Beta-human chorionic gonadotrophin point of care testing for the management of pregnancy of unknown location.

RESEARCH QUESTION: Does a commercially available quantitative beta-human chorionic gonadotrophin (BHCG) point of care testing (POCT) device improve workflow management in early pregnancy by performing comparably to gold standard laboratory methods, and is the performance of a validated pregnancy of unknown location (PUL) triage strategy maintained using POCT BHCG results? DESIGN: Women classified with a PUL between 2018 and 2021 at three early pregnancy units were included. The linear relationship of untreated whole-blood POCT and serum laboratory BHCG values was defined using coefficients and regression. Paired serial BHCG values were then incorporated into the validated M6 multinomial logistic regression model to stratify the PUL as at high risk or at low risk of clinical complications. The sensitivity and negative predictive value were assessed. The timings required for equivocal POCT and laboratory care pathways were compared. RESULTS: A total of 462 PUL were included. The discrepancy between 571 laboratory and POCT BHCG values was -5.2% (-6.2 IU/l), with a correlation coefficient of 0.96. The 133 PUL with paired 0 and 48 h BHCG values were compared using the M6 model. The sensitivity for high-risk outcomes (96.2%) and negative predictive values (98.5%) was excellent for both. Sample receipt and laboratory processing took 135 min (421 timings), compared with 12 min (91 timings) when using POCT (P < 0.0001). CONCLUSIONS: POCT BHCG values correlated well with laboratory testing measurements. The M6 model retained its performance when using POCT BHCG values. Using the model with POCT may improve workflow and patient care without compromising on effective PUL triage.

Cost-effectiveness analysis of expectant vs active management for treatment of persistent pregnancies of unknown location.

BACKGROUND: Persistent pregnancies of unknown location are defined by abnormally trending serum human chorionic gonadotropin with nondiagnostic ultrasound. There is no consensus on optimal management. OBJECTIVE: This study aimed to assess the cost-effectiveness of 3 primary management strategies for persistent pregnancies of unknown location: (1) expectant management, (2) empirical 2-dose methotrexate, and (3) uterine evacuation followed by methotrexate, if indicated. STUDY DESIGN: This was a prospective economic evaluation performed concurrently with the Expectant versus Active Management for Treatment of Persistent Pregnancies of Unknown Location multicenter randomized trial that was conducted from July 2014 to June 2019. Participants were randomized 1:1:1 to expectant management, 2-dose methotrexate, or uterine evacuation. The analysis was from the healthcare sector perspective with a 6-week time horizon after randomization. Costs were expressed in 2018 US dollars. Effectiveness was measured in quality-adjusted life years and the rate of salpingectomy. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were generated. Sensitivity analyses were performed to assess the robustness of the analysis. RESULTS: Methotrexate had the lowest mean cost ($875), followed by expectant management ($1085) and uterine evacuation ($1902) (P=.001). Expectant management had the highest mean quality-adjusted life years (0.1043), followed by methotrexate (0.1031) and uterine evacuation (0.0992) (P=.0001). The salpingectomy rate was higher for expectant management than for methotrexate (9.4% vs 1.2%, respectively; P=.02) and for expectant management than for uterine evacuation (9.4% vs 8.1%, respectively; P=.04). Uterine evacuation, with the highest costs and the lowest quality-adjusted life years, was dominated by both expectant management and methotrexate. In the base case analysis, expectant management was not cost-effective compared with methotrexate at a willingness to pay of $150,000 per quality-adjusted life year given an incremental cost-effectiveness ratio of $175,083 per quality-adjusted life year gained (95% confidence interval, -$1,666,825 to $2,676,375). Threshold analysis demonstrated that methotrexate administration would have to cost $214 (an increase of $16 or 8%) to favor expectant management. Moreover, expectant management would be favorable in lower-risk patient populations with rates of laparoscopic surgical management for ectopic pregnancy not exceeding 4% of pregnancies of unknown location. Based on the cost-effectiveness acceptability curves, the probability of expectant management being cost-effective compared with methotrexate at a willingness to pay of $150,000 per quality-adjusted life year gained was 50%. The results were dependent on the cost of surgical intervention and the expected rate of methotrexate failure. CONCLUSION: The management of pregnancies of unknown location with a 2-dose methotrexate protocol may be cost-effective compared with expectant management and uterine evacuation. Although uterine evacuation was dominated, expectant management vs methotrexate results were sensitive to modest changes in treatment costs of both methotrexate and surgical management.

Ambulatory human chorionic gonadotrophin (hCG) testing: a verification of two hCG point of care devices.

OBJECTIVES: Quantitative human chorionic gonadotropin (hCG) measurements are used to manage women classified with a pregnancy of unknown location (PUL). Two point of care testing (POCT) devices that quantify hCG are commercially available. We verified the i-STAT 1 (Abbott) and the AQT 90 FLEX (Radiometer) prior to use in PUL triage. METHODS: Tests for precision, external quality assurance (EQA), correlation, hook effect and recovery were undertaken alongside a POCT usability assessment during this prospective multi-center verification. RESULTS: Coefficients of variation ranged between 4.0 and 5.1 % for the three i-STAT 1 internal quality control (IQC) solutions and between 6.8 and 7.3 % for the two AQT IQC solutions. Symmetric differences in POCT EQA results when compared with laboratory and EQA stock values ranged between 3.2 and 24.5 % for the i-STAT 1 and between 3.3 and 36.9 % for the AQT. Correlation coefficients (i-STAT 1: 0.96, AQT: 0.99) and goodness of fit curves (i-STAT 1: 0.92, AQT: 0.99) were excellent when using suitable whole blood samples. An hCG hook effect was noted with the i-STAT 1 between 572,194 and 799,089 IU/L, lower than the hook effect noted with the AQT, which was between 799,089 and 1,619,309 IU/L. When hematocrit concentration was considered in sample types validated for use with each device, hCG recovery was 108 % with the i-STAT 1 and 98 % with the AQT. The i-STAT 1 scored lower on usability overall (90/130) than the AQT (121/130, p<0.001, Mann-Whitney). CONCLUSIONS: Both hCG POCT devices were verified for use in clinical practice. Practical factors must also be considered when choosing which device to use in each unit.

Safety of methotrexate administration in women with pregnancy of unknown location at high risk of ectopic pregnancy.

OBJECTIVES: To evaluate the safety of current guidelines on methotrexate (MTX) administration in women with pregnancy of unknown location (PUL) who are considered to have a high risk of underlying ectopic pregnancy (EP), and to investigate whether implementation of these guidelines would result in inadvertent exposure to MTX of viable intrauterine pregnancies (IUPs). METHODS: This was a retrospective observational study of consecutive clinically stable women who were classified with PUL at the early pregnancy unit of Nepean Hospital, Sydney, Australia, between 2007 and 2021. PUL was defined as a positive pregnancy test in the absence of signs of IUP or EP on transvaginal ultrasound. Patients with a PUL that behaved biochemically like an EP, but for which the location of pregnancy was not confirmed on ultrasound, were eligible for MTX to minimize the risk of subsequent tubal rupture. Criteria discussed in the guidelines of the American College of Obstetricians and Gynecologists (ACOG), American Society for Reproductive Medicine (ASRM), Royal College of Obstetricians and Gynaecologists (RCOG) and National Institute for Health and Care Excellence (NICE) were applied to the PUL database. The number of patients eligible to receive MTX and the number with an underlying viable IUP who would be inadvertently prescribed MTX were calculated. RESULTS: A total of 816 women with PUL were reviewed, of whom 724 had complete data and were included in the final analysis. Six patients had persistent PUL and the remaining 718 had a diagnosis of viable IUP, non-viable IUP, EP or failed PUL. According to the ACOG, ASRM, RCOG and NICE guidelines, the rate of MTX administration among patients with PUL would have been 2.76%, 4.56%, 0.41% and 35.36%, respectively. However, no persistent PUL would have received MTX according to the ACOG, ASRM and RCOG protocols (the NICE protocol identified patients with persistent PUL with a sensitivity of 100%), and the majority of MTX treatments were unnecessary because those patients were later classified as having non-viable IUP or failed PUL. Application of ACOG and ASRM guidance could result theoretically in inadvertent MTX administration to women with an underlying viable IUP at a rate of 4.1/1000 (3/724). CONCLUSIONS: Current guidelines used to predict high risk of EP in the PUL population lead to inadvertent MTX administration to women with an underlying viable IUP. These guidelines should be used wisely to ensure that no wanted pregnancy is exposed to MTX. Women with PUL should be monitored carefully, and MTX should be used judiciously when the location of pregnancy is yet to be confirmed. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Updating M6 pregnancy of unknown location risk-prediction model including evaluation of clinical factors.

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 ß-human chorionic gonadotropin (ß-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 ß-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.

Preliminary findings on the experiences of care for women who suffered early pregnancy losses during the COVID-19 pandemic: a qualitative study.

BACKGROUND: Women who suffer an early pregnancy loss require specific clinical care, aftercare, and ongoing support. In the UK, the clinical management of early pregnancy complications, including loss is provided mainly through specialist Early Pregnancy Assessment Units. The COVID-19 pandemic fundamentally changed the way in which maternity and gynaecological care was delivered, as health systems moved to rapidly reconfigure and re-organise services, aiming to reduce the risk and spread of SARS-CoV-2 infection. PUDDLES is an international collaboration investigating the pandemic's impact on care for people who suffered a perinatal bereavement. Presented here are initial qualitative findings undertaken with UK-based women who suffered early pregnancy losses during the pandemic, about how they navigated the healthcare system and its restrictions, and how they were supported. METHODS: In-keeping with a qualitative research design, in-depth semi-structured interviews were undertaken with an opportunity sample of women (N = 32) who suffered any early pregnancy loss during the COVID-19 pandemic. Data were analysed using a template analysis to understand women's access to services, care, and networks of support, during the pandemic following their pregnancy loss. The thematic template was based on findings from parents who had suffered a late-miscarriage, stillbirth, or neonatal death in the UK, during the pandemic. RESULTS: All women had experienced reconfigured maternity and early pregnancy services. Data supported themes of: 1) COVID-19 Restrictions as Impractical & Impersonal; 2) Alone, with Only Staff to Support Them; 3) Reduction in Service Provision Leading to Perceived Devaluation in Care; and 4) Seeking Their Own Support. Results suggest access to early pregnancy loss services was reduced and pandemic-related restrictions were often impractical (i.e., restrictions added to burden of accessing or receiving care). Women often reported being isolated and, concerningly, aspects of early pregnancy loss services were reported as sub-optimal. CONCLUSIONS: These findings provide important insight for the recovery and rebuilding of health services in the post-pandemic period and help us prepare for providing a higher standard of care in the future and through any other health system shocks. Conclusions made can inform future policy and planning to ensure best possible support for women who experience early pregnancy loss.

Expectant management versus systemic methotrexate in the management of persistent pregnancy of unknown location, a seven-year retrospective analysis.

PURPOSE: To compare Expectant management to systemic methotrexate in the management of persistent pregnancy of unknown location with beta-hCG levels below the discrimination zone. METHODS: A retrospective cohort study was conducted on 71 women with persistent pregnancy of unknown location. They were divided into two groups according to the applied management; Group 1, (n = 40) who were managed expectantly and Group 2 (n = 31) who were given a single dose of methotrexate. Data variables were collected and analyzed to evaluate whether expectant management was as effective as methotrexate. RESULTS: There was no significant difference between the two groups regarding age, parity, gestational age, body mass index and day seven beta-hCG. Success rates were (32 patients (80%) and 28 patients (90.3%) in expectant management and methotrexate groups, respectively (P > 0.05). The mean values for day zero and day four beta-hCG were significantly higher and the mean duration for complete recovery was statistically shorter in the methotrexate group (P < 0.05). There were no significant differences between the two groups regarding prior ectopic, percentage of beta-hCG level drop on day four and day seven, success rate, occurrence of sequelae and patient satisfaction that area under the curve (AUC) for group 1 (expectant management) is 0.566 at 95% Confidence Interval of (0.388: 0.745). CONCLUSION: Expectant management is an effective and safe alternative to single-dose methotrexate for persistent PUL with beta-hCG levels below the discrimination zone.

The predictors of successful methotrexate treatment of tubal ectopic pregnancy.

BACKGROUND: The pre-treatment characteristics of the patient and ectopic pregnancy to determine the patients who are likely to successfully respond to methotrexate (MTX) therapy remain controversial. This study investigated the outcomes of ectopic pregnancy after one and two MTX doses and their independent predictors. METHODS: Retrospective cross-sectional study of women who consented to MTX treatment in 2017-2018 at our institution (N = 317). Of these, patients with Caesarean scar pregnancies were excluded because they require different treatment protocols (n = 25). All patients were treated according to our institution's protocol based on international guidelines and standardised across the three hospitals included in the current study. We retrieved patients' demographics, laboratory, ultrasonography, and clinical characteristics from our hospital database. Serum ß-human chorionic gonadotropin (ß-hCG) was measured using electrochemiluminescence immunoassay; ectopic pregnancy was diagnosed using ultrasonography (transvaginal probe). RESULTS: Two ninety-two patients were included in the current analysis. Age, pre-treatment ß-hCG levels, sonographic presence of yolk sac, presence of foetal cardiac activity, and pelvic pain were significantly different between patients with successful and unsuccessful outcomes. Younger age (adjusted odds ratio [aOR] 2.33, 95% confidence interval (CI) 1.16-4.66, p = .017), no pelvic pain (aOR 2.65, 95%CI 1.03-6.83, p = .043), lower initial ß-hCG level (aOR 1.32, 95%CI 1.08-1.59, p = .005), and absence of foetal cardiac activity (aOR 12.63; 95% CI 1.04-153.6; p = .047) were independently associated with success. Treatment failure odds were >2 folds higher for each 10-year age increase (p = .017), 32% higher for each 1000 IU/L increase in initial ß-hCG level (p = .005), and >2 folds higher in presence of pelvic pain (p = .043). CONCLUSIONS: MTX is effective in most patients, averting invasive surgery, which might affect fertility. Pre-treatment ß-hCG levels, age, pelvic pain, and foetal cardiac activity was independently associated with outcomes. Research should assess the relationship between the ectopic pregnancy size and treatment outcomes and refine ß-hCG titres where treatment would be ineffective.

Ectopic pregnancy is a pregnancy that occurs outside the uterus. It needs to be identified and treated quickly to prevent serious health complications. Ectopic pregnancies can be treated surgically or medically using a drug called methotrexate. Medical treatment of ectopic pregnancy is not always successful. Identifying the factors that predict the failure of medical treatment helps patients and doctors to choose more accurately between surgical and medical treatment options.A total of 292 women who received methotrexate for ectopic pregnancy and the factors that influence the outcomes of treatment were examined, 39 patients had treatment failure and required surgery. Older age, higher initial levels of ß-human chorionic gonadotropin (ß-hCG) hormone, the presence of pelvic pain, and foetal cardiac activity had increased risk of treatment failure. In the future, research could consider the relationship between the size of the ectopic pregnancy and the treatment outcomes and refine the ß-hCG level cut-off for better treatment effects.

Telephone-Based Intervention to Improve Family Planning Care in Pregnancies of Unknown Location: Retrospective Pre-Post Study.

BACKGROUND: Patients followed for a pregnancy of unknown location are generally followed by a team of clinicians through telephone calls, and their contraceptive needs at the time of pregnancy resolution may not be addressed. OBJECTIVE: This study aimed to assess contraceptive counseling and contraceptive uptake before and after a telephone-based intervention. METHODS: This was a retrospective pre-post study assessing pregnancy intendedness in patients with a pregnancy of unknown location and the proportion of patients who received contraceptive counseling and a contraceptive prescription before and after the initiation of a telephone-based intervention. We reviewed medical records 1 year before and 1 year after implementation of our intervention for demographic characteristics, pregnancy intendedness, pregnancy outcome, contraceptive counseling documentation, receipt of contraception, and repeat pregnancy within 6 months. We assessed the effects of an implementation strategy to address family planning needs once pregnancy was resolved by comparing the proportions of patients who were counseled and received contraception before and after our intervention was implemented. We performed logistic regression to identify associations between covariates and the outcomes of contraceptive counseling documentation and receipt of contraception. RESULTS: Of the 220 patients in the combined cohort, the majority were Black (161/220, 73%) and ultimately had a resolved pregnancy of unknown location (162/220, 74%), and the proportion of pregnancies documented as unintended was 60% (132/220). Before our intervention, 27 of 100 (27%) patients received contraceptive counseling, compared with 94 of 120 (78%) patients after the intervention (odds ratio [OR] 9.77, 95% CI 5.26-18.16). Before the intervention, 17 of 90 (19%) patients who did not desire repeat pregnancy received contraception, compared with 32 of 86 (37%) patients after the intervention (OR 2.54, 95% CI 1.28-5.05). Our postintervention cohort had an increased odds of receiving contraceptive counseling (OR 9.77, 95% CI 5.26-18.16) and of receiving a contraceptive prescription (OR 2.54, 95% CI 1.28-5.05) compared with our preintervention cohort. CONCLUSIONS: We found that over half of patients with a pregnancy of unknown location have an unintended pregnancy, and standardization of care through a telephone-based intervention improves contraceptive counseling and prescribing in patients with a resolved pregnancy of unknown location. This intervention could be used at any institution that follows patients with a pregnancy of unknown location remotely to improve care.

The incidence and importance of the pseudogestational sac revisited.

BACKGROUND: In a pregnancy of unknown location, an intrauterine fluid collection may represent either the early gestational sac of an intrauterine pregnancy, or as reported in previous literature, the pseudogestational sac of an ectopic pregnancy. Various sonographic features have been used to distinguish these 2 entities, but the clinical relevance of the pseudogestational sac remains unclear. OBJECTIVE: To establish the incidence and relative rate of intrauterine fluid collection among ectopic and intrauterine pregnancies and to determine if the size of the collection differs between ectopic and intrauterine pregnancies STUDY DESIGN: We performed a retrospective cohort study of women with pregnancies of unknown location and pelvic or abdominal pain or bleeding. We calculated the incidences of intrauterine fluid collections among ectopic and intrauterine pregnancies, including both ongoing pregnancies and spontaneous abortions, given that that our focus was location and not viability. We calculated the relative risk of ectopic pregnancy if an intrauterine fluid collection was present, adjusting for age and vaginal bleeding. We compared the incidences of ectopic and intrauterine pregnancies among those with and without intrauterine fluid collections. Among those with collections, we compared the mean sac diameter between ectopic and intrauterine pregnancies in continuous and categorical fashions. RESULTS: We evaluated 1236 women presenting with a pregnancy of unknown location. The rates of ectopic and intrauterine pregnancies (including spontaneous abortions) were 13.1% and 63.9%, respectively, with the remainder lost to follow-up. On ultrasound, 452 women (36.6%) had an intrauterine fluid collection. Eight of 162 ectopic pregnancies (4.9%) had a collection, compared with 363 of 789 intrauterine pregnancies (46.0%) (P=.01). Of the ectopics with a fluid collection, 5 had an adnexal mass. The presence of intrauterine fluid collection decreased the risk of ectopic pregnancy (adjusted relative risk, 0.09; 95% confidence interval, 0.05-0.19) after adjusting for age and the presence of bleeding. Among those with an intrauterine fluid collection, the rate of ectopic pregnancy was 2.2%, and the rate of intrauterine pregnancy was 97.8%; among those without a collection, the rate of ectopic pregnancy was 26.7%, and the rate of intrauterine pregnancy was 73.3%. The mean sac diameter did not differ between ectopic and intrauterine pregnancies, whether analyzed continuously or categorically. CONCLUSION: In the presence of an intrauterine fluid collection, the rate of ectopic pregnancy is very low. The size of the intrauterine fluid collection in a woman with a pregnancy of unknown location cannot be used to distinguish between a gestational sac and a pseudogestational sac. Pseudogestational sacs are uncommon and of little clinical consequence. In assessing pregnancies of unknown location, clinicians should incorporate the entire clinical picture, including other sonographic findings, to avoid incorrect or delayed diagnoses.

Evaluating cut-off levels for progesterone, ß human chorionic gonadotropin and ß human chorionic gonadotropin ratio to exclude pregnancy viability in women with a pregnancy of unknown location: A prospective multicenter cohort study.

INTRODUCTION: There is no global agreement on how to best determine pregnancy of unknown location viability and location using biomarkers. Measurements of progesterone and ß human chorionic gonadotropin (ßhCG) are still used in clinical practice to exclude the possibility of a viable intrauterine pregnancy (VIUP). We evaluate the predictive value of progesterone, ßhCG, and ßhCG 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 ßhCG 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, ßhCG, and ßhCG ratio. RESULTS: Data from 2507 of 3272 (76.6%) women were suitable for analysis. All had data for ßhCG levels, 2248 (89.7%) had progesterone levels, and 1809 (72.2%) had ßhCG 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 ßhCG 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 ßhCG ratio. Although the median ßhCG 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 ßhCG ratio below 0.87 were unlikely to be associated with viability but were not definitive when considering multiple imputation. CONCLUSIONS: Cut-off levels for ßhCG, ßhCG ratio, and progesterone are not safe to be used clinically to exclude viability in early pregnancy. Although ßhCG ratio and progesterone have slightly better performance in comparison, single ßhCG used in this manner is highly unreliable.

Pregnancies lost and found: a quality improvement project to increase follow-up for early pregnancy complications.

Pregnancy of unknown location (PUL) and medically managed ectopic pregnancy (EP) require longitudinal surveillance to avoid adverse outcomes; however, patients with PUL/EP in the United States (U.S.) are often unable to adhere to recommended treatment plans. This quality improvement (QI) project sought to improve PUL/EP follow-up using a three-pronged intervention: standardised recall procedures, direct patient-provider communication and electronic medical record (EMR) documentation templates and tracking. We compared patients with PUL/EP managed before and after the QI project. Our primary outcome was completion of PUL/EP clinical care. Demographics, initial diagnoses and adverse outcomes were similar between 87 pre-QI and 81 post-QI patients. Significantly more patients completed PUL/EP clinical care post-QI (80.2 vs. 65.5% p = .03). Post-QI, more providers contacted patients at standard intervals (100 vs. 57.1%, p < .0001), and EMR documentation was improved (100 vs. 69.0%, p < .001). Simple changes to PUL/EP management improved completion of clinical care and compliance with standardised recall and documentation.IMPACT STATEMENTWhat is already known on this subject? Pregnancy of unknown location (PUL) and medically managed ectopic pregnancy (EP) require longitudinal surveillance to avoid adverse outcomes; however, patients with PUL/EP in the United States (U.S.) are often unable to adhere to recommended treatment plans.What do the results of this study add? By standardising recall procedures, ensuring direct communication between patients and providers using a dedicated cell phone, and integrating case tracking and documentation into the electronic medical record (EMR), this quality improvement (QI) project improved completion of clinical follow-up for patients with PUL/EP (overall, 80.2 vs. 65.5% pre-QI, p=.03) and for the subgroup with medically managed EP not requiring surgery (76.5 vs. 36.4% pre-QI, p= .05). We also improved providers' compliance with standardised recall procedures and EMR documentation post-QI (p < .0001). There was no difference in the number of attempts to contact patients, or in the number of surveillance blood draws actually performed. Post-QI, survey responses indicated that patients were easily able to contact their provider and understood the importance of follow-up processes.What are the implications of these findings for clinical practice and/or research? Early pregnancy care providers can utilise simple strategies to improve follow-up of patients with PUL and medically managed EP, without increasing burdens to their health systems. Patients' favourable experiences with this management support its implementation.

External validation of models to predict the outcome of pregnancies of unknown location: a multicentre cohort study.

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.

Management of early gestations with low beta-human chorionic gonadotropin conceived by assisted reproductive technologies: performance of M4 predictive model.

OBJECTIVES: To assess the safety and performance of the M4 model for classifying as high risk or low risk for ectopic pregnancy (EP) pregnancies conceived by assisted reproductive technologies (ART) that present with low beta-human chorionic gonadotropin (ß-hCG) concentration in early gestation. METHODS: This was a prospective cohort study of 243 pregnancies conceived by ART with low ß-hCG levels (5-50 IU/L) at 4 + 0 to 4 + 2 weeks' gestation. After subsequent ß-hCG testing at 48 h, pregnancies were classified according to the M4 model into the following categories: (i) high risk, probable EP/persistent pregnancy of unknown location (PPUL), when the risk for EP was ≥ 5%; (ii) low risk, probable intrauterine pregnancy (IUP), when the risk of EP was < 5% and the likelihood of IUP was greater than that of a failed pregnancy of unknown location (FPUL); and (iii) low risk, probable FPUL, when the risk of EP was < 5% and the likelihood of a FPUL was greater than that of an IUP. The predictive performance of the M4 model for EP and its ability to discriminate between high- and low-risk pregnancies was assessed using the final pregnancy outcome at 11 to 13 weeks of gestation as reference, which was classified as EP/PPUL, FPUL or IUP. RESULTS: The sensitivity and specificity of the M4 model in detecting a high-risk pregnancy (EP/PPUL) were 60.0% (95% CI, 43.6-74.4%) and 79.8% (95% CI, 73.8-84.7%), respectively. The area under the receiver-operating-characteristics curve of the M4 model for discriminating between high-risk and low-risk (FPUL/IUI) pregnancies was 0.72 (95% CI, 0.62-0.81). The model had a positive likelihood ratio of 2.97 (95% CI, 2.03-4.36) and a negative likelihood ratio of 0.50 (95% CI, 0.33-0.76). The kappa index was 0.30 (95% CI, 0.16-0.43), indicating a low degree of agreement between the model classification and the final diagnosis. No serious adverse events related directly to the application of the M4 model were observed, although 14 pregnancies classified ultimately as high risk had been categorized initially as low risk by the M4 model. Of these, seven resolved with expectant management, five with methotrexate (MTX) and two required laparoscopic surgery (one after failure of medical treatment with MTX and one after deviation from the follow-up protocol). There were no cases of EP/PPUL with additional complications or need for blood or other blood product transfusion. Of the 243 ART pregnancies with low ß-hCG concentration in early gestation, only 47 (19.3%) had an IUP, half (24/47) of which had an early miscarriage, resulting in only 9.5% (23/243) cases having an ongoing pregnancy. CONCLUSIONS: Application of the M4 model in pregnancies conceived by ART with low ß-hCG concentration in early gestation showed limited capacity in classifying them as being at low or high risk for EP, therefore, its use in pregnancies of this type is not recommended. No serious adverse events or complications related to the use of the model were observed. These pregnancies have a low probability of ending in an IUP as well as a high rate of early miscarriage. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Tubal Ectopic Pregnancy with Undetectable Initial Serum ß-Human Chorionic Gonadotropin Level.

We present a case of a tubal ectopic pregnancy (EP) in a patient with an initially undetectable serum ß-human chorionic gonadotropin (ß-hCG) level. A 33-year-old woman in a same-sex relationship underwent timed donor intrauterine insemination. Her serum ß-hCG level was <5 mIU/mL 14 days after the intrauterine insemination. She reported menstrual bleeding 3 days after her negative pregnancy test and returned to the office 10 days later to begin a new treatment cycle. Her serum levels of estradiol, progesterone, and ß-hCG were 119 pg/mL, 6.1 ng/mL and 1157 mIU/mL, respectively. Transvaginal ultrasonography did not show an intrauterine pregnancy. Her ß-hCG level increased to 1420 mIU/mL the next day. She was diagnosed with a pregnancy of unknown location and treated with methotrexate. Her ß-hCG levels continued to increase despite 3 methotrexate doses, necessitating laparoscopy. The diagnostic laparoscopy demonstrated approximately 100 mL of hemoperitoneum in the posterior cul-de-sac with an intact right fallopian tube that was dilated at its distal end by the EP. A total right salpingectomy was performed. Her ß-hCG level was <5 mIU/mL 3 weeks later. The current case supports that although rare, an undetectable serum ß-hCG level does not completely rule out the diagnosis of an EP.

How do the M4 and M6 models perform in an Australian pregnancy of unknown location population?

BACKGROUND: The diagnosis of a pregnancy of unknown location (PUL) is made when there is an elevated serum ß human chorionic gonadotropin (ßhCG) and no pregnancy on transabdominal and transvaginal ultrasound. Most of these pregnancies end as intra-uterine pregnancies or unsuccessful pregnancies and can be safely managed expectantly. However, up to 20% of these women will have an ectopic pregnancy. Several mathematical models, including the M4 and M6 protocols, have been developed using biochemical markers to triage PUL presentations. This rationalises numbers of tests and visits made without compromising safety and allowing timely intervention. AIMS: We aimed to externally validate the M4 and M6 models in an Australian tertiary early pregnancy assessment service (EPAS). MATERIALS AND METHODS: We performed a retrospective single-centre cohort study across five years. Our study population included all women attending our EPAS with a PUL who had at least two serum ßhCG levels and one progesterone level measured. The M4 and M6 models were retrospectively applied. RESULTS: Of the 360 women in the study population, there were 26 confirmed ectopic pregnancies (7.2%) and six persisting PULs (2%). The M4 model had a sensitivity and specificity of 72%. The M6P model had a sensitivity of 91% and specificity of 63%. The M6P misclassified two ectopic pregnancies into the low-risk group, compared with seven in the M4 model. CONCLUSIONS: The M6P model has the highest sensitivity of the three models and a negative predictive value of 99%. These numbers are comparable to the original United Kingdom population. Further prospective validation is planned.

Triaging women with pregnancy of unknown location using two-step protocol including M6 model: clinical implementation study.

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.

Rationalizing the management of pregnancies of unknown location: Diagnostic accuracy of human chorionic gonadotropin ratio-based decision tree compared with the risk prediction model M4.

INTRODUCTION: The objective was to compare the diagnostic accuracy of the decision tree analysis prediction model P1, which incorporates the human chorionic gonadotropin (hCG) ratio (hCG 48 hours/hCG 0 hour), and risk prediction model M4 in the management of women with pregnancy of unknown location (PUL). MATERIAL AND METHODS: A retrospective diagnostic accuracy study was performed on PUL data collected between August 2011 and September 2018. Women with a PUL were prospectively managed according to the P1 prediction model, which utilizes the hCG ratio and, if necessary, a day (D) 7 hCG. We compared the performance of P1 with the M4 model, a logistic regression mathematical model using initial hCG and hCG ratio, to classify PULs as low risk (failed PUL [failed] or intrauterine pregnancy) or high risk (ectopic pregnancy or persistent PUL). The reference standard was defined as the final PUL outcome. RESULTS: Transvaginal ultrasound was done in 3847 consecutive women for early pregnancy complications, 437 (11.3%) of whom were classified as PUL. Final analysis comprised 413 cases with complete data. Final PUL clinical outcomes were: 247 (59.8%) failed PUL, 94 (22.7%) intrauterine pregnancy, 49 (11.8%) ectopic pregnancy and 23 (5.5%) persistent PUL. The sensitivity of P1 and M4 in predicting high-risk PUL were 81.9% (95% confidence interval [CI] 71.1-90.0) and 80.6% (95% CI 69.5-88.9), respectively. The specificities were 74.5% (95% CI 69.5-79.1) and 75.6% (95% CI 70.7-80.1), respectively. CONCLUSIONS: P1 and M4 performed similarly with respect to diagnostic accuracy in predicting PUL outcome. P1 needs to be externally validated.

External validation of risk prediction model M4 in an Australian population: Rationalising the management of pregnancies of unknown location.

BACKGROUND: The prediction model M4 can successfully classify pregnancy of unknown location (PUL) into a low- or high-risk group in developing ectopic pregnancy. M4 was validated in UK centres but in very few other countries outside UK. AIM: To validate the M4 model's ability to correctly classify PULs in a cohort of Australian women. MATERIALS AND METHODS: A retrospective analysis of women classified with PUL, attending a Sydney-based teaching hospital between 2006 and 2018. The reference standard was the final characterisation of PUL: failed PUL (FPUL) or intrauterine pregnancy (IUP; low risk) vs ectopic pregnancy (EP) or persistent PUL (PPUL; high risk). Each patient was entered into the M4 model calculator and an estimated risk of FPUL/IUP or EP/PPUL was recorded. Diagnostic accuracy of the M4 model was evaluated. RESULTS: Of 9077 consecutive women who underwent transvaginal sonography, 713 (7.9%) classified with a PUL. Six hundred and seventy-seven (95.0%) had complete study data and were included. Final outcomes were: 422 (62.3%) FPULs, 150 (22.2%) IUPs, 105 (15.5%) EPs and PPULs. The M4 model classified 455 (67.2%) as low-risk PULs of which 434 (95.4%) were FPULs/IUPs and 21 (4.6%) were EPs or PPULs. EPs/PPULs were correctly classified with sensitivity of 80.0% (95% CI 71.1-86.5%), specificity of 75.9% (95% CI 72.2-79.3%), positive predictive value of 37.8% (95% CI 33.8-42.1%) and negative predictive value of 95.3% (95% CI 93.1-96.9%). CONCLUSIONS: We have externally validated the prediction model M4. It classified 67.2% of PULs as low risk, of which 95.4% were later characterised as FPULs or IUPs while still classifying 80.0% of EPs as high risk.

Diagnostic protocols for the management of pregnancy of unknown location: a systematic review and meta-analysis.

BACKGROUND: There is no international consensus on how to manage women with a pregnancy of unknown location (PUL). OBJECTIVES: To present a systematic quantitative review summarising the evidence related to management protocols for PUL. SEARCH STRATEGY: MEDLINE, COCHRANE and DARE databases were searched from 1 January 1984 to 31 January 2017. The primary outcome was accurate risk prediction of women initially diagnosed with a PUL having an ectopic pregnancy (high risk) as opposed to either a failed PUL or intrauterine pregnancy (low risk). SELECTION CRITERIA: All studies written in the English language, which were not case reports or series that assessed women classified as having a PUL at initial ultrasound. DATA COLLECTION AND ANALYSIS: Forty-three studies were included. QUADAS-2 criteria were used to assess the risk of bias. We used a novel, linear mixed-effects model and constructed summary receiver operating characteristic curves for the thresholds of interest. MAIN RESULTS: There was a high risk of differential verification bias in most studies. Meta-analyses of accuracy were performed on (i) single human chorionic gonadotrophin (hCG) cut-off levels, (ii) hCG ratio (hCG at 48 hours/initial hCG), (iii) single progesterone cut-off levels and (iv) the 'M4 model' (a logistic regression model based on the initial hCG and hCG ratio). For predicting an ectopic pregnancy, the areas under the curves (95% CI) for these four management protocols were as follows: (i) 0.42 (0.00-0.99), (ii) 0.69 (0.57-0.78), (iii) 0.69 (0.54-0.81) and (iv) 0.87 (0.83-0.91), respectively. CONCLUSIONS: The M4 model was the best available method for predicting a final outcome of ectopic pregnancy. Developing and validating risk prediction models may optimise the management of PUL. TWEETABLE ABSTRACT: Pregnancy of unknown location meta-analysis: M4 model has best test performance to predict ectopic pregnancy.