Methotrexate Administration to Patients With Presumed Ectopic Pregnancy Leads to Methotrexate Exposure of Intrauterine Pregnancies

Fridman, Dmitry; Hawkins, E.; Dar, P.; Chudnoff, S.; Rotenberg, O.; Chong, Woojin; Xie, Xianhong; Mehta, S; Levie, M.

doi:10.1002/jum.14751

Cited by 11 publications

(8 citation statements)

References 30 publications

(70 reference statements)

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“…The clinical course of this participant emphasizes the need to ensure a gestation is nonviable before active intervention that will result in termination or possible teratogenicity. 20 The American College of Obstetricians and Gynecologists and NICE defines an increase of hCG levels of more than 49% (for initial values <1500 mIU/mL) and more than 63% over 48 hours as potentially viable, respectively. 2,3 However, a rise below these thresholds, which are based on probabilistic models using serial hCG measurements, does not define nonviability.…”

Section: Discussionmentioning

confidence: 99%

“…Despite conservative inclusion criteria to confirm a nonviable gestation, 1 participant randomized to expectant management eventually had a live birth. The clinical course of this participant emphasizes the need to ensure a gestation is nonviable before active intervention that will result in termination or possible teratogenicity . The American College of Obstetricians and Gynecologists and NICE defines an increase of hCG levels of more than 49% (for initial values <1500 mIU/mL) and more than 63% over 48 hours as potentially viable, respectively .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location

Barnhart

Hansen

Stephenson

et al. 2021

JAMA

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IMPORTANCEWomen with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities.OBJECTIVE To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed. DESIGN, SETTING, AND PARTICIPANTS This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019).INTERVENTIONS Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82). MAIN OUTCOMES AND MEASURESThe primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of −12%. RESULTS Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, −8.4% to ϱ]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%).CONCLUSIONS AND RELEVANCE Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location

Barnhart

Hansen

Stephenson

et al. 2021

JAMA

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“…The NICE recommendations study inclusion criteria may be considered questionable, as current standard of care includes use of i.m. methotrexate but not oral methotrexate (American College of Obstetrics and Gynecology (ACOG), 2018; National Institute for Health and Care Excellence (NICE), 2019 ) and not treating patients with PUL classification with methotrexate ( Fridman et al , 2019 ). Our sensitivity analysis included the van Mello (2013 , 2015 ) studies that recruited patients with PULs and this did not change the result of our primary analysis, but we did not include the study with oral methotrexate, which may explain the difference in results from the NICE recommendations.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis

Colombo

Leonardi

Armour

et al. 2020

Human Reproduction Open

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STUDY QUESTION Is expectant management (EM) of tubal ectopic pregnancy (EP) an effective and safe treatment strategy when compared to alternative interventions? SUMMARY ANSWER There is insufficient evidence to conclude EM yields a difference in the resolution of tubal EP, the avoidance of surgery or time to resolution of tubal EP when compared to intramuscular methotrexate in stable patients with β-hCG <1500 IU/l. WHAT IS ALREADY KNOWN The utilisation of medical and surgical management for EP is well established. EM aims to allow spontaneous resolution of the EP without intervention. STUDY DESIGN, SIZE, AND DURATION We performed a systematic review and meta-analysis, searching Ovid MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, OpenGrey.eu, Google Scholar, cross-referencing citations and trial registries to 15 December 2019. There were no limitations placed on language or publication date. Search terms included tubal EP and EM as well as variations of these terms. PARTICIPANTS/MATERIALS, SETTING AND METHOD We considered studies that included patients with tubal EP, EM as a comparator, and that were randomised controlled trials (RCTs). The primary outcome was resolution of tubal EP. Secondary outcomes included avoidance of surgery and the time to resolution of EP. Two reviewers independently selected the studies, assessed bias and extracted data. Relative risk (RR) and mean difference with 95% CI were assessed using a random effects model. The certainty of evidence was scored according to Grading of Recommendations Assessment, Development and Evaluation guidelines. MAIN RESULTS AND THE ROLE OF CHANCE In total, 920 studies were screened. Five studies were eligible for inclusion in the systematic review. Two RCTs comparing methotrexate to EM were identified as being eligible for inclusion in meta-analysis. No RCTs comparing surgery to EM were identified. Compared with EM, there was insufficient evidence that methotrexate yields a difference on resolution of tubal EP (RR 1.04, 95% CI 0.88–1.23, P = 0.67; two RCTs, moderate-certainty evidence), avoiding surgery (RR 1.10, 95% CI 0.94–1.29, P = 0.25; two RCTs, low-certainty evidence) or the time to resolution of tubal EP (−2.56 days (favouring EM), 95% CI −7.93–2.80, P = 0.35; two RCTs, low-certainty evidence). LIMITATIONS, REASONS FOR CAUTION Only two RCTs with a total of 103 patients were eligible for inclusion in this meta-analysis. Further RCTs comparing EM to medical and surgical management are needed and these should also report adverse events. Patient preference should also be evaluated. WIDER IMPLICATIONS OF THE FINDINGS We found insufficient evidence of differences in terms of resolution, avoidance of surgery and time to resolution between expectant and medical management. Given the imprecision in the effect estimates as demonstrated by the wide CIs, resulting in the downgrading of certainty of evidence for all outcomes in this meta-analysis, larger RCTs comparing interventions for tubal EP are needed. Caution should be exercised when trying to decide between EM and methotrexate to treat tubal EP. STUDY FUNDING/COMPETING INTEREST(S) There was no funding for this study. NICM receives funding from various sources; none specifically supported this research. M.L. reports grants from Australian Women and Children's Research Foundation, outside the submitted work. M.A.: As a medical research institute, NICM Health Research Institute receives research grants and donations from foundations, universities, government agencies and industry. Sponsors and donors provide untied and tied funding for work to advance the vision and mission of the Institute. This systematic review was not specifically supported by donor or sponsor funding to NICM. M.A. reports a partnership grant with Metagenetics outside the submitted work. G.C. reports grants from Australian Women and Children's Research Foundation, personal fees from Roche and GE Healthcare, outside the submitted work. The remaining authors report no conflicts of interest. PROSPERO REGISTRATION NUMBER CRD42020142736

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“…The variation in effectiveness is also due to differences in selection criteria, diagnosis of tubal EP and definitions of treatment success. In studies where tubal EP is not visualized on ultrasound scan, one must be cautious caution not to use MTX to treat miscarriages or normally sited live pregnancies 38,39 . There could be scope for use in ectopic pregnancies with higher hCG 27,40–42 .…”

Section: Discussionmentioning

confidence: 99%

“…In studies where tubal EP is not visualized on ultrasound scan, one must be cautious caution not to use MTX to treat miscarriages or normally sited live pregnancies. 38,39 There could be scope for use in ectopic pregnancies with higher hCG.…”

Section: Ta B L E 5 Combined Outcomesmentioning

confidence: 99%

Methotrexate vs expectant management for treatment of tubal ectopic pregnancy: An individual participant data meta‐analysis

Solangon

Wely

Mello

et al. 2023

Acta Obstet Gynecol Scand

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IntroductionEctopic pregnancy is an important health condition which affects up to 1 in 100 women. Women who present with mild symptoms and low serum human chorionic gonadotrophin (hCG) are often treated with methotrexate (MTX), but expectant management with close monitoring is a feasible alternative. Studies comparing the two treatments have not shown a statistically significant difference in uneventful resolution of ectopic pregnancy, but these studies were too small to define whether certain subgroups could benefit more from either treatment.Material and methodsWe performed a systematic review and individual participant data meta‐analysis (IPD‐MA) of randomized controlled trials comparing systemic MTX and expectant management in women with tubal ectopic pregnancy and low hCG (<2000 IU/L). A one‐stage IPD‐MA was performed to assess overall treatment effects of MTX and expectant management to generate a pooled intervention effect. Subgroup analyses and exploratory multivariable analyses were undertaken according to baseline serum hCG and progesterone levels. 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. Secondary outcomes were need for blood transfusion, surgical intervention, additional MTX side‐effects and hCG resolution times. Trial registration number: PROSPERO: CRD42021214093.Results1547 studies reviewed and 821 remained after duplicates removed. Five studies screened for eligibility and three IPD requested. Two randomized controlled trials supplied IPD, leading to 153 participants for analysis. Treatment success rate was 65/82 (79.3%) after MTX and 48/70 (68.6%) after expectant management (IPD risk ratio [RR] 1.16, 95% confidence interval [CI] 0.95–1.40). Surgical intervention rates were not significantly different: 8/82 (9.8%) vs 13/70 (18.6%) (RR 0.65, 95% CI 0.23–1.14). Mean time to success was 19.7 days (95% CI 17.4–22.3) after MTX and 21.2 days (95% CI 17.8–25.2) after expectant management (P = 0.25). MTX specific side‐effects were reported in 33 MTX compared to four in the expectant group.ConclusionsOur IPD‐MA showed no statistically significant difference in treatment efficacy between MTX and expectant management in women with tubal ectopic pregnancy with low hCG. Initial expectant management could be the preferred strategy due to fewer side‐effects.

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Methotrexate Administration to Patients With Presumed Ectopic Pregnancy Leads to Methotrexate Exposure of Intrauterine Pregnancies

Cited by 11 publications

References 30 publications

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location

Efficacy and safety of expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis

Methotrexate vs expectant management for treatment of tubal ectopic pregnancy: An individual participant data meta‐analysis

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