over the bulging antimesenteric portion of the tube. The ectopic mass was removed with an irrigation probe for hydroextrusion of the ectopic mass. Bipolar hemostasis of the edges of the incision was done, avoiding cauterization of the tubal mucosa. If significant bleeding persisted, bipolar cauterization of blood vessels running just beneath the tube in the mesosalpinx or injection of vasoconstrictor in the mesosalpinx was done. After hemostasis had been achieved the tubal incision was left open to allow secondary healing. The pelvis was then irrigated 12.
In patients allocated systemic MTX, treatment was undertaken on an outpatient basis. Following the protocol of Stovall and Ling 13, patients were treated with intramuscular MTX at 1.0 mg/kg.
Monitoring after primary treatment
- Immediate follow-up:
- Assays of β-HCG concentrations were required before starting the management protocol (baseline), then on days 4 and 7 after the procedure, and then weekly until normalization (<10 mIU/ml).
- Complete blood counts were analyzed, and liver and renal functions were monitored to detect MTX toxicity.
- Transvaginal sonography (Hitachi EUB 415/515; Hitachi Medical Corporation, Tokyo, Japan) was performed in both treatment groups routinely within 1 week after the start of treatment or whenever complications were suspected. Patients who received systemic MTX were followed up until resolution of the ectopic mass was completed.
- Treatment success was defined as complete elimination of the tubal pregnancy (serum β-HCG concentration<10 mIU/ml). Failure of serum β-HCG concentration to fall by at least 15% during any successive week and/or the onset of significant abdominal pain warranted prompt further evaluation and management. In patients treated with systemic MTX, a second course of MTX or laparoscopy was administered to asymptomatic patients. In patients treated with laparoscopic salpingotomy, a course of systemic MTX was given to asymptomatic patients. Emergency surgical intervention was reserved to patients if severe intraperitoneal bleeding or acute abdomen occurred at any time.
- Maintained follow-up:
- All patients were followed up for at least 1 year to evaluate their spontaneous reproductive performance and to update the fertility and obstetric history.
- Hysterosalpingography (HSG) was performed 3 months after completion of treatment to assess tubal patency.
- Second-look laparoscopy was performed if there was failure of pregnancy or evidence of pelvic pathology by ultrasonography or HSG.
Treatment success was defined as complete elimination of the tubal pregnancy (serum β-HCG<10 mIU/l). The success rates were calculated after primary treatment (i.e. one systemic MTX course or salpingotomy alone). We also calculated tubal preservation rates after primary treatment plus any additional therapeutic intervention.
In addition, homolateral tubal patency rates on HSG were compared. Overall homolateral tubal patency rates were calculated by including those patients who underwent salpingectomy in the denominator. All comparisons were made by calculation of rate ratios and the corresponding 95% confidence interval. The median number of days for undetectable serum β-HCG concentrations to be reached (serum β-HCG clearance time) was calculated in each treatment group and compared by Wilcoxon’s statistics.
One hundred patients were included in this prospective randomized clinical trial. Baseline characteristics of the treatment groups are given in Table 1. No statistically significant differences were found in the clinical criteria between the two study groups.
Of the 49 patients allocated to laparoscopic salpingotomy, 43 (87.8%) were successfully treated by laparoscopic salpingotomy alone; salpingectomy was needed in two (4.1%) patients, and four (8.2%) needed MTX for persistent trophoblast. Of the 51 patients assigned and treated with systemic MTX, one course was successful in 36 (70.6%) patients. Three (5.9%) patients were successfully treated but needed a second course for persistent trophoblast 12 and 23.5% of patients needed surgical intervention (Table 2).
Surgical intervention was necessary during or after the first MTX course in 10 of these patients, and after a second course in two patients. Conservative surgery was possible in six patients: in two patients with laparoscopic salpingotomy for active bleeding and in four patients with salpingotomy during laparotomy. In the remaining six patients salpingectomy was necessary for tubal rupture, either by laparoscopy or by laparotomy. The tube was preserved in 47 (95.9%) patients in the salpingotomy group versus 45 (88.2%) patients in the MTX group (rate ratio 0.98, 95% confidence interval 0.87–1.1). Median serum β-HCG clearance time was comparable between the two groups: 14 (range 2–50) days after laparoscopic salpingotomy and 19 (range 2–53) days after systemic MTX treatment.
In the salpingotomy group, HSG was not performed in the two patients who needed salpingectomy. Of the remaining 47 patients eligible for HSG, four became pregnant while awaiting this diagnostic procedure. Seven patients refused to give informed consent or were lost to follow-up. Thus, 36 patients underwent HSG. Homolateral tubal patency was found in 34 (94.4%) patients. The overall homolateral tubal patency rate, including the two patients who underwent salpingectomy, was 89.5% (34/38).
In the systemic MTX group, HSG was not performed in the six patients who underwent secondary salpingectomy. Of the remaining 45 patients eligible for HSG, three became pregnant while awaiting this diagnostic procedure. Nine patients refused to give informed consent or were lost to follow-up. Thus, 33 patients underwent HSG. Homolateral tubal patency was found in 26 (78.8%) patients. The overall homolateral tubal patency rate, including the six patients who underwent salpingectomy, was 66.7% (26/39) (Table 3). The tube was preserved in 47 (95.9%) patients in the salpingotomy group versus 45 (88.2%) patients in the MTX group. The overall homolateral tubal patency rate on HSG (including patients who underwent salpingectomy) was 89.5% (34/38) in the laparoscopic salpingotomy group of patients versus 66.7% (26/39) in the MTX group (P<0.05).
The spontaneous reproductive outcome in patients desiring fertility with the two treatment modalities are summarized in Table 4.
In this prospective randomized clinical trial of systemic MTX versus laparoscopic salpingotomy in patients with undisturbed tubal pregnancy, both treatment modalities were successful in treating the majority of cases. Although the advantage of systemic medical therapy over surgical treatment is the avoidance of surgical trauma to the tube, the homolateral tubal patency rate after systemic MTX was lower than that with laparoscopic salpingotomy. This could not be attributed to a higher number of treatment failures necessitating salpingectomy, nor to selective dropouts before HSG. Five published randomized clinical trials have compared conservative laparoscopic surgery with medical treatment. Laparoscopic salpingotomy has been compared with MTX injected laparoscopically 14–16, with MTX injected transvaginally 17, and with hyperosmolar glucose injected laparoscopically 18. However, the comparison of a complete nonsurgical and noninvasive treatment modality by the systemic administration of MTX with laparoscopic salpingotomy was found only in one randomized clinical trial 19.
In a study of 100 patients conducted by Shalev et al. 20 to test the effectiveness of laparoscopic intratubal MTX injection or salpingotomy in the treatment of ectopic pregnancy, salpingotomy was found to be successful in 51 of 55 (92.7%) patients, whereas intratubal MTX injection was successful in only 27 of 44 (61.4%) women. MTX injection was particularly unsuccessful if the initial β-HCG was less than 2000 mIU/ml or the size of the tubal mass was smaller than 2.0 cm, as measured during laparoscopy.
Fernandez et al. 21, in a study on MTX (group 1), or laparoscopic salpingotomy (group 2), reported successful treatment in 88.2% of patients in group 1 and 95.9% in group 2.
In similar comparative studies, MTX had also a lower success rate compared with laparoscopic salpingotomy, even though the criterion for conservative management had been strictly followed 15,22.
Selection criteria for MTX treatment varied in these studies. Although all studies limited recruitment to hemodynamically stable patients with unruptured ectopic pregnancy, in some series large ectopic pregnancies (>3.5 cm), fetal cardiac activity, and serum β-HCG concentrations above 10 000 IU/l were classified as contraindications to systemic MTX treatment. In the present study there were no limitations to the size of the ectopic mass or the initial serum HCG concentration. We did exclude patients with fetal cardiac activity, as we expected this feature to have an adverse effect on clinical outcome.
Despite the long-term persistence of the ectopic mass in the systemic MTX group, serum β-HCG clearance time did not differ between the two treatment groups.
An advantage of linear salpingotomy was the predictable and consistent decline of circulating β-HCG, and consequently a reduced need for reintervention. This was concluded by Porpora et al. 22 in a study performed to compare local injection of MTX and linear salpingostomy in the conservative treatment of ectopic pregnancy.
Concerns about potential toxicity due to treatment may also hamper the replacement of a surgical approach to ectopic pregnancy by a medical one. To investigate whether these concerns are shared by patients with ectopic pregnancy, assessment of their health-related quality of life during different treatment modalities is necessary 23. In conclusion, the results of the present study prove that, in hemodynamically stable patients with undisturbed tubal pregnancy, systemic MTX and laparoscopic salpingotomy were successful in treating the majority of cases.
When fertility is of concern, laparoscopic salpingotomy is superior to MTX in the preservation of future fertility because laparoscopy performed for treatment of ectopic pregnancy enables better evaluation and correction of pelvic anatomy, as well as avoidance of possible distortion of pelvic anatomy, as it sometimes complicates MTX treatment (pelvic adhesions due to pelvic hematoma). In addition, in patients with previous pelvic surgery, previous attack of pelvic inflammatory disease, suspected endometriosis, and previous history of infertility, resorting to laparoscopy for treatment of ectopic pregnancy is preferable as it enables proper evaluation and correction of disturbed pelvic anatomy in addition to its benefit of ectopic treatment.
Whenever future fertility is not the main concern, MTX is a good alternative to laparoscopy with the advantages of being noninvasive, free of surgical and anesthetic risks, cheap, and easy.
Conflicts of interest
There are no conflicts of interest.
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