A randomised trial comparing single dose systemic methotrexate and laparoscopic surgery for the treatment of unruptured tubal pregnancy

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Abstract

Objective To compare single dose systemic methotrexate (50 mg/m2) with laparoscopic surgery for the treatment of unruptured tubal pregnancy.

Design An open, pragmatic, prospective randomised trial.

Setting Departments of obstetrics and gynaecology at three hospitals in Auckland, New Zealand.

Participants Clinically stable women with an unruptured tubal pregnancy diagnosed by transvaginal ultrasound and quantitative serum β-hCG measurement. Inclusion criteria included a serum β-hCG concentration < 5000 IU/L, and a tubal pregnancy of < 3.5 cm diameter.

Main outcome measures Treatment success, physical and psychological functioning, side effects, and subsequent ipsilateral tubal patency.

Results Two hundred and eighteen women with ectopic pregnancies were seen at the three hospitals. 79 women (36% eligibility rate) were eligible for trial entry and 62 women (78% recruitment rate) were recruited. Twenty-six of the 28 women (93%) randomised to laparoscopic surgery required no further treatment, compared with 22 of the 34 women (65%) randomised to methotrexate (95% CI of difference in success rate 10 - 47%; P<0.01). Two women (7%) in the laparoscopic surgery group had persistent trophoblast. Nine women (26%) in the methotrexate group required more than one dose of methotrexate and five women (15%) underwent laparoscopy during follow up. In the laparoscopy group three women (11%) had negative laparoscopies and two women (7%) had were found to have a ruptured fallopian tube at the time of surgery. Women treated with methotrexate had significantly better objective physical functioning scores but there were no differences in any other psychological outcomes. Women treated with methotrexate experienced greater and more prolonged vaginal bleeding. The likelihood of methotrexate treatment failure was greater at higher serum β-hCG concentrations. Ipsilateral tubal patency rates were similar in each group.

Conclusion This trial shows that in the treatment of tubal pregnancy single dose systemic methotrexate is a less effective treatment than laparoscopic salpingotomy. It is well tolerated, but should only be offered as an alternative to surgery to women who have mild symptoms and present at low serum β-hCG concentrations. In our population this likely to be no more than a quarter of women presenting with a tubal pregnancy.

Introduction

The concept of combining transvaginal ultrasound and quantitative serum β-hCG measurement within a diagnostic algorithm has resulted in a profound change occurring in both the diagnosis and management of ectopic pregnancy. In many women a confident diagnosis of ectopic pregnancy can now be made without resort to laparoscopy1. This diagnosis is increasingly being made before tubal rupture has occurred2., 3., and with earlier diagnosis it has become apparent that many tubal pregnancies follow a relatively indolent course with a low chance of sudden haemorrhage4., 5.. This has resulted in increasing interest in the use of medical therapy for the treatment of ectopic pregnancy.

Many agents have been tried, but the great majority of women receiving medical therapy for ectopic pregnancy have been treated with methotrexate6. This has been administered either locally, using transvaginal ultrasound7 or laparoscopy8, or systemically as a multiple9, or more recently a single dose regimen10. Local administration is necessarily invasive and multiple doses of systemic methotrexate have been associated with a high incidence of side effects, making these approaches relatively unattractive. If effective and well tolerated, the most appropriate treatment for suitable women could be a single intra-muscular dose of methotrexate given without prior diagnostic laparoscopy. Such a treatment regimen would permit the management of ectopic pregnancy entirely within an outpatient setting. Potentially, this would considerably reduce treatment costs and cause less disruption to the lives of women undergoing treatment. However, despite high success rates reported in some uncontrolled studies10., 11., 12., 13. relatively few centres currently use methotrexate with any frequency14. Some authors have suggested that single dose systemic methotrexate may have a relatively limited role6., 15.. From our own clinical experience prior to initiating this study we were uncertain whether methotrexate was as effective as laparoscopic salpingotomy, our most frequently used treatment for ectopic pregnancy. The aim of this study was to test the hypothesis that systemic methotrexate, as a single dose regimen is less effective than operative laparoscopy for the treatment of unruptured tubal pregnancy. We employed widely used eligibility criteria16 and women treated with methotrexate did not undergo prior diagnostic laparoscopy.

In order to assess whether the less invasive nature of methotrexate therapy might make it an acceptable treatment even if less effective than laparoscopy health-related quality of life and psychological outcomes as well as treatment side effects have been evaluated. A cost effectiveness study undertaken alongside this trial has been reported separately17.

Section snippets

Methods

Women were recruited from 28 July 1997 to 27 September 1998 at three Hospitals in Auckland, New Zealand (National Women's Hospital, North Shore hospital, and Middlemore Hospital). The ethics committee of North Health approved the trial protocol. A non-laparoscopic diagnostic algorithm utilising quantitative serum β-hCG measurement and trans vaginal ultrasound was used to diagnose the presence of an ectopic pregnancy1., 18.. Women were eligible for entry into the trial if they had a serum β-hCG

Results

During the recruitment period 218 women with an ectopic pregnancy were seen at the three hospitals. 79 women (36% eligibility rate) were eligible for trial entry. Sixty-two women (78% recruitment rate; 28% of total population) consented to randomisation. Trial recruitment was stopped after 62 women had been recruited because fewer women than anticipated were eligible for trial entry, and there was uncertainty about continued funding. The baseline characteristics of the two treatment groups and

Discussion

In this trial we hoped to determine whether the promising results reported in uncontrolled studies for single dose systemic methotrexate would be apparent under the more rigorous conditions of a randomised trial. Inclusion criteria were based on those of previously published uncontrolled trials24and ACOG guidelines16. We found that treatment with a single dose of intramuscular methotrexate had a 65% success rate, with 26% of women requiring further injections of methotrexate and 15% undergoing

Conclusion

This randomised trial shows that a single dose of systemic methotrexate is only likely to be an effective alternative to operative laparoscopy in women presenting at relatively low serum β-hCG concentrations. We would expect no more than a quarter of our patient population to be suitable for methotrexate therapy and difficulties in using a non-laparoscopic approach to diagnosis and patient assessment may limit its use further. At serum β-hCG concentrations over 1500 IU/L women are likely to

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