Methotrexate versus expectant management for treatment of tubal ectopic pregnancy: an individual participant data meta-analysis (IPD-MA)

Abstract Study question Is medical management with methotrexate superior over expectant management in the resolution of tubal ectopic pregnancy in clinically stable women and low serum hCG? Summary answer In women with tubal ectopic pregnancy and low serum hCG, methotrexate was not better than expectant management. There were no subgroups benefiting from methotrexate. What is known already Women with tubal pregnancy who are clinically stable and have low hCG concentrations can be treated medically with methotrexate, an anti-folate drug that has a range of adverse effects and requires women to avoid conceiving three months after administration due to teratogenic effects. Expectant management with close monitoring is as effective compared to methotrexate in this subgroup of women. There are three randomised controlled trials (RCTs) not showing a statistically significant difference in uneventful resolution of ectopic pregnancy between methotrexate and expectant management. These studies were too small to define if certain subgroups could benefit from either treatment. Study design, size, duration We performed an individual participant data meta-analysis (IPD-MA) of RCTs based on a search of international scientific databases. We selected RCTs comparing methotrexate and expectant management in women with suspected tubal ectopic pregnancy. The primary outcome was treatment success, defined as resolution of clinical symptoms and decline in level of serum hCG to < 20 IU/L or a negative urine pregnancy test by the initial intervention strategy, without any additional treatment. Participants/materials, setting, methods Analyses were performed on an intention-to-treat basis. A one-stage IPDMA was performed to assess overall treatment effects of methotrexate and expectant management to generate a pooled intervention effect. This included a random intercept (for baseline differences between studies) and random slope (for differences in treatment effect between studies). A log-binomial model for dichotomous outcomes yielded a risk ratio (RR) with 95% confidence interval (CI). Subgroup analyses were undertaken according to baseline serum β-hCG levels. Main results and the role of chance We obtained data from two relevant trials reporting on 153 women with suspected tubal ectopic pregnancy who were randomised to expectant management or methotrexate. The third RCT was excluded as their inclusion criteria required declining titres of hCG 48 hours prior to treatment. The success rate was 65/82 (79.3%) after methotrexate and 48/70 (68.6%) after expectant management (IPD RR 1.16, 95%CI 0.71-2.38). 9/82 (11%) in the methotrexate group and 9/70 (12.8%) after expectant required additional methotrexate. 8/82 (9.8%) in the methotrexate group and 13/70 (18.6%) in the expectant group required surgical intervention (RR 0.65, 95%CI 0.66-3.54). The mean time to success was 21.2 days (95%CI 17.4 to 25.6) after expectant management and 19.7 days (95%CI 17.1-22.2) after methotrexate (p = 0.25). There was no interaction with treatment of maternal age, parity, previous ectopic pregnancy, and serum β-hCG on success rate. Serum hCG <1000 IU/l was associated with a higher success rate in both groups. Only one woman in the expectant group required a blood transfusion. Methotrexate users had side effects (N = 7/49) including vomiting, diarrhoea, mucositis, conjunctivitis and photosensitivity that were not seen in the expectant group (N = 0/49). Limitations, reasons for caution One of the trials had a higher proportion of pregnancy of unknown location (PUL) which were presumed to be tubal ectopic pregnancies due to plateauing serum hCG levels and caution is therefore advised on the application of these findings to ectopic pregnancies visualised on ultrasound. Wider implications of the findings Initial expectant management might be the preferred strategy for women with suspected tubal ectopic pregnancy in clinically stable women with lower hCG levels in view of less adverse effects, less cost and enabling women who wish to conceive soon after resolution of ectopic pregnancy to do so. Trial registration number Prospero ID: CRD42021214093