Subsequent pregnancy outcomes among women with tubal ectopic pregnancy treated with methotrexate

Abstract

Lay summary
An ectopic pregnancy occurs when an embryo implants outside of the uterus, usually in a fallopian tube. When detected early, treatment is often with a medication called methotrexate. When methotrexate does not work, surgery is required. A recent clinical trial of ectopic pregnancy treatment (called GEM3) found that adding a drug called gefitinib to methotrexate did not reduce the need for surgery. We have used data from the GEM3 trial, combined with data collected 12 months after the trial finished, to investigate post-methotrexate pregnancy outcomes. We found no difference in pregnancy rates, pregnancy loss rates and recurrent ectopic pregnancy rates between those treated medically only and those who subsequently also needed surgery. The surgical technique used also did not affect pregnancy rates. This research provides reassurance that women with ectopic pregnancies treated medically who need surgery have similar post-treatment pregnancy outcomes to those treated successfully medically.

Full text

S C Mackenzie etal. 4:2 e230019
RESEARCH LETTER
Subsequent pregnancy outcomes among
women with tubal ectopic pregnancy treated
with methotrexate
ScottC Mackenzie 1, CatherineA Moakes2, WColin Duncan 1, Stephen Tong3 and AndrewW Horne 1
1MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
2Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK
3Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia
Correspondence should be addressed to A W Horne: andrew.horne@ed.ac.uk
Graphical abstract
Lay summary
An ectopic pregnancy occurs when an embryo implants outside of the uterus, usually in a fallopian tube. When detected
early, treatment is often with a medication called methotrexate. When methotrexate does not work, surgery is required. A
recent clinical trial of ectopic pregnancy treatment (called GEM3) found that adding a drug called getinib to methotrexate
did not reduce the need for surgery. We have used data from the GEM3 trial, combined with data collected 12 months
after the trial nished, to investigate post-methotrexate pregnancy outcomes. We found no dierence in pregnancy
rates, pregnancy loss rates and recurrent ectopic pregnancy rates between those treated medically only and those who
subsequently also needed surgery. The surgical technique used also did not aect pregnancy rates. This research provides
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https://raf.bioscientica.com © 2023 the author(s)
Published by Bioscientica Ltd
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S C Mackenzie etal. 4:2 e230019
reassurance that women with ectopic pregnancies treated medically who need surgery have similar post-treatment
pregnancy outcomes to those treated successfully medically.
Keywords:  tubal ectopic pregnancy  methotrexate  pregnancy outcomes  recurrence  risk factor
Reproduction and Fertility (2023) 4 e230019
Research letter
Pre-treatment counselling for women with unruptured
tubal ectopic pregnancies considering their treatment
options requires the provision of information on post-
treatment pregnancy outcomes, including rates of ectopic
pregnancy recurrence. Current UK NICE early pregnancy
guidelines are based on low-quality evidence and estimate
the long-term ectopic pregnancy recurrence rate at
~18.5% (NICE 2021). Further, they relay findings showing
no dierences in rates of subsequent pregnancy or ectopic
pregnancy recurrence between management methods (de
Bennetot etal. 2012, Fernandez etal. 2013 , Park etal. 2017 ).
Approximately 30% of women with a scan-diagnosed
ectopic pregnancy actively managed with methotrexate
experience treatment failure and require rescue surgery,
and little is known about subsequent pregnancy outcomes
in this group.
We describe subsequent pregnancy outcomes
in women with tubal ectopic pregnancy managed
with methotrexate using data from a UK multicentre
randomised controlled trial comparing methotrexate and
gefitinib vs methotrexate and placebo for the treatment of
tubal ectopic pregnancy (GEM3: Horne etal. 2023). Trial
participants were women with an ultrasound diagnosed
definite (or probable) tubal ectopic pregnancy with pre-
treatment serum hCG levels of ≥1000 IU/L and ≤5000
IU/L. The trial found adding gefitinib to methotrexate was
not superior to placebo. After randomisation to treatment,
trial participants were contacted at 12 months to provide
subsequent pregnancy outcome data. Where telephone
contact was unsuccessful, electronic health records were
reviewed. Post-treatment pregnancy outcomes were
summarised with descriptive statistics and the groups
were compared using chi-squared tests.
Subsequent pregnancy outcome data were obtained
for 283/327 trial participants (167 contacted by telephone;
116 from electronic health records). Follow-up data from
both randomisation groups (methotrexate and gefitinib;
methotrexate and placebo) were combined owing to
no between-group dierences in subsequent pregnancy
outcomes (Supplementary Table 1, see section on
supplementary materials given at the end of this article).
Pregnancy occurred in 53% (149/283) of participants in
the 12-month follow-up period. There was no dierence
in subsequent pregnancy rates between ‘medical
management only’ and ‘medical management and rescue
surgery’ groups (Table 1). Surgical approach to ectopic
pregnancy treatment (salpingectomy vs salpingotomy)
did not aect subsequent pregnancy rates. Among women
who had a pregnancy within the follow-up period, a
live birth occurred in 65% (93/142), any pregnancy
Table 1 Pregnancy rates and subsequent pregnancy outcomes among women with tubal ectopic pregnancy treated medically.
Data are presented as n or as n (%).
MM + RS
MM only
P-value*
Salpingectomy Salpingotomy All
n86 11 97 228
Any pregnancy post-treatment 37 (51) 4 (50) 41 (51) 108 (53) 0.66
Missing 13 3 16 26
Any live birth post-treatment†20 (61) 3 (75) 23 (62) 70 (67) 0.62
Missing 404 3
Any pregnancy loss post-treatment†,‡ 16 (52) 1 (25) 17 (49) 38 (38) 0.26
Missing 6067
Any ectopic pregnancy post-treatment†6 (22) 0 (-) 6 (19) 16 (16) 0.66
Missing 10 0 10 8
*Medical management and rescue surgery vs medical management only; †Only in women whom have had a pregnancy post-treatment; ‡Dened as
miscarriage, ectopic pregnancy, stillbirth or molar pregnancy (excluding termination of pregnancy).
MM, medical management; RS, rescue surgery.
This work is licensed under a Creative Commons
Attribution 4.0 International License.
https://doi.org/10.1530/RAF-23-0019
https://raf.bioscientica.com © 2023 the author(s)
Published by Bioscientica Ltd
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S C Mackenzie etal. 4:2 e230019
loss occurred in 40% (55/136) and recurrent ectopic
pregnancy occurred in 17% (22/131). No dierence was
observed in the rates of live birth, pregnancy loss or
recurrent ectopic pregnancy between treatment groups or
between those who had salpingectomy vs salpingotomy.
Participant characteristics (body mass index, chlamydial
infection history and smoking status) were investigated
for association with recurrent ectopic pregnancy using
univariate and multivariate log-binomial models. No
significant associations were identified; however, this
analysis was limited by the small sample of women in
which ectopic pregnancy occurrence recurred. Similarly,
the power to detect dierences in subsequent pregnancy
outcomes between treatment groups was limited owing
to the small sample sizes in observed groups. Intention to
conceive in the follow-up period was not recorded and we
were therefore unable to stratify results accordingly.
This prospective dataset strengthens current
knowledge of the likelihood of ectopic pregnancy
recurrence. Furthermore, it provides reassurance that
women with tubal ectopic pregnancy who required
rescue surgery following medical treatment have similar
outcomes in their subsequent pregnancy as those with
successful medical treatment alone. However, this study
only reports on a 12-month follow-up period, which
should be considered when interpreting the comparatively
low post-treatment pregnancy rates (Fernandez etal. 2013 ).
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/
RAF-23-0019.
Declaration of interest
AWH is a Co-Editor-in-Chief and WCD is an Associate Editor of Reproduction
& Fertility. AWH and WCD were not involved in the review or editorial
process for this paper, on which they are listed as authors. AWH has
received honoraria for consultancy for Ferring, Roche Diagnostics, Nordic
Pharma, Gesynta and Abbvie. WCD has received honoraria from Merck
and Guerbet, and research funding from Galvani Biosciences. The other
authors declare no competing interests.
Funding
This project was supported by funding from the Ecacy and Mechanism
Evaluation programme, a Medical Research Council and National Institute
for Health Research partnership (grant reference number 14/150/03).
Trial registration number
This study is a follow-up analysis of participants from the GEM3 trial
(ISRCTN Registry ISRCTN67795930).
Author contribution statement
SCM drafted the manuscript. CAM analysed the data. All authors reviewed
and contributed to the nal manuscript.
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Received 15 March 2023
Accepted 30 May 2023
Available online 30 May 2023
Version of Record published 15 June 2023
This work is licensed under a Creative Commons
Attribution 4.0 International License.
https://doi.org/10.1530/RAF-23-0019
https://raf.bioscientica.com © 2023 the author(s)
Published by Bioscientica Ltd
Downloaded from Bioscientifica.com at 06/16/2023 07:52:30AM
via free access