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Objectives: Ectopic pregnancy (EP) is a major high‐risk outcome following a pregnancy of unknown location (PUL) classification. Biochemical markers are used to triage PUL as high vs low risk to guide appropriate follow‐up. The M6 model is currently the best risk‐prediction model. We aimed to update the M6 model and evaluate whether performance can be improved by including clinical factors. Methods: This prospective cohort study recruited consecutive PUL between January 2015 and January 2017 at eight units (Phase 1), with two centers continuing recruitment between January 2017 and March 2021 (Phase 2). Serum samples were collected routinely and sent for β‐human chorionic gonadotropin (β‐hCG) and progesterone measurement. Clinical factors recorded were maternal age, pain score, bleeding score and history of EP. Based on transvaginal ultrasonography and/or biochemical confirmation during follow‐up, PUL were classified subsequently as failed PUL (FPUL), intrauterine pregnancy (IUP) or EP (including persistent PUL (PPUL)). The M6 models with (M6P) and without (M6NP) progesterone were refitted and extended with clinical factors. Model validation was performed using internal–external cross‐validation (IECV) (Phase 1) and temporal external validation (EV) (Phase 2). Missing values were handled using multiple imputation. Results: Overall, 5473 PUL were recruited over both phases. A total of 709 PUL were excluded because maternal age was < 16 years or initial β‐hCG was ≤ 25 IU/L, leaving 4764 (87%) PUL for analysis (2894 in Phase 1 and 1870 in Phase 2). For the refitted M6P model, the area under the receiver‐operating‐characteristics curve (AUC) for EP/PPUL vs IUP/FPUL was 0.89 for IECV and 0.84–0.88 for EV, with respective sensitivities of 94% and 92–93%. For the refitted M6NP model, the AUCs were 0.85 for IECV and 0.82–0.86 for EV, with respective sensitivities of 92% and 93–94%. Calibration performance was good overall, but with heterogeneity between centers. Net Benefit confirmed clinical utility. The change in AUC when M6P was extended to include maternal age, bleeding score and history of EP was between −0.02 and 0.01, depending on center and phase. The corresponding change in AUC when M6NP was extended was between −0.01 and 0.03. At the 5% threshold to define high risk of EP/PPUL, extending M6P altered sensitivity by −0.02 to −0.01, specificity by 0.03 to 0.04 and Net Benefit by −0.005 to 0.006. Extending M6NP altered sensitivity by −0.03 to −0.01, specificity by 0.05 to 0.07 and Net Benefit by −0.005 to 0.006. Conclusions: The updated M6 model offers accurate diagnostic performance, with excellent sensitivity for EP. Adding clinical factors to the model improved performance in some centers, especially when progesterone levels were not suitable or unavailable. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: To validate externally five approaches to predict ectopic pregnancy (EP) in pregnancies of unknown location (PUL): the M6P and M6NP risk models, the two‐step triage strategy (2ST, which incorporates M6P), the M4 risk model, and beta human chorionic gonadotropin ratio cut‐offs (BhCG‐RC). Design: Secondary analysis of a prospective cohort study. Setting: Eight UK early pregnancy assessment units. Population: Women presenting with a PUL and BhCG >25 IU/l. Methods: Women were managed using the 2ST protocol: PUL were classified as low risk of EP if presenting progesterone ≤2 nmol/l; the remaining cases returned 2 days later for triage based on M6P. EP risk ≥5% was used to classify PUL as high risk. Missing values were imputed, and predictions for the five approaches were calculated post hoc. We meta‐analysed centre‐specific results. Main outcome measures: Discrimination, calibration and clinical utility (decision curve analysis) for predicting EP. Results: Of 2899 eligible women, the primary analysis excluded 297 (10%) women who were lost to follow up. The area under the ROC curve for EP was 0.89 (95% CI 0.86–0.91) for M6P, 0.88 (0.86–0.90) for 2ST, 0.86 (0.83–0.88) for M6NP and 0.82 (0.78–0.85) for M4. Sensitivities for EP were 96% (M6P), 94% (2ST), 92% (N6NP), 80% (M4) and 58% (BhCG‐RC); false‐positive rates were 35%, 33%, 39%, 24% and 13%. M6P and 2ST had the best clinical utility and good overall calibration, with modest variability between centres. Conclusions: 2ST and M6P performed best for prediction and triage in PUL. The M6 model, as part of a two‐step triage strategy, is the best approach to characterise and triage PULs. The M6 model, as part of a two‐step triage strategy, is the best approach to characterise and triage PULs. [ABSTRACT FROM AUTHOR]

An abstract of the article "A multicentre trial on the performance and complications of a two-step triage protocol based on initial serum progesterone and serial serum hCG to manage pregnancy of unknown location (PUL)," by S. Bobdiwala and colleagues is presented.

Introduction: There is no global agreement on how to best determine pregnancy of unknown location viability and location using biomarkers. Measurements of progesterone and β human chorionic gonadotropin (βhCG) are still used in clinical practice to exclude the possibility of a viable intrauterine pregnancy (VIUP). We evaluate the predictive value of progesterone, βhCG, and βhCG ratio cut-off levels to exclude a VIUP in women with a pregnancy of unknown location., Material and Methods: This was a secondary analysis of prospective multicenter study data of consecutive women with a pregnancy of unknown location between January 2015 and 2017 collected from dedicated early pregnancy assessment units of eight hospitals. Single progesterone and serial βhCG measurements were taken. Women were followed up until final pregnancy outcome between 11 and 14 weeks of gestation was confirmed using transvaginal ultrasonography: (1) VIUP, (2) non-viable intrauterine pregnancy or failed pregnancy of unknown location, and (3) ectopic pregnancy or persisting pregnancy of unknown location. The predictive value of cut-off levels for ruling out VIUP were evaluated across a range of values likely to be encountered clinically for progesterone, βhCG, and βhCG ratio., Results: Data from 2507 of 3272 (76.6%) women were suitable for analysis. All had data for βhCG levels, 2248 (89.7%) had progesterone levels, and 1809 (72.2%) had βhCG ratio. The likelihood of viability falls with the progesterone level. Although the median progesterone level associated with viability was 59 nmol/L, VIUP were identified with levels as low as 5 nmol/L. No single βhCG cut-off reliably ruled out the presence of viability with certainty, even when the level was more than 3000 IU/L, there were 39/358 (11%) women who had a VIUP. The probability of viability decreases with the βhCG ratio. Although the median βhCG ratio associated with viability was 2.26, VIUP were identified with ratios as low as 1.02. A progesterone level below 2 nmol/L and βhCG ratio below 0.87 were unlikely to be associated with viability but were not definitive when considering multiple imputation., Conclusions: Cut-off levels for βhCG, βhCG ratio, and progesterone are not safe to be used clinically to exclude viability in early pregnancy. Although βhCG ratio and progesterone have slightly better performance in comparison, single βhCG used in this manner is highly unreliable., (© 2021 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objective: To validate externally five approaches to predict ectopic pregnancy (EP) in pregnancies of unknown location (PUL): the M6P and M6NP risk models, the two-step triage strategy (2ST, which incorporates M6P), the M4 risk model, and beta human chorionic gonadotropin ratio cut-offs (BhCG-RC)., Design: Secondary analysis of a prospective cohort study., Setting: Eight UK early pregnancy assessment units., Population: Women presenting with a PUL and BhCG >25 IU/l., Methods: Women were managed using the 2ST protocol: PUL were classified as low risk of EP if presenting progesterone ≤2 nmol/l; the remaining cases returned 2 days later for triage based on M6P. EP risk ≥5% was used to classify PUL as high risk. Missing values were imputed, and predictions for the five approaches were calculated post hoc. We meta-analysed centre-specific results., Main Outcome Measures: Discrimination, calibration and clinical utility (decision curve analysis) for predicting EP., Results: Of 2899 eligible women, the primary analysis excluded 297 (10%) women who were lost to follow up. The area under the ROC curve for EP was 0.89 (95% CI 0.86-0.91) for M6P, 0.88 (0.86-0.90) for 2ST, 0.86 (0.83-0.88) for M6NP and 0.82 (0.78-0.85) for M4. Sensitivities for EP were 96% (M6P), 94% (2ST), 92% (N6NP), 80% (M4) and 58% (BhCG-RC); false-positive rates were 35%, 33%, 39%, 24% and 13%. M6P and 2ST had the best clinical utility and good overall calibration, with modest variability between centres., Conclusions: 2ST and M6P performed best for prediction and triage in PUL., Tweetable Abstract: The M6 model, as part of a two-step triage strategy, is the best approach to characterise and triage PULs., (© 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)