Updating the M6 pregnancy of unknown location risk prediction model including an evaluation of clinical factors

Abstract

ABSTRACTIntroductionEctopic pregnancy (EP) is the major high‐risk outcome following a pregnancy of unknown location (PUL) classification. Biochemical markers are used to triage PUL to high versus low risk to decide appropriate follow up. The M6 model is currently the best risk prediction model. We aimed to update the M6 model and evaluate whether the model can be improved by including clinical factors.MethodsThis prospective cohort study recruited consecutive PUL between January 2015 and January 2017 (phase one) at eight units, with two center recruitment between January 2017 and March 2021 (phase two). Serum samples were routinely collected and sent for BhCG and progesterone measurement. Clinical factors recorded were maternal age, pain score, bleeding score and history of previous EP. Based on transvaginal ultrasonography and/or biochemical confirmation during follow‐up, PUL were subsequently classified as failed PUL, intrauterine pregnancy, or EP (including persistent PUL (PPUL)). The M6 models with (M6P) and without progesterone (M6NP) were refitted and extended with clinical factors. Model validation was performed using internal‐external cross validation (IECV ‐ phase one), and external validation (EV ‐ phase two). Missing values were handled using multiple imputation.Results5473 PUL were recruited over both phases. 709 PUL were excluded because maternal age was <16 years or initial BhCG was ≤25 IU/L, leaving 4764 (86%) PUL for analysis (2894 in phase one, 1870 in phase 2). For the refitted M6P, the area under the receiver operating characteristic curve (AUROC) for EP/PPUL vs other was 0.89 for IECV and 0.84‐0.88 with EV. For the refitted M6NP, the AUROC was 0.85 for IECV and 0.82‐0.86 with EV. Calibration performance was good overall, but with heterogeneity between centers. Net Benefit confirmed clinical utility. The change in AUROC when extending M6P with maternal age, bleeding score, and EP history was ‐0.02 to 0.01 depending on center and phase. The change in AUROC when extending M6NP was ‐0.01 to 0.03. At the 5% threshold defining high EP/PPUL risk, 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.ConclusionsThe updated M6 model offers accurate diagnostic performance, with excellent sensitivity for EP. Adding clinical factors to the model improves performance in some centers, especially when progesterone levels are not suitable or unavailable.This article is protected by copyright. All rights reserved.