In this 36-month retrospective study, systemic MTX was administered to women diagnosed with tubal EP, CSP and PPUL in early pregnancy. Though the majority of women were successfully treated, we identified that the use of systemic MTX differs among clinicians based on the results of sonography, blood tests and period of surveillance.

We report a success rate of 88% in women with tubal EP treated with systemic MTX (single dose and repeated doses) in keeping with success rates in other studies, which range from 65 to 95% [15,16,17]. The inclusion and exclusion criteria for systemic MTX in treating tubal EP varied in our study in keeping with the literature [18,19,20]. Most authors agree on the use of MTX preferentially in cases of hemodynamic stability and absence of foetal cardiac activity [6, 12, 18,19,20]. The presence of foetal cardiac activity in tubal EP is a contraindication to MTX treatment due to high rates of failure and morbidity. The woman in our study with foetal cardiac activity who opted for MTX treatment did so following extensive counselling having declined elective surgery. There are adverse effects associated with MTX such as marrow suppression, renal injury and liver injury; therefore, studies emphasise the importance of excluding renal, liver or haematologic diseases prior to MTX treatment (which is an area for improvement in our hospital) [6, 12, 18,19,20].

Pre-MTX serum β-hCG cut-off values for tubal EP differ in the literature and in our study [21,22,23]. According to Irish guidelines on tubal EP, systemic MTX should be considered when serum β-hCG levels are < 1500 IU/L [12]. Though pre-MTX serum β-hCG levels up to 5000 IU/L have been described in women with tubal EP, the risk of emergency surgery rises with increasing serum β-hCG levels [21, 22, 24]. Thresholds using the size of tubal EP also vary with no consensus on whether size is predictive of successful outcomes [23, 25]. Irish guidelines on tubal EP suggest using systemic MTX when the size is < 35 mm [12]. Only one patient in our study received treatment with tubal EP size measurements larger than recommended by national standards, but this patient was treated successfully. Outcomes following treatment for our women with tubal EP were similar to Irish standards, which report an incidence rate of 15% for repeat MTX administration and approximately 7% for emergency surgery [12].

Case reviews of women with CSP describe success rates of up to 41% with systemic MTX alone, and to improve success, treatment may be paired with evacuation or excision of the pregnancy [8]. Planned surgery has been described up to 7 days after systemic MTX in women with CSP [8]. Current national guidelines do not provide further details on the factors that influence CSP management decisions like CSP imaging features (e.g. size, viability, myometrial thickness) [12]. Newer studies on CSP management comparing combined MTX and uterine evacuation with uterine evacuation alone have shown that preoperative MTX did not reduce intraoperative estimated blood loss [26]. There was no significant difference in the presence of retained products of conception on follow-up scans treated with combined treatment and uterine evacuation alone [26]. This suggests that preoperative MTX does not provide additional benefit to women with CSP. A recent systematic review and network meta-analysis which assessed a total of 8369 women and 17 different CSP treatment modalities concluded that the use of MTX (both locally injected or systemically given) as a standalone treatment is not recommended [27]. This analysis which included 73 trials (with seven randomised controlled trials) identified that operative options such as laparoscopy, transvaginal resection, hysteroscopic curettage and high-intensity focused ultrasound combined with suction curettage were the most efficacious treatment options for CSP and exhibited the least complications [27]. Although the primary focus of this review was not on CSP, it is worth noting that due to its current relevance, our unit’s success with MTX in these cases merits further examination and suggests the need for additional review. Our CSP cases were treated successfully, but perhaps they would have benefited from operative management and avoided systemic MTX and its potential side effects.

There is no national or universal definition for PPUL and no recommendations for when to use systemic MTX in PPUL. This is reflected in our study by the differences in the number of scans performed, the number of serum β-hCG levels collected, the duration of surveillance and serum β-hCG treatment thresholds prior to treatment in women diagnosed with PPUL. PPUL diagnoses recorded in this study were according to the impression of the responsible clinician. Though our success rate with MTX therapy for women with PPUL was 93%, the use of systemic MTX for women with PPUL is controversial. There is a risk of misdiagnosing an intrauterine pregnancy as a PPUL as demonstrated in our study. MTX-induced embryopathy is a serious and avoidable complication occurring when a viable pregnancy is misdiagnosed as an EP or PPUL and is exposed to MTX [28].

Many early pregnancy specialists advocate that systemic MTX should never be given empirically in cases of PUL as it is an interim diagnosis, but in PPUL, there is no consensus on the duration of surveillance or serum β-hCG threshold before offering MTX [13]. Clinical practice guidelines in France suggest that asymptomatic women with PPUL who are observed for at least 10 days and have serum β-hCG levels > 2000 (IU/L) may be offered MTX [29]. Women in our study with a diagnosis of PPUL had a large range of serum β-hCG levels before receiving MTX. A multicentre randomised control trial in the United States studying the optimal management strategy for PPUL found that active management of PPUL (MTX therapy alone or uterine evacuation followed by MTX) was more effective in achieving pregnancy resolution than expectant management [30, 31]. Furthermore, active management of PPUL resulted in less unscheduled surgical interventions than expectant management. However, the study did identify that women had a stronger preference for expectant management of PPUL by surveillance of serum β-hCG kinetics [30]. There is a need for further studies to better distinguish PUL from PPUL and to identify predictors for treatment success in women with PPUL given significant adverse side effects of MTX.

Given the varied MTX prescribing and administration practices in our unit, care standardisation would make the results of future studies on the use of MTX in early pregnancy more robust. In response to the findings of this review, we have updated our local MTX prescribing and administration guidelines. Changes include the development of an improved electronic prescription which will minimise human error dose calculations and provide enhanced clinical decision support for prescribers. We introduced dose-banding and the use of pre-filled MTX syringes to avoid cytotoxic spillage and waste. We advocate that systemic MTX be given by two healthcare staff to ensure correct administration and handling of biochemicals, and that timing of administration should be limited to weekday daytime hours when pharmacy and a full staff complement are present. To improve patient selection for treatment, this study proposes reserving decisions for systemic MTX to clinicians specialised in early pregnancy. Early pregnancy specialists can ensure that appropriate investigations have been performed and provide continuity of care. Shared decision-making for treatment could involve pharmacists, nurse specialists, sonographers, bereavement services and the patient. A multi-disciplinary approach to EPs and PUL may improve systemic MTX success rates and patient satisfaction.

This retrospective study was conducted in a single tertiary centre and, to the best of our knowledge, is the largest study in Ireland reviewing MTX use in early pregnancy. The findings have facilitated improvements in safe MTX prescribing and administration practices for women with early pregnancy complications. We recognise that a limitation of our study is that choice for systemic MTX may have been influenced by clinical presentations not documented in the women’s records. A second limitation is that the diagnosis of PPUL in this study was based on the assessments made by the attending clinician and that the thresholds or criteria for MTX treatment for PPUL were not clearly specified. Another limitation is that two women did not complete follow-up and their outcomes are unknown.