Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

Journal Pre-proof Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies Mathew Leonardi, Eleanor Allison, Chuan Lu, Batool Nadim, George Condous

PII:

S0301-2115(20)30097-X

DOI:

https://doi.org/10.1016/j.ejogrb.2020.02.029

Reference:

EURO 11208

To appear in: Biology

European Journal of Obstetrics & Gynecology and Reproductive

Received Date:

9 December 2019

Revised Date:

12 February 2020

Accepted Date:

17 February 2020

Please cite this article as: Leonardi M, Allison E, Lu C, Nadim B, Condous G, Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies, European Journal of Obstetrics and amp; Gynecology and Reproductive Biology (2020), doi: https://doi.org/10.1016/j.ejogrb.2020.02.029

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.

Leonardi et al. 2020

Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

Mathew Leonardi MDa, Eleanor Allison MDa, Chuan Lu PhDb, Batool Nadim

a.

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MBChBa, George Condous MBBS, MDa

Acute Gynaecology, Early Pregnancy and Advanced Endoscopy Surgery Unit, Nepean

*Corresponding

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Department of Computer Sciences, Aberystwyth University, Wales, United Kingdom

Author:

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b.

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Hospital, Sydney Medical School Nepean, University of Sydney, Sydney, Australia

Dr Mathew Leonardi

Acute Gynaecology, Early Pregnancy & Advanced Endoscopic Surgery Unit

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Sydney Medical School Nepean, University of Sydney 62 Derby Street, Kingswood, NSW 2747

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[email protected]

DECLARATIONS OF INTEREST

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None

WORD COUNT: 2483

Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

ABSTRACT Objective: To evaluate if a decreasing human chorionic gonadotropin (hCG) between day (D) 1 and D7 is an equal or better predictor of tubal ectopic pregnancy (EP) resolution following methotrexate (MTX) treatment than the current standard of care.

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Study Design: This was a retrospective cohort prognostic accuracy study of women with a transvaginal ultrasound (TVS)-confirmed tubal EP (November 2006-

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December 2015). After single-dose MTX treatment, D4/7 hCG ratios were

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compared with that of D1/D7 in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) to predict EP resolution.

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Results: Tubal EP was diagnosed in 301/7350 (4.1%) women who underwent TVS

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for early pregnancy-related complaints. The patients were managed accordingly: expectant, 84/301 (27.9%); MTX, 65/301 (21.6%); surgery, 152/301 (50.5%). A D1/D7 hCG ratio ≤0.85 predicted successful resolution of tubal EPs (P<0.001)

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treated with MTX with sensitivity 0.84 [95% confidence interval (CI), 0.69–0.94]), specificity 0.71 [95%CI, 0.48-0.89], PPV 0.84 [95%CI, 0.69-0.94], NPV 0.84 [95%CI, 0.69-0.94], which is comparable to the prognostic performance of the D4/7

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protocol.

Conclusion: In patients with tubal EP carefully selected for and treated with MTX, it may be reasonable to eliminate the D4 hCG in the follow-up algorithm.

Keywords:

Ectopic

pregnancy;

Tubal

pregnancy;

Pregnancy

outcome;

Methotrexate; Prognostic accuracy; Resource allocation

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

1 | INTRODUCTION Medical management of patients with tubal ectopic pregnancy (EP) using intramuscular methotrexate (MTX) is widely adopted owing to safety, effectiveness, and a decreased necessity to undergo surgery. Following MTX treatment, serum human Chorionic Gonadotropin (hCG) levels at specific time points can be used to

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monitor resolution and decide on supplementary therapy. Various protocols have been validated, allowing a standardized post-treatment approach [1]. Many

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institutions have implemented the single-dose MTX protocol, whereby patients are

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treated on day (D) 1 with MTX and initially monitored with hCG on D4 and D7. A 15% decrease in hCG between D4 and D7 after treatment has been validated as a

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good indicator of the likely success of EP resolution without further intervention [2].

With advancements in ultrasound technology and knowledge, we are witnessing increasingly early detection of EP in asymptomatic women [3], evoking questions

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about the applicability of these readily acceptable protocols. Management appears to be transitioning to focusing on reducing morbidity and improving resource allocation [4] thus providing impetus for robust evidence that reduces interventional

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approaches without compromising safety. Increasing the utilization of expectant management is one strategy to achieve this as many EPs may spontaneously resolve without intervention [5–7]. Another proposed method is to reconsider the post-MTX treatment monitoring protocol; it has been found that the interval hCG change from D1 to D7 may be sufficient to advise clinicians on the necessity for additional therapy, questioning the need for hCG testing on D4 [8].

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

The primary aim is to determine if the D1/D7 hCG ratio has the same prognostic performance as the D4/D7 ratio in a population of clinically stable women with tubal EP that routinely undergo a period of expectant management for 48 hours before a

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decision on intervention is made.

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

2 | MATERIALS AND METHODS This is a retrospective prognostic accuracy study. Participants include consecutive women presenting to the Early Pregnancy Assessment Unit at Nepean Hospital, Sydney between November 2006 and December 2015 (human research ethics committee approval: LNR NEAF AU/6/09F529). This group of women were also

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analyzed to assess the relationship between sonographic and biochemical markers of EP and success of subsequent management, the results of which are published

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elsewhere [9].

Women were self-referred or referred by their general practitioner or emergency

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department physician. Comprehensive clinical history, physical examination,

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quantitative serum hCG and transvaginal ultrasound (TVS) were performed by clinical fellows, supervised by the lead consultant. Ectopic pregnancies were diagnosed on TVS when one of the following was noted: (i) an inhomogeneous

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mass or “blob” sign adjacent to the ovary and moving separately to ovary; or (ii) a mass with a hyperechoic ring around the gestational sac or “bagel” sign; or (iii) an extrauterine gestational sac with yolk sac and/or embryo with or without cardiac

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activity [10–12].

Surgical

management

was

indicated

in

patients

with

EP

who

were

hemodynamically unstable, had symptoms that interfered with activities of daily living, and/or had demonstrated embryonic cardiac activity or signs of tubal rupture on TVS. The absolute hCG level did not act as an absolute indication or

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

contraindication. In those without surgical indication, a period of 48 hours of expectant management was implemented, after which a repeat hCG was drawn (as close to the 48-hour interval as possible). The repeat hCG, together with symptoms, determined eligibility for ongoing expectant management. In those who remained hemodynamically stable, with no surgical indications, the change in hCG

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dictated the care pathway (expectant or medical management). The absolute value of the hCG was not used to direct care. Specifically, criteria for MTX treatment

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included an increasing hCG 48 hours after diagnosis. Expectant management was

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instituted when a decreasing hCG 48 hours after diagnosis was noted.

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If MTX was indicated and there were no contraindications, MTX was administrated

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on what was defined as D1. Women returned on D4 and D7 for repeat quantitative hCG. If at any time, women exhibited a change in their clinical state, they were advised to seek medical attention. Any of the above indications for surgery were

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utilized to direct patient care.

The hCG ratio was used to determine the need for a second MTX dose. If the

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D4/D7 ratio was ≤0.85, the patient was followed weekly until hCG levels fell to <5 IU/L, whereas if the ratio was >0.85, a second dose was given and the day of administration would be redefined as D1. The hCG monitoring protocol would then be reinitiated. Successful treatment was defined as resolution of the EP without need for further intervention (additional MTX dose or surgery).

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

Descriptive statistics for continuous variables were obtained using two sample ttests or non-parametric Wilcoxon rank sum tests whenever appropriate. In order to determine if the D1/D7 hCG ratio has the same prognostic performance as the D4/D7 ratio in a population of clinically stable women with tubal EP, Day 4/7 hCG ratios were compared with that of D1/D7 in terms of sensitivity, specificity, positive

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predictive value (PPV) and negative predictive value (NPV). Those who did not undergo D4 or D7 hCG bloodwork due to surgical intervention before D7 were not

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included in this analysis. For example, a test is felt to be a sensitive test when it

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correctly identifies those who have achieved success with one dose of methotrexate. A highly specific test in this case indicates those who not have

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achieved successful resolution with one dose and require a subsequent dose.

Receiver operating characteristic (ROC) analysis used to determine threshold levels that would best predict cut-off points of falling in hCG levels. The 95%

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confidence interval (CI) was calculated for diagnostic performance and AUC values. P-values ≤ 0.05 represented statistical significance. Statistical analysis was

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performed with R version 3.4.0.

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

3 | RESULTS A total of 7350 consecutive women underwent TVS with 301 (4.1%) tubal EPs diagnosed during the study period. Of these, 84/301 (27.9%) were initially managed expectantly and 65/301 (21.6%) initially managed medically with MTX. All other tubal EPs were immediately selected for surgical management (152/301,

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(50.5%)). In the expectant management group, five ultimately received MTX, 12 required surgical intervention, and two were lost to follow-up. Of the 65 women

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initially managed medically with MTX, 13 required surgical intervention after the

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initial MTX dose and 13 required a second dose of MTX on D7, two of whom went on to require surgical intervention (Figure 1). Table 1 details the initial management

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versus initial outcome for those treated with MTX and expectant management.

Of the 65 women initially managed medically with MTX, 2 and 6 did not undergo hCG testing on D4 and D7, respectively, due to emergency surgical intervention.

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Only hCG-related variables were found to be significant predictors for successful resolution of an EP with a single dose of MTX (Table 2). Other variables such as age of woman, gestational age and previous obstetric history had no predictive

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value. When comparing hCG values on the day of diagnosis or D1, there was no statistically significant difference in absolute value medians between MTX success and failure (Table 2). Table 3 outlines the statistically significant differences between MTX success and failure identified when comparing hCG percentage changes for the D1/D4, D4/D7 and D1/7 protocols. Note that median hCG levels increase between diagnosis and D1 and between D1 and D4.

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

The current management protocol cut-off of a 15% fall in hCG between D4 and D7 continued to be predictor of likely resolution without further intervention (P<0.001), as seen in Table 4. The rate of hCG decline between D1 and D7 was also a predictor of success or failure after initial MTX management (P<0.001). A fall of

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15% in hCG between D1 and D7 had sensitivity 0.84 [95%CI, 0.69–0.94]), specificity 0.71 [95%CI, 0.48-0.89], PPV 0.84 [95%CI, 0.69-0.94], NPV 0.84

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[95%CI, 0.69-0.94], which is comparable to the prognostic performance of the 15%

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fall in hCG between D4 and D7 (Table 4). Figure 2 depicts a ROC curve with hCG D4/D7 and hCG D1/D7 achieving an AUC of 0.887 [95%CI, 0.803-0.970] and

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0.846 [95%CI, 0.746-0.946] (P=0.395 using DeLong's test for two correlated ROC

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curves), respectively.

In a hypothetical scenario where we apply the D1/D7 ratio to this retrospective

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sample, we find 12/65 (18.5%) women who were initially managed medically with MTX would have experienced a different management strategy on D7 when compared to the guidance provided by the D4/D7 algorithm. Using the D1/D7 ratio,

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six women would have been administered a second dose of MTX while the other six would not have been, when compared to the standard management using the D4/D7 ratio.

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

4 | DISCUSSION Our findings suggest that there may be a safe and effective alternative protocol to the current standard of care (15% fall in hCG between D4 and D7) for managing hemodynamically stable women with EP. Specifically, this novel model implements a 48-hour period of expectant management from the day of diagnosis to ensure

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that women who have naturally-resolving EPs are not inappropriately treated. Should MTX administration be indicated, it may be possible to abandon the D4

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hCG and D4/D7 hCG ratio, instead using the D1/D7 hCG ratio as a guide to predict

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the need for additional doses of MTX. In this study, we demonstrate that a 15% fall in hCG between D1 and D7 has equivalent prognostic performance in predicting

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successful resolution of tubal EP as the standard of care 15% fall from D4 to D7.

The patients in our study treated with a single dose of MTX achieved successful resolution at a rate of 60% which is very close to the published findings of a large

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comparative study of 400 cases where single MTX dose was effective for 63.5% of the women [16]. After a second dose of MTX (still following the single-dose protocol), success rates reach 76.9%, also aligned with published data (52.0-

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96.7%) [2,13,14]. The significant range in success rate stems from widelyheterogeneous studies, particularly with respect to groups of participants, upper thresholds of pre-treatment hCG, and availability of active expectant management [15].

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

With respect to the proposed alternative hCG monitoring schemes, Atkinson et al. concluded that a ≥25% hCG fall between D1 and D7 is a useful but uncertain predictor of successful resolution of a tubal EP treated with MTX [8]. Another study by Shaamash et al. proposed a more conservative D1 to D7 hCG percentage drop of 33% to represent successful resolution, which yields a specificity and PPV of

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73% and 85%, respectively [17]. Thurman et al. postulate a 50% drop in hCG between D1 and D7 could form the basis for an alternative MTX monitoring

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regimen [18]. In the event of a drop less than 50%, they recommend a second

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dose of MTX be administered. However, this would result in many more patients being treated, potentially unnecessarily; for every one D4 hCG avoided, an

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additional two women would be given a second dose of MTX. Given that the focus

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of management of EP is shifting from preventing mortality to improving morbidity, maintaining fertility, and optimizing resource allocation, it is the opinion of these authors that this 50% cut off produces an unacceptably high rate of unrequired

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MTX exposure and the potential side effects this entails. When compared to other studies, the results from this study (which demonstrate the lowest D1 to D7 fall in serum hCG levels) indicate that the application of this new D1 to D7 rule will result

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in the lowest rate of second dose MTX administration.

Research has tended to focus on hCG level at diagnosis to select appropriate women for MTX treatment. In contrast to other published studies [19,20], hCG at diagnosis or day of administration was not predictive of success with single dose MTX. Interestingly, both success and failure groups had a median hCG much lower

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

than the upper threshold of 2,234 - 6,000 IU/mL previously reported as predictive of successful outcome [19,20], though closer to the recently reported initial hCG level <1,000 IU/mL [16] - <1,600 IU/L [21]. This may reflect a tendency of the study site to offer surgery with higher hCG levels or perhaps an improvement in early diagnosis of EP. Moreover, our protocol of not implementing an intervention in

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clinically stable women until 48 hours after diagnosis, based on the 48/0-hour hCG ratio, results in a filtering out of a proportion of women that would have likely

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received MTX, though did not necessarily require it, in other studies.

Expectant management minimizes the over-estimation of MTX’s effectiveness.

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Spontaneous resolution of EP with expectant management is between 88-96% if

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initial hCG is equal or less than 200 IU/L, 76% when hCG is below 1500 IU/L, and 21-25% when hCG levels >1,500 IU/L [5,22]. Our success rate of expectant management of 76.2% is comparable to published rates with similar selection

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criteria [23,24] and much higher than those in the retrospective cohort study of Mavrelos et al. [6]. Despite initial fears that expectant management would increase health-related anxiety in women, van Mello et al. showed an equivalent health-

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related quality of life when compared with those receiving treatment with MTX [25]. With appropriate patient selection, and after thorough review of clinical details, expectant management can be considered as it has been shown to be safe, welltolerated and acceptable. Where other studies investigating abolishing the D4 hCG have excluded data from women that may have undergone spontaneous resolution

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

[8], we have demonstrated that outcomes are favorable in combining the expectant management and D1/D7 testing approach.

This study is limited by its retrospective, hypothesis-generating design and may be subject to bias innate to this form of investigation. As a retrospective study, sample

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size was not calculated to ensure a particular level of power. Therefore, a prospective cohort study or randomized controlled trial that is appropriately

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powered would inform clinicians of differences in outcomes when comparing the

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current single-dose MTX standard of care model (D1/D4/D7) and the novel model proposed here (D1/D7). Though the prognostic accuracy of the D1/D7 ratio is

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comparable to the D4/D7 ratio, a number of patients would have undergone a

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different clinical course on D7 if the D1/D7 ratio was utilized. In this hypothetical scenario, it is not possible to know if their eventual outcomes would differ from what actually happened. Considering we are still questioning the appropriate

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number of MTX doses, especially in patients with higher hCG levels [26], and the “standard” success rate of single-dose MTX hovers around 60%, this finding should not hinder future prospective studies. Moreover, until there is greater

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acceptance of expectant management of women with tubal EP, the model proposed here may not be readily accepted. However, this study serves to further this particular agenda, encouraging the use of expectant management. Even in the event that MTX is administered on the day of diagnosis, these results validate the aforementioned studies, which suggest eliminating the D4 hCG.

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

Taken together, these findings suggest that in an appropriately-selected group of women with tubal EP and demonstrated clinical stability, utilizing hCG changes from D1 to D7 and eliminating the D4 hCG has the same ability to predict when a second dose of MTX will be required.

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STATEMENTS

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AUTHOR CONTRIBUTIONS

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ML, EA, CL, BN, and GC all contributed to study conception and design; data

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acquisition, analysis, and interpretation; and writing and revising the manuscript.

None

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FUNDING

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ACKNOWLEDGEMENTS

No financial assistance was received in the completion of this research.

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DECLARATIONS OF INTEREST None

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

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Kirk E, Condous G, Van Calster B, Haider Z, Van Huffel S, Timmerman D, et al. A validation of the most commonly used protocol to predict the success of single-dose methotrexate in the treatment of ectopic pregnancy. Hum Reprod 2007;22:858–63. doi:10.1093/humrep/del433.

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Marion LL, Meeks GR. Ectopic Pregnancy: History, Incidence, Epidemiology, and Risk Factors. Clin Obstet Gynecol 2012;55:376–86. doi:10.1097/GRF.0b013e3182516d7b.

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Nadim B, Leonardi M, Infante F, Lattouf I, Reid S, Condous G. Rationalizing the management of pregnancies of unknown location: diagnostic accuracy of human chorionic gonadotropin ratio‐based decision tree compared to the risk prediction model M4. Acta Obstet Gynecol Scand 2019:aogs.13752. doi:10.1111/aogs.13752.

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Elson J, Tailor A, Banerjee S, Salim R, Hillaby K, Jurkovic D. Expectant management of tubal ectopic pregnancy: prediction of successful outcome using decision tree analysis. Ultrasound Obstet Gynecol 2004;23:552–6. doi:10.1002/uog.1061.

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Mavrelos D, Memtsa M, Helmy S, Derdelis G, Jauniaux E, Jurkovic D. β-hCG resolution times during expectant management of tubal ectopic pregnancies. BMC Womens Health 2015;15:43. doi:10.1186/s12905-015-0200-7.

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Kirk E, Van Calster B, Condous G, Papageorghiou AT, Gevaert O, Van Huffel S, et al. Ectopic pregnancy: Using the hCG ratio to select women for expectant or medical management. Acta Obstet Gynecol Scand 2011;90:264–272. doi:10.1111/j.1600-0412.2010.01053.x.

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Atkinson M, Gupta S, Mcgee T. βhCG monitoring after single-dose methotrexate treatment of tubal ectopic pregnancy: is the Day 4 βhCG necessary? A retrospective cohort study. Aust New Zeal J Obstet Gynaecol 2014;54:475–9. doi:10.1111/ajo.12257.

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Nadim B, Lu C, Infante F, Reid S, Condous G. Relationship between ultrasonographic and biochemical markers of tubal ectopic pregnancyand success of subsequent management. J Ultrasound Med 2018;37:2899–907. doi:10.1002/jum.14652.

[10] Condous G, Okaro E, Khalid A, Lu C, Van Huffel S, Timmerman D, et al. The accuracy of transvaginal ultrasonography for the diagnosis of ectopic pregnancy prior to surgery. Hum Reprod 2005;20:1404–9.

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doi:10.1093/humrep/deh770. [11] Casikar I, Reid S, Condous G. Ectopic pregnancy: Ultrasound diagnosis in modern management. Clin Obstet Gynecol 2012;55:402–9. doi:10.1097/GRF.0b013e31825109bd. [12] Nadim B, Infante F, Lu C, Sathasivam N, Condous G. Morphological ultrasound types known as ‘blob’ and ‘bagel’ signs should be reclassified from suggesting probable to indicating definite tubal ectopic pregnancy. Ultrasound Obstet Gynecol 2018;51:543–9. doi:10.1002/uog.17435.

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[13] Capmas P, Bouyer J, Fernandez H. Treatment of ectopic pregnancies in 2014: New answers to some old questions. Fertil Steril 2014;101:615–20. doi:10.1016/j.fertnstert.2014.01.029.

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[14] Lipscomb GH, McCord ML, Stovall TG, Huff G, Portera SG, Ling FW. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 1999;341:1974–8. doi:10.1056/NEJM199912233412604.

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[15] Cohen A, Zakar L, Gil Y, Amer-Alshiek J, Bibi G, Almog B, et al. Methotrexate success rates in progressing ectopic pregnancies: a reappraisal. Am J Obstet Gynecol 2014;211:128.e1-128.e5. doi:10.1016/j.ajog.2014.03.043.

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[16] Bonin L, Pedreiro C, Moret S, Chene G, Gaucherand P, Lamblin G. Predictive factors for the methotrexate treatment outcome in ectopic pregnancy: A comparative study of 400 cases. Eur J Obstet Gynecol Reprod Biol 2017;208:23–30. doi:10.1016/j.ejogrb.2016.11.016.

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[17] Shaamash AH, Alshahrani MS, Awadalla NJ, Hakami HW. Falling in serum β human chorionic gonadotropin levels between days 1 and 7 as a new protocol to predict successful single-dose of methotrexate therapy for ectopic pregnancy. Middle East Fertil Soc J 2015;20:159–64. doi:10.1016/j.mefs.2014.11.001.

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[18] Thurman AR, Cornelius M, Korte JE, Fylstra DL. An alternative monitoring protocol for single-dose methotrexate therapy in ectopic pregnancy. Am J Obstet Gynecol 2010;202:139.e1-139.e6. doi:10.1016/j.ajog.2009.09.031. [19] Cho GJ, Lee SH, Shin JW, Lee NW, Kim T, Kim HJ, et al. Predictors of success of repeated injections of single-dose methotrexate regimen for tubal ectopic pregnancy. J Korean Med Sci 2006;21:86–9. doi:10.3346/jkms.2006.21.1.86. [20] Cohen A, Bibi G, Almog B, Tsafrir Z. Second-dose methotrexate in ectopic pregnancies: The role of beta human chorionic gonadotropin. Fertil Steril 2014;102:1646–9. doi:10.1016/j.fertnstert.2014.08.019.

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[21] Levin G, Saleh NA, Haj-Yahya R, Matan LS, Avi B. Predicting success of methotrexate treatment by pretreatment HCG level and 24-hour HCG increment. Int J Gynecol Obstet 2018;141:70–3. doi:10.1002/ijgo.12395. [22] Korhonen J, Stenman UH, Ylöstalo P, Ylostalo P. Serum human chorionic gonadotropin dynamics during spontaneous resolution of ectopic pregnancy. Fertil Steril 1994;61:632–6. doi:10.1016/S0015-0282(16)56638-2.

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[23] Mavrelos D, Nicks H, Jamil A, Hoo W, Jauniaux E, Jurkovic D. Efficacy and safety of a clinical protocol for expectant management of selected women diagnosed with a tubal ectopic pregnancy. Ultrasound Obstet Gynecol 2013;42:102–7. doi:10.1002/uog.12401.

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[24] Van Mello NM, Mol F, Verhoeve HR, Van Wely M, Adriaanse AH, Boss EA, et al. Methotrexate or expectant management in women with an ectopic pregnancy or pregnancy of unknown location and low serum hCG concentrations? A randomized comparison. Hum Reprod 2013;28:60–7. doi:10.1093/humrep/des373.

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[25] Van Mello NM, Mol F, Hajenius PJ, Ankum WM, Mol BW, Van Der Veen F, et al. Randomized comparison of health-related quality of life in women with ectopic pregnancy or pregnancy of unknown location treated with systemic methotrexate or expectant management. Eur J Obstet Gynecol Reprod Biol 2015;192:1–5. doi:10.1016/j.ejogrb.2015.06.007.

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[26] Alur-Gupta S, Cooney LG, Senapati S, Sammel MD, Barnhart KT. Two-dose versus single-dose methotrexate for treatment of ectopic pregnancy: a metaanalysis. Am J Obstet Gynecol 2019;221:95-108.e2. doi:10.1016/j.ajog.2019.01.002.

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FIGURE CAPTIONS FIGURE 1 Caption: Study flow diagram. 0 hours defines the day of diagnosis, at which point surgical management was provided, if indicated. For those eligible for expectant

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management, hCG absolute value and ratio was assessed 48 hours after diagnosis, at which point expectant or MTX management was offered. If MTX was

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administered, this was defined as Day (D) 1. The D4/7 hCG ratio was used to

determine the need for a second MTX dose. If the D4/D7 ratio was >0.85, a 2nd

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dose was given and the day of administration would be redefined as D1.

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Abbreviations: MTX, methotrexate; D, day; 2nd, second.

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FIGURE 2

Caption: Receiver operator characteristic curve for prediction of successful

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resolution of tubal EP with single-dose MTX showing percentage fall in hCG between D1-D4, D4-D7, and D1-D7. Abbreviations: EP, ectopic pregnancy; MTX, methotrexate; hCG, human chorionic gonadotropin; D, day; hCG 0, hCG at diagnosis; hCG48, hCG 48 hours after

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diagnosis; hCG.Ratio, hCG at 48 hours / hCG at diagnosis; D1, hCG on day 1; D4, hCG on day 4; D7, hCG on day 7; hCG RF.D1D4, hCG on day 4 / hCG on day 1; hCG RF.D4D7, hCG on day 7 / hCG on day 4; hCG RF.D1D7, hCG on day 7 / hCG on day 1.

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

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Fig 1

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

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Fig 2

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

TABLE 1 Cross-tabulation of initial management by initial outcome.

Failure

Initial Management

n (%)

n (%)

Expectant

64 (76.2%)

20 (23.8%)

Methotrexate

39 (60.0%)

26 (40.0%)

Total

103 (69.1%)

46 (30.9%)

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Success

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Initial outcome

All (n=65)

Success

Failure

(n=39)

(n=26)

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Feature

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TABLE 2 Features of women initially managed with MTX grouped according to initial success or failurea.

P value

29.3 ± 5.37

29.3 ± 5.4

29.3 ± 5.43

0.948

38.2 ± 17.7

35.8 ± 18.5

41.9 ± 15.9

0.186

0 (0-1)

0(0-1)

0.5 (0-2)

0.530

0 (0-0)

0 (0-0)

0 (0-0)

0.249

666 (1991900)

388 (1601892)

1173 (2572244)

0.122

hCG day 1c (IU/L)

976 (2602491)

494 (2282687)

1448 (5822324)

0.180

hCG day 4d (IU/L)

1103 (2642648)

561 (1642396)

1758 (9712754)

0.030

Age, years

Parity

ur na

Calculated gestation at diagnosis (days)b

Previous EP

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hCG at diagnosis (IU/L)

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

hCG day 7e (IU/L)

679 (1441982)

329 (621085)

1570 (7672318)

0.001

Abbreviations: MTX, methotrexate; EP, ectopic pregnancy; hCG, human chorionic gonadotropin; IQR, interquartile range; IU/L, international units per liter. a

Values are given as mean ± SD or median (IQR).

b

As estimated on transvaginal ultrasound.

c

Day 1 is 48 hours after diagnosis and is day of methotrexate administration.

d

of

All (n=63); Success (n=39); Failure (n=24)

d

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All (n=59); Success (n=39); Failure (n=20)

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

TABLE 3 Percent difference in hCG levels between success or failure after initial medical management with MTXa.

Success

Failure

P value

Diagnosis: Day 1b

-0.03 (-0.23 – 0.00)

-0.14(-0.38 – 0.00)

0.180

Day 1: Day 4

0.09 (-0.17 - 0.31)

-0.16 (-0.31 - 0.04)

0.002

Day 4: Day 7

0.34 (0.23 - 0.61)

0.04 (-0.15 - 0.18)

< 0.001

Day 1: Day 7

0.45 (0.19 - 0.78)

-0.15 (-0.64 - 0.19)

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hCG levels (IU/L)

< 0.001

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Abbreviations: hCG, human chorionic gonadotropin; MTX, methotrexate; IU/L, international units per liter; IQR, interquartile range. a

Values are given as median (IQR).

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Day 1 is 48 hours after diagnosis and is day of methotrexate administration.

hCG

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TABLE 4 Prognostic performance (estimate and corresponding 95% CI) for using different declining rate of hCG variables to predict the successful resolution of tubal EP with singledose MTX.

Sensitivity

Specificity

PPV

NPV

>10% decline

0.95 [0.820.99]

0.62 [0.380.82]

0.82 [0.670.92]

0.87 [0.600.98]

>15% declinea

0.89 [0.750.97]

0.71 [0.480.89]

0.85 [0.700.94]

0.79 [0.540.94]

>20% decline

0.79 [0.630.9]

0.76 [0.530.92]

0.86 [0.700.95]

0.67 [0.450.84]

>10% decline

0.87 [0.720.96]

0.67 [0.430.85]

0.82 [0.670.93]

0.87 [0.720.96]

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Day 4: Day 7

Cut-off

hCG

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Leonardi et al. 2020 Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies

Day 1: Day 7

>15% declinea

0.84 [0.690.94]

0.71 [0.480.89]

0.84 [0.690.94]

0.84 [0.690.94]

>20% decline

0.71 [0.540.85]

0.76 [0.530.92]

0.84 [0.670.95]

0.71 [0.540.85]

Abbreviations: CI, confidence interval; EP, ectopic pregnancy; MTX, methotrexate; PPV, positive predictive value; NPV, negative predictive value; hCG, human chorionic gonadotropin. a

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Current standard of care cut offs

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