Persistent Pregnancy Of Unknown Location Research Articles

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

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. 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. 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 by0.03 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. 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.

Safety of methotrexate administration in women with pregnancy of unknown location deemed to have high risk of ectopic pregnancy.

This study evaluates the safety of current guidelines on methotrexate (MTX) administration in women with pregnancy of unknown location (PUL) who are considered to have high risk of underlying ectopic pregnancy (EP) and to investigate whether this would result in inadvertent exposure of MTX to viable intra-uterine pregnancy (IUP). A retrospective observational study was conducted on clinically stable women who were classified PUL at Early Pregnancy Unit, Nepean Hospital, between 2007 and 2021. PUL is defined as when a woman presents with a positive pregnancy test but has no signs of IUP or EP on the transvaginal ultrasound (TVS). If patients with a PUL behave biochemically like an EP but the location is not confirmed on ultrasound, these women are eligible for MTX to minimize the risk of subsequent tubal rupture.Criteria discussed in the guidelines of American College of Obstetricians and Gynaecologists (ACOG),American Society for Reproductive Medicine (ASRM),Royal College of Obstetricians & Gynaecologists(RCOG)and National Institute for Health Care Excellence (NICE)were applied to the collected PUL database. The number of patients eligible to receive MTX and the number of women with underlying viable IUP who would be inadvertently given MTX were calculated. A total of 816 consecutive women with PUL were reviewed, and 724 had complete data and were included in the final analysis. 6 patients were persistent PULs,and 718 fell among outcomes of 4 subgroups: viable IUP, non-viable IUP, EP, failed PUL. According to the ACOG, ASRM, RCOG and NICE, the rate of possible MTX administration among patients with a PUL is 2.76%, 4.56%, 0.41% and 35.36%, respectively. However, no single persistent-PUL would have received MTX according to the above protocols, and majority of the MTX treatment were unnecessary because those patients were classified as NVIUP or FPUL later. More importantly, ACOG and ASRM could theoretically result in inadvertent MTX administration to women with an underlying IVUP at rates of 4.1/1000 (3/724). Current guidelines used to predict high risk of EP among PUL population are not safe enough to avoid inadvertent MTX administration to women with an underlying viable IUP.These guidelines need to be wisely used to ensure that no wanted pregnancy is exposed to MTX. Women with PULs should be carefully monitored and MTX should be used with judicious care when the location of pregnancy is yet to be confirmed. This article is protected by copyright. All rights reserved.

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

To compare Expectant management to systemic methotrexate in the management of persistent pregnancy of unknown location with beta-hCG levels below the discrimination zone. 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. 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). Expectant management is an effective and safe alternative to single-dose methotrexate for persistent PUL with beta-hCG levels below the discrimination zone.

Primary Hepatic Ectopic Pregnancy: Diagnosis and Laparoscopic Management

To demonstrate and discuss a case of primary hepatic ectopic pregnancy and laparoscopic management. Case presentation with demonstration of surgical hepatic wedge resection. Tertiary referral center in Manchester, United Kingdom. A 33-year-old women gravida 13 para 2 with a body mass index of 55 kg/m2 and previous 2 cesarean sections and a laparoscopic cholecystectomy presented to the emergency services after a private ultrasound scan showing a pregnancy of unknown location and a serum human chorionic gonadotropin (hCG) of 18 336 IU/mL. A diagnostic laparoscopy was performed but fallopian tubes were normal with no signs of ectopic pregnancy seen. An abdominal ultrasound scan was performed but did not identify the ectopic pregnancy. Owing to worsening symptoms of pain and rising hCG levels, she underwent a further laparoscopy converted to laparotomy and a left salpingo-oophorectomy for suspected left ovarian pregnancy. However, serum hCG levels continued to rise after the surgery, reaching 36 960 IU/mL. An magnetic resonance imaging scan of her abdomen and pelvis was arranged that showed a 4 cm cystic lesion in the segment V of the liver. Further ultrasound correlation showed a hyperechoic lesion with echogenic components suspicious of an ectopic pregnancy with a fetal pole. Fetal heart action was not visualized. A multidisciplinary team approach was adopted with involvement of the hepatobiliary surgical team, and the option of medical management with methotrexate and surgical excision was considered. A decision was made for surgical excision based on the accessible location of the ectopic pregnancy on segment V and the more controlled and predictable outcome with surgical excision. A preoperative computed tomography scan confirmed the lesion in segment V of liver in keeping with liver capsular implantation of ectopic pregnancy (Video still 1). At laparoscopy the ectopic pregnancy was visualized on the inferior surface of liver close to the inferior margin with a band of overlying omental adhesion (Video still 2). The overlying omental adhesions were sealed and cut with advanced bipolar diathermy, keeping a safe margin from the ectopic pregnancy to minimize any bleeding. The liver capsule was then opened with monopolar diathermy, and the small segment of liver with the ectopic pregnancy was excised using a combination of Bowa-Lotus liver blade (Bowa Medical Ltd). Hemostasis was controlled using Floseal hemostatic matrix and applied pressure laparoscopically. Total operating time was 80 minutes with an estimated blood loss of 500 mL. The patient was discharged on day 3 postoperatively, and follow-up serum hCG excluded residual trophoblastic disease. On review of the clinical case, earlier imaging of the upper abdomen when confronted by a persistent pregnancy of unknown location with high levels of serum hCG would have prevented the second laparoscopy, laparotomy, and salpingo-oophorectomy. In similar cases, it would also help exclude poorly differentiated malignancies as a source of serum hCG. Only 27 cases of ectopic pregnancy on the liver have been identified in English literature since 1952, based on a MEDLINE and Embase enquiry and further review of all case reports by the authors to avoid duplicates. Estimated incidence of hepatic implantation is 1 in 15 000 pregnancies; 4 case reports of laparoscopic liver resection have been identified and another case managed by suction from the liver surface [1,2]. The key principle demonstrated is to resect the ectopic pregnancy with a safe margin of liver tissue and any adhesions to avoid catastrophic bleeding from direct handling of the ectopic pregnancy.

Frequency of outcomes of patients with pregnancy of unknown location at a tertiary care hospital.

Background: A pregnancy of unknown location (PUL) is said to occur when empty uterus is seen on a Transvaginal Scan in a female with a positive pregnancy test with absence of signs of an intrauterine pregnancy (IUP) or an ectopic pregnancy. Aim: To determine the frequency of outcomes of patients with pregnancy of unknown location at a tertiary care hospital. Methods: The study was carried out at Department of Obstetrics &amp;Gynecology, Lady Willingdon hospital, Lahore. It was a Descriptive case series conducted from 2021 to May 2022. 160 subjects meeting the inclusion criteria were enrolled in the study. A thorough history was obtained and levels of serum Beta-HCG recorded. Serum beta HCG levels of 25IU/L represented a positive pregnancy test. The follow up consisted of monitoring serum beta HCG levels after 48 hours and evaluation of findings of transvaginal ultrasound. The females were followed till they were placed in the category of failing PUL, an intrauterine pregnancy or an ectopic pregnancy. Data was collected from women categorized as having a PUL. Results: In this trial, of 160 cases, it was seen that 109(68.13%) had amenorrhea whereas 51(31.87%) had bleeding at the time of presentation. Frequency of outcomes of patients with pregnancy of unknown location showed that 75(46.88%) had failing PUL, 19(11.87%) had ectopic pregnancy, 15(9.38%) had persistent PUL and 51(31.87%) had intrauterine pregnancy. Conclusion: Failing PUL was the leading entity in cases of pregnancy of s unknown location followed by ectopic pregnancy and persistent PUL. However, this data is primary and needs validation through some other local trials. Keywords: Pregnancy of unknown location, outcome, failing PUL, ectopic pregnancy, persistent PUL

VP01.14: Safety of methotrexate on women with a persistent pregnancy of unknown location: a retrospective observational study

VP01.14: Safety of methotrexate on women with a persistent pregnancy of unknown location: a retrospective observational study

Persistent Pregnancy of Unknown Location: Which Strategy Is Best?

Among women presenting with early pregnancies, ultrasound often fails to identify the implantation site. In one third of such pregnancies, monitoring

Active Treatment or No Treatment (ACT or NOT) for Persisting Pregnancy of Unknown Location;&amp;nbsp; A Randomized Clinical Trial

Background: Women in early gestation without a pregnancy visualized on ultrasound and serial hCG values consistent with a nonviable gestation are at high risk for ectopic pregnancy. The goal of this trial was to determine if active management is superior to expectant management, and if two active management strategies are non-inferior. Methods: This multi-center study, 255 women with a persistent pregnancy of unknown location were randomized to expectant management or active management in a 1:2 ratio, and 1:1 within active management to a) uterine evacuation followed by methotrexate if needed or b) empiric methotrexate. The primary outcome was successful resolution of the pregnancy without change from initial strategy. Findings: Women treated with active management had a significantly higher percentage of successful resolution, Rate ratio 1·43 (1·04–1·96) intention to treat (ITT) and 1·64 (1·39–1·94) as treated (AT) and a lower rate of unscheduled surgery RR 0·43 (0·25-0·74) ITT and 0·24 (0·11-0·55) AT. Methotrexate was non-inferior to uterine evacuation (difference=6·6% (-8.4% to 21.6%) ITT. As treated, time to resolution was 8·1 days shorter after uterine evacuation compared to methotrexate. All strategies were safe and were rated with high acceptability and satisfaction. Women expressed a preference for expectant management with differential cross-over within this trial. Interpretation: A greater percentage of women achieved uneventful resolution with active management compared to expectant management with at least a 50% reduction in unscheduled interventions. Uterine evacuation resulted in a shorter time to resolution. Acceptability and safety of treatment were high for all strategies, but subjects expressed a preference for expectant management. Trial Registration: The trial was performed under IND #56407 and clinical trial registration number NCT02152696. Funding Statement: This work was supported by the National Institutes of Health (NIH)/ Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Declaration of Interests: Dr. Barnhart reports consulting fees to Swiss Precision Diagnostics and Bayer. Dr. Hansen reports research grants from Roche Diagnostics and Ferring outside of the submitted work. Dr. Diamond reports institutional grants/contracts from Bayer, ObsEva, and AbbVie; serving as a member of the Board of Directors and a stockholder of Advanced Reproductive Care; and serving as a Consultant for Seikagaku, Actamax, AEGEA, Temple Therapeutics, and ARC Medical Devices. Dr. Steiner reports consulting fees from Seikagaku and Prima-Temp. Dr. Cedars reports research funding from Ferring Pharmaceuticals outside of the submitted work. Dr. Wild reports Ablacare PCOS, Amgen Repatha in Pg and Partners Mass General Menopause Reviews, outside of the submitted work. Dr Hoeger reports consultation to Bayer and Ablacare and research funding from Abbvie. Dr. Krawetz reports a research grant from Merck outside of the submitted work. Dr. Santoro reports consulting for Ansh Lab, and is a Scientific Advisor to Astellas and Menogenix, Inc. Ethics Approval Statement: The protocol was approved by a National Institutes of Health appointed advisory board and a data and safety monitoring board. The University of Pennsylvania served as single IRB (IRB # 815013).

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

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. To validate the M4 model's ability to correctly classify PULs in a cohort of Australian women. 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. 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%). 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.

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

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 (Step2). 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. 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. 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. 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.

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). 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. 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. P1 and M4 performed similarly with respect to diagnostic accuracy in predicting PUL outcome. P1 needs to be externally validated.

Prediction of Tubal Ectopic Pregnancy Using Offline Analysis of 3-Dimensional Transvaginal Ultrasonographic Data Sets: An Interobserver and Diagnostic Accuracy Study.

To assess interobserver reproducibility in detecting tubal ectopic pregnancies by reading data sets from 3-dimensional (3D) transvaginal ultrasonography (TVUS) and comparing it with real-time 2-dimensional (2D) TVUS. Images were initially classified as showing pregnancies of unknown location or tubal ectopic pregnancies on real time 2D TVUS by an experienced sonologist, who acquired 5 3D volumes. Data sets were analyzed offline by 5 observers who had to classify each case as ectopic pregnancy or pregnancy of unknown location. The interobserver reproducibility was evaluated by the Fleiss κ statistic. The performance of each observer in predicting ectopic pregnancies was compared to that of the experienced sonologist. Women were followed until they were reclassified as follows: (1) failed pregnancy of unknown location; (2) intrauterine pregnancy; (3) ectopic pregnancy; or (4) persistent pregnancy of unknown location. Sixty-one women were included. The agreement between reading offline 3D data sets and the first real-time 2D TVUS was very good (80%-82%; κ = 0.89). The overall interobserver agreement among observers reading offline 3D data sets was moderate (κ = 0.52). The diagnostic performance of experienced observers reading offline 3D data sets had accuracy of 78.3% to 85.0%, sensitivity of 66.7% to 81.3%, specificity of 79.5% to 88.4%, positive predictive value of 57.1% to 72.2%, and negative predictive value of 87.5% to 91.3%, compared to the experienced sonologist's real-time 2D TVUS: accuracy of 94.5%, sensitivity of 94.4%, specificity of 94.5%, positive predictive value of 85.0%, and negative predictive value of 98.1%. The diagnostic accuracy of 3D TVUS by reading offline data sets for predicting ectopic pregnancies is dependent on experience. Reading only static 3D data sets without clinical information does not match the diagnostic performance of real time 2D TVUS combined with clinical information obtained during the scan.

Accuracy of Ultrasonography in Detecting Ectopic Pregnancy

To determine the accuracy of ultrasonography in detecting ectopic pregnancy. Prospective review of the outcome of women presenting with suspected ectopic pregnancy from June 2015 to December 2016, and who underwent ultrasonography in a single institution, was performed. The ultrasound findings were categorized as intrauterine pregnancy, miscarriage, ectopic pregnancy or pregnancy of unknown location. Women with pregnancy of unknown location were followed up to determine the location of the pregnancy. Those who default follow-up and persistent pregnancy of unknown location were excluded. The final outcome was confirmed either through surgical findings or follow-up obstetric ultrasound scans. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) with 95% confidence intervals (CIs) for the diagnosis of ectopic pregnancy were assessed each month. From June 2015 to December 2016, there were 2315 consecutive women who were suspected of ectopic pregnancy. Outcome data were available for 1729 (74.7%) women. The accuracy of ultrasound scan in detecting ectopic pregnancy ranges from 96.8% to 100%. There were 529 confirmed ectopic pregnancies and 1200 had either intrauterine pregnancies or miscarriages. The overall sensitivity for ultrasound in detecting ectopic pregnancy was 98.87% (95% CI: 97.55-99.58) with a specificity of 99.0% (95% CI: 98.26-99.48), a positive predictive value of 97.76% (95% CI: 96.13-98.71) and a negative predictive value of 99.5% (95% CI: 98.89-99.77). In women who are suspected of ectopic pregnancy, 98.9% of ectopic pregnancies can be accurately diagnosed by ultrasonography.

Association between three-dimensional transvaginal sonographic markers and outcome of pregnancy of unknown location: a pilot study.

To assess the accuracy of three-dimensional (3D) transvaginal sonographic (TVS) parameters in predicting the evolution of a pregnancy of unknown location (PUL). This was a prospective observational study performed at the early pregnancy unit of a university hospital from September 2008 to June 2012. Women with a positive pregnancy test without any signs of intra- or extrauterine pregnancy at their first TVS examination were considered eligible and a 3D dataset containing the entire uterus was acquired. An experienced observer analyzed all 3D datasets for assessment of the following parameters: endometrial thickness, volume, mean gray-scale index and asymmetry. Women were followed until they were classified as having: (i) non-visualized pregnancy loss (NVPL); (ii) intrauterine pregnancy (IUP); or (iii) ectopic pregnancy or persistent PUL. We compared the values of the TVS parameters across the three groups. We also assessed the area under the receiver-operating characteristics curve of the 3D-TVS parameters in comparison to that for serum β-human chorionic gonadotropin (β-hCG) ratio (48 h/baseline) to predict PUL outcome. We then evaluated whether combining the 3D-TVS parameters with serum β-hCG ratio improved the predictive accuracy for PUL outcome by performing a logistic regression analysis. During the study period 4939 consecutive pregnant women presented at the unit for their initial TVS examination and 325 (7%) were classified as having a PUL, of whom 161 women were enrolled and had a 3D scan of the uterus. However, 19 were excluded because of incomplete follow-up. Data from 142 women with PUL were therefore included in the analysis and the outcomes of these women were: NVPL in 98 (69%), IUP in 27 (19%) and ectopic pregnancy + persistent PUL in 14 + 3 = 17 (12%). Endometrial thickness, endometrial volume and the proportion of women with asymmetric endometrial shape differed significantly between the outcome groups. Endometrial thickness and volume could be used as reasonable predictors of both NVPL and IUP, whereas asymmetric endometrial shape and mean gray-scale index could be used as reasonable predictors of IUP only. The best single parameter to predict PUL outcomes was the β-hCG ratio. Regression analysis demonstrated that endometrial volume and endometrial shape asymmetry added significantly to the β-hCG ratio in predicting IUP but not NVPL. 3D-TVS markers have a low diagnostic accuracy in predicting PUL outcome. The addition of endometrial volume and shape asymmetry improves the accuracy of the β-hCG ratio in predicting IUP. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

The clinical performance of the M4 decision support model to triage women with a pregnancy of unknown location as at low or high risk of complications.

What are the adverse outcomes associated with using the M4 model in everyday clinical practice for women with pregnancy of unknown location (PUL)? There were 17/835 (2.0%) adverse events and no serious adverse events associated with the performance of the M4 model in clinical practice. 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). 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. 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. 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. 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. 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. None. Not applicable.

Frozen-thawed embryo transfer is associated with a significantly reduced incidence of ectopic pregnancy

To compare the incidence of ectopic pregnancy (EP) after fresh ET and thawed ET. Retrospective cohort study. Private fertility center. This retrospective study included 2,150 blastocyst transfers, including all 1,460 fresh autologous blastocyst transfers and all 690 transfers of autologous blastocysts derived from post-thaw extended culture of thawed bipronuclear oocytes in the 8-year study period 2004-2011. None. Visualized EP and treated persistent pregnancy of unknown location. The rate of visualized EP was 1.5% in pregnancies in fresh autologous cycles, which was significantly more than the rate of 0 with autologous post-thaw extended culture. The rates of treated persistent pregnancy of unknown location were 2.5% and 0.3% in these two groups, respectively, a difference that was also statistically significant (relative risk 7.3, 95% confidence interval 1.7-31.0). Relative to fresh transfer, thawed ET was associated with significantly reduced incidence of EP. These findings are consistent with ovarian stimulation increasing the risk of EP.

Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome

To improve the interpretation of future studies in women who are initially diagnosed with a pregnancy of unknown location (PUL), we propose a consensus statement with definitions of population, target disease, and final outcome. A review of literature and a series of collaborative international meetings were used to develop a consensus for definitions and final outcomes of women initially diagnosed with a PUL. Global differences were noted in populations studied and in the definitions of outcomes. We propose to define initial ultrasound classification of findings into five categories: definite ectopic pregnancy (EP), probable EP, PUL, probable intrauterine pregnancy (IUP), and definite IUP. Patients with a PUL should be followed and final outcomes should be categorized as visualized EP, visualized IUP, spontaneously resolved PUL, and persisting PUL. Those with the transient condition of a persisting PUL should ultimately be classified as nonvisualized EP, treated persistent PUL, resolved persistent PUL, or histologic IUP. These specific categories can be used to characterize the natural history or location (intrauterine vs. extrauterine) of any early gestation where the initial location is unknown. Careful definition of populations and classification of outcomes should optimize objective interpretation of research, allow objective assessment of future reproductive prognosis, and hopefully lead to improved clinical care of women initially identified to have a PUL.