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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]

Objectives: To investigate and compare post-traumatic stress (PTS), depression and anxiety in women and their partners over a 9-month period following miscarriage or ectopic pregnancy.Methods: This was a prospective cohort study. Consecutive women and their partners were approached in the early pregnancy units of three hospitals in central London. At 1, 3 and 9 months after early pregnancy loss, recruits were e-mailed links to surveys containing the Hospital Anxiety and Depression Scale and the Post-traumatic Stress Diagnostic Scale. The proportion of participants meeting the screening criteria for moderate or severe anxiety or depression and PTS was assessed. Mixed-effects logistic regression was used to analyze differences between women and their partners and their evolution over time.Results: In total, 386 partners were approached after the woman in whom the early pregnancy loss had been diagnosed consented to participate, and 192 couples were recruited. All partners were male. Response rates were 60%, 48% and 39% for partners and 78%, 70% and 59% for women, at 1, 3 and 9 months, respectively. Of the partners, 7% met the criteria for PTS at 1 month, 8% at 3 months and 4% at 9 months, compared with 34%, 26% and 21% of women, respectively. Partners also experienced lower rates of moderate/severe anxiety (6% vs 30% at 1 month, 9% vs 25% at 3 months and 6% vs 22% at 9 months) and moderate/severe depression (2% vs 10% at 1 month, 5% vs 8% at 3 months and 1% vs 7% at 9 months). The odds ratios for psychological morbidity in partners vs women after 1 month were 0.02 (95% CI, 0.004-0.12) for PTS, 0.05 (95% CI, 0.01-0.19) for moderate/severe anxiety and 0.15 (95% CI, 0.02-0.96) for moderate/severe depression. Morbidity for each outcome decreased modestly over time, without strong evidence of a different evolution between women and their partners.Conclusions: Some partners report clinically relevant levels of PTS, anxiety and depression after pregnancy loss, though to a far lesser extent than women physically experiencing the loss. © 2020 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: The M6 risk-prediction model was published as part of a two-step protocol using an initial progesterone level of ≤ 2 nmol/L to identify probable failing pregnancies (Step 1) followed by the M6 model (Step 2). The M6 model has been shown to have good triage performance for stratifying women with a pregnancy of unknown location (PUL) as being at low or high risk of harboring an ectopic pregnancy (EP). This study validated the triage performance of the two-step protocol in clinical practice by evaluating the number of protocol-related adverse events and how effectively patients were triaged.Methods: This was a prospective multicenter interventional study of 3272 women with a PUL, carried out between January 2015 and January 2017 in four district general hospitals and four university teaching hospitals in the UK. The final pregnancy outcome was defined as: a failed PUL (FPUL), an intrauterine pregnancy (IUP) or an EP (including persistent PUL (PPUL)). FPUL and IUP were grouped as low-risk and EP/PPUL as high-risk PUL. Serum progesterone and human chorionic gonadotropin (hCG) levels were measured at presentation in all patients. If the initial progesterone level was ≤ 2 nmol/L, patients were discharged and were asked to have a follow-up urine pregnancy test in 2 weeks to confirm a negative result. If the progesterone level was > 2 nmol/L or a measurement had not been taken, hCG level was measured again at 48 h and results were entered into the M6 model. Patients were managed according to the outcome predicted by the protocol. Those classified as 'low risk, probable FPUL' were advised to perform a urine pregnancy test in 2 weeks and those classified as 'low risk, probable IUP' were invited for a scan a week later. When a woman with a PUL was classified as high risk (i.e. risk of EP ≥ 5%) she was reviewed clinically within 48 h. One center used a progesterone cut-off of ≤ 10 nmol/L and its data were analyzed separately. If the recommended management protocol was not adhered to, this was recorded as a protocol deviation and classified as: unscheduled visit for clinician reason, unscheduled visit for patient reason or incorrect timing of blood test or ultrasound scan. The classifications outlined in the UK Good Clinical Practice (GCP) guidelines were used to evaluate the incidence of adverse events. Data were analyzed using descriptive statistics.Results: Of the 3272 women with a PUL, 2625 were included in the final analysis (317 met the exclusion criteria or were lost to follow-up, while 330 were evaluated using a progesterone cut-off of ≤ 10 nmol/L). Initial progesterone results were available for 2392 (91.1%) patients. In Step 1, 407 (15.5%) patients were classified as low risk (progesterone ≤ 2 nmol/L), of whom seven (1.7%) were ultimately diagnosed with an EP. In 279 of the remaining 2218 women with a PUL, the M6 model was not applied owing to protocol deviation or because the outcome was already known (usually on the basis of an ultrasound scan) before a second hCG reading was taken; of these patients, 30 were diagnosed with an EP. In Step 2, 1038 women with a PUL were classified as low risk, of whom eight (0.8%) had a final outcome of EP. Of 901 women classified as high risk at Step 2, 275 (30.5%) had an EP. Therefore, 275/320 (85.9%) EPs were correctly classified as high risk. Overall, 1445/2625 PUL (55.0%) were classified as low risk, of which 15 (1.0%) were EP. None of these cases resulted in a ruptured EP or significant clinical harm. Sixty-two women participating in the study had an adverse event, but no woman had a serious adverse event as defined in the UK GCP guidelines.Conclusions: This study has shown that the two-step protocol incorporating the M6 model effectively triaged the majority of women with a PUL as being at low risk of an EP, minimizing the follow-up required for these patients after just two visits. There were few misclassified EPs and none of these women came to significant clinical harm or suffered a serious adverse clinical event. The two-step protocol incorporating the M6 model is an effective and clinically safe way of rationalizing the management of women with a PUL. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. [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]

Study Question: What are the adverse outcomes associated with using the M4 model in everyday clinical practice for women with pregnancy of unknown location (PUL)?Summary Answer: There were 17/835 (2.0%) adverse events and no serious adverse events associated with the performance of the M4 model in clinical practice.What Is Known Already: The M4 model has previously been shown to stratify women classified as a PUL as at low or high risk of complications with a good level of test performance. The triage performance of the M4 model is better than single measurements of serum progesterone or the hCG ratio (serum hCG at 48 h/hCG at presentation).Study Design, Size, Duration: A prospective multi-centre cohort study of 1022 women with a PUL carried out between August 2012 and December 2013 across 2 university teaching hospitals and 1 district general hospital.Participants/materials, Setting, Methods: All women presenting with a PUL to the early pregnancy units of the three hospitals were recruited. The final outcome for PUL was either a failed PUL (FPUL), intrauterine pregnancy (IUP) or ectopic pregnancy (EP) (including persistent PUL (PPUL)), with EP and PPUL considered high-risk PUL. Their hCG results at 0 and 48 h were entered into the M4 model algorithm. If the risk of EP was ≥5%, the PUL was predicted to be high-risk and the participant was asked to re-attend 48 h later for a repeat hCG and transvaginal ultrasound scan by a senior clinician. If the PUL was classified as 'low risk, likely failed PUL', the participant was asked to perform a urinary pregnancy test 2 weeks later. If the PUL was classified as 'low risk, likely intrauterine', the participant was scheduled for a repeat scan in 1 week. Deviations from the management protocol were recorded as either an 'unscheduled visit (participant reason)', 'unscheduled visit (clinician reason)' or 'differences in timing (blood test/ultrasound)'. Adverse events were assessed using definitions outlined in the UK Good Clinical Practice Guidelines' document.Main Results and the Role Of Chance: A total of 835 (82%) women classified as a PUL were managed according to the M4 model (9 met the exclusion criteria, 69 were lost to follow-up, 109 had no hCG result at 48 h). Of these, 443 (53%) had a final outcome of FPUL, 298 (36%) an IUP and 94 (11%) an EP. The M4 model predicted 70% (585/835) PUL as low risk, of which 568 (97%) were confirmed as FPUL or IUP. Of the 17 EP and PPUL misclassified as low risk, 5 had expectant management, 7 medical management with methotrexate and 5 surgical intervention.Nineteen PUL had an unscheduled visit (participant reason), 38 PUL had an unscheduled visit (clinician reason) and 68 PUL had deviations from protocol due to a difference in timing (blood test/ultrasound).Adverse events were reported in 26 PUL and 1 participant had a serious adverse event. A total of 17/26 (65%) adverse events were misclassifications of a high risk PUL as low risk by the M4 model, while 5/26 (19%) adverse events were related to incorrect clinical decisions. Four of the 26 adverse events (15%) were secondary to unscheduled admissions for pain/bleeding. The serious adverse event was due to an incorrect clinical decision.Limitations, Reasons For Caution: A limitation of the study was that 69/1022 (7%) of PUL were lost to follow-up. A 48 h hCG level was missing for 109/1022 (11%) participants.Wider Implications Of the Findings: The low number of adverse events (2.0%) suggests that expectant management of PUL using the M4 prediction model is safe. The model is an effective way of triaging women with a PUL as being at high- and low-risk of complications and rationalizing follow-up. The multi-centre design of the study is more likely to make the performance of the M4 model generalizable in other populations.Study Funding/competing Interests: None.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

An abstract of the article "A multicentre study to predict outcome in pregnancies of unknown location ( PUL): the role of the bleeding score," by S. Bobdiwala and colleagues is presented.

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.

Risk prediction models utilising hCG and progesterone are effective tools to manage PUL pending a final diagnosis by TVUS. The M6 prediction model uses progesterone, hCG and the hCG ratio (hCG 48 hours/hCG 0 hours). We assessed the effectiveness of PUL risk stratification at 96 hours using the M6 model and the time taken to confirm a diagnosis of ectopic pregnancy using TVUS. [Extracted from the article]

OC19.05: Evaluating cut-off values for progesterone, single hCG and hCG ratio to define pregnancy viability and location in women with a pregnancy of unknown location (PUL) We aimed to define the performance of single measurements of serum hCG, progesterone and the hCG ratio (hCG 48hrs/hCG 0hrs) for diagnosing pregnancy viability and location. We found 19.6% VIUP when single hCG >1000 IU/L, 14.4% when single hCG >2000 IU/L and 11.4% when single hCG >3000 IU/L. No single hCG cut-off excludes an EP. [Extracted from the article]

OC01.04: A multicentre trial on the performance of a two-step triage protocol based on initial serum progesterone and serial hCG used to manage pregnancies of unknown location (PUL) We previously published a two-step triage protocol based on the presenting serum progesterone (step 1) and M6 model, a logistic regression model based on the initial hCG and hCG ratio two days later (step 2) to select PUL at high-risk of ectopic pregnancy (EP). In seven centres, if the progesterone was <=2nmol/l, patients were discharged with a follow-up urine pregnancy test in two weeks to confirm a negative result. [Extracted from the article]