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This JAMA Patient Page describes ectopic pregnancy and its risk factors, symptoms, diagnosis, and treatment. [ABSTRACT FROM AUTHOR]

Objective: To assess whether variation in serum human chorionic gonadotropin (hCG) measures, used to assess early gestation viability, are associated with differences in clinical presentation and patient factors.Method: This retrospective cohort study included 285 women with first-trimester pain and bleeding and a pregnancy of unknown location for whom a normal intrauterine pregnancy was ultimately confirmed. Serial samples were collected at three U.S. sites and hCG changes were analyzed for differences by race, ethnicity, and clinical factors. A nonlinear, mixed-effects regression model was used assuming a random subject shift in the time axis.Results: The hCG rise in symptomatic women with ongoing intrauterine pregnancy differs by patient factors and level at presentation. The 2-day minimum (first percentile) rise in hCG was faster when presenting hCG values were low and slower when presenting hCG value was high. African American women had a faster hCG rise (P<.001) compared with non-African American women. Variation in hCG curves was associated with prior miscarriage (P=.014), presentation of bleeding (P<.001), and pain (P=.002). For initial hCG values of less than 1,500, 1,500-3,000 and greater than 3,000 milli-international units/mL, the predicted 2-day minimal (first percentile) rise was 49%, 40%, and 33%, respectively.Conclusion: The rise of hCG levels in women with viable intrauterine pregnancies and symptoms of potential pregnancy failure varies significantly by initial value. Changes in hCG rise related to race should not affect clinical care. To limit interruption of a potential desired intrauterine pregnancy, a more conservative "cutoff" (slower rise) is needed when hCG values are high.Clinical Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00194168. [ABSTRACT FROM AUTHOR]

The evolution of the diagnosis and management of women with an early pregnancy loss has been a success story. The mortality from ectopic pregnancy has objectively been decreased in the past few decades. However, modern management has resulted in a new set of issues. Over-interpretation of a single ultrasound, misunderstanding of the utility of serial hCG values, and inappropriate use of methotrexate can result in iatrogenic complications. Modern management has successfully improved the diagnosis of ectopic pregnancy before rupture; it should now also focus on ensuring that an intrauterine pregnancy is not interrupted as a result of diagnosis and treatment. This article reviews some of the pitfalls of the modern management of early pregnancy failure and introduces a series of articles on the subject. [ABSTRACT FROM AUTHOR]

The article discusses the use of serum biomarkers such as Human chorionic gonadotropin (hCG) in the diagnosis of ectopic pregnancies. The article describes the various new markers that have been proposed as indicators of ectopic pregnancies such as markers of abnormal trophoblast, corpus luteum and inflammatory markers. These include vascular endothelial growth factor (VEGF) and pregnancy associated plasma protein-A PAPP-A). Use of combinations and novel biomarkers has also been discussed.

The incidence of ectopic pregnancies is increasing, which may be related to better diagnostic tools as well as the increasing use of assisted reproductive technologies. However, the signs and symptoms of ectopic pregnancy can be similar to other complications of early pregnancy such as miscarriage. Diagnosis often requires serial human chorionic gonadotropin levels along with ultrasound and, in some cases, dilation and curettage. Once a diagnosis has been made, treatment options include medical therapy with methotrexate and surgery, which can often be performed via the laparoscope. Fertility rates after therapy are similar for both medically and surgically treated patients. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between ectopic pregnancy (EP) and clinical and historical factors among women presenting with pain and/or bleeding in early pregnancy. Design: Nested case–control study. Setting: University medical center. Patient(s): Women with symptomatic early pregnancies of unknown location presenting for care between January 1, 1990 and July 31, 1999. Intervention(s): None. Main Outcome Measure(s): Clinical and historical risk factors were compared between women with EP and women with ongoing intrauterine pregnancies or spontaneous abortions. Result(s): The following factors were associated with increased risk of EP: prior EP (odds ratio, 2.98 [95% confidence interval, 1.88–4.73] for one prior EP and 16.04 [5.39–47.72] for 2 or more), pelvic inflammatory disease history (1.5 [1.11–2.05]), pain at presentation (1.42 [1.06–1.92]), vaginal bleeding at presentation (1.42 [1.04–1.93]), and hCG of 501–2,000 mIU/mL (1.73 [1.24–2.42]). Age younger than 25 years (0.59 [0.41–0.85]) and a history of abortion were protective from EP (0.58 [0.38–0.90]). Prior nontubal pelvic surgery, past intrauterine device use, prior cesarean section, and current cervical infection demonstrated no association with EP. Conclusion(s): Evaluation of women with a symptomatic early pregnancy confirms and refutes some of the classical risk factors for EP. Prior EP is a strong risk factor, whereas pelvic inflammatory disease has an unexpected weak association. Previous abortion was found to have a negative association, whereas nontubal surgery, cesarean section, and a history of or concomitant cervical infection have no association. Knowledge of historical and clinical factors associated with EP may aid in early diagnosis. [Copyright &y& Elsevier]

The article discusses the issues related to ectopic pregnancies. Damaged fallopian tubes from prior tubal surgery or pelvic infection, smoking, and conception using assisted reproduction are predisposing factors to ectopic pregnancies. Symptoms of and risk factors for ectopic pregnancies are enumerated. Diagnostic procedures for ectopic pregnancies are explained.

OBJECTIVE:To evaluate the accuracy of the diagnosis of presumed ectopic pregnancy.METHODS:This was a retrospective cohort analysis at a tertiary care medical center. The patient population was composed of 1) clinically stable pregnant women with human chorionic gonadotropin (hCG) above 2000 mIU/mL and no evidence of an intrauterine pregnancy by ultrasound, or 2) women with an abnormal rise or fall of serial hCG below 2000 mIU/mL. Outcome was determined by pathologic evidence of chorionic villi in the endometrial curettings (or fallopian tube), or complete resolution of hCG.RESULTS:Overall, 38.4% (43/112) of the women were diagnosed with a miscarriage and 61.6% (69/112) were found to have an ectopic pregnancy. No significant difference was found in race, age, gravity, parity, hCG trends, or time to diagnosis between women with ectopic pregnancies and those with miscarriages. Patients were more likely to be diagnosed with an ectopic pregnancy if the initial hCG value was below the discriminatory zone (relative risk 2.44; 95% confidence interval 1.07, 5.52). Ultrasound correlated well with the final diagnosis (P = .001) but was not definitive.CONCLUSION:In an effort to save time, avoid dilation and curettage (D&C), and treat with methotrexate, the presence of an ectopic pregnancy is often presumed. The presumed diagnosis of ectopic pregnancy is inaccurate in almost 40% of cases. A D&C is necessary to differentiate an ectopic pregnancy from a miscarriage before a woman is presumptively treated with methotrexate. [Copyright &y& Elsevier]

Infertility has long-term effects beyond the inability to conceive. Infertility may be a harbinger of future disease and altered longevity. Understanding the mechanisms of how fertility is a window to health opens new avenues of important investigation addressing interdependent physiologic processes. Identification of healthy persons at risk for future cardiovascular disease, diabetes, or cancer could allow a change in reproductive medical care by altering long-term surveillance and reduction of risk. [ABSTRACT FROM AUTHOR]

To verify the accuracy of an online algorithm using Bayes' theorem for diagnosing ectopic pregnancy (EP) using human chorionic gonadotropin (hCG), ultrasound, and clinical data in a real cohort. A retrospective cohort study. Gynecologic emergency unit in a tertiary teaching hospital. First-trimester pregnant women who attended the gynecologic emergency unit for any reason. Those who had <13 weeks of pregnancy confirmed by a recent positive pregnancy test; a digital image or electronic report of transvaginal ultrasound (TVUS) obtained from hospital database; and a follow-up with a pathology report or a clinical resolution of a confirmed pregnancy were included in the study. Clinical signs and symptoms, the presence of risk factors for EP, the TVUS findings in each consultation, and the hCG levels were independent variables obtained from the electronic medical records. From these data, the pretest probability, based on the clinical presentation and risk factors, and the likelihood ratio for each variable were calculated for their use in the algorithm, yielding a posttest probability. Not applicable. The accuracy of the online algorithm to identify cases of EP using clinical signs and symptoms, the presence of risk factors for EP, the TVUS findings in each consultation, and the hCG levels. The main outcome was EP, confirmed either by pathology report or by the presence of fetal heartbeat or gestational sac outside the uterine cavity. Between January 1, 2009 and December 27, 2016, 2,495 women were analyzed, and the algorithm was applied to 2,185 of them. The incidence of EP was 8.5% (212/2,495); 310 women were excluded because they were submitted to surgery with decision thresholds <95%. The algorithm was applied to 2,185 women. Just one case remained inconclusive after 3 consultations, and it was considered as an error in prediction. The sensitivity, specificity, and accuracy values (95% confidence interval) of the algorithm were 98.9% (96.1%–99.8%), 98.9% (98.3%–99.2%), and 98.9% (98.3%–99.2%), respectively. The accuracy of the Bayesian algorithm to confirm or rule out EP is excellent. Online Nomogram https://docs.google.com/spreadsheets/d/1jStXlMBjbPyDf6_W0deKGKQLZHU5EFAe8rLhNVPuJuY/edit?usp=sharing [ABSTRACT FROM AUTHOR]

Objective: We sought to determine utility of uterine evacuation for diagnosis of nonviable pregnancy of unknown location (PUL). Study Design: We conducted a cohort study to assess the prevalence of ectopic pregnancy (EP), overall, and stratified by presenting signs and symptoms in women with a nonviable PUL. Results: Of the 173 women, 66 (38%) had miscarriage (spontaneous abortion [SAB]) and 107 (62%) had EP. When initial human chorionic gonadotropin (hCG) was <2000 mIU/mL, the odds of an EP were greater (odds ratio, 4.32; 95% confidence interval, 2.04–9.12). Demographic factors, obstetric history, and clinical presentation were not useful in distinguishing between EP and SAB. Pre-evacuation hCG increase had strong trend association with EP (odds ratio, 2.14; 95% confidence interval, 0.98–4.68). A >30% fall in postcurettage hCG was suggestive, but was not a diagnostic indicator of SAB. Conclusion: Uterine evacuation is a useful diagnostic aid for women with nonviable PUL. Nondiagnostic ultrasound findings and absolute and serial hCG values are associated with, but do not accurately predict final diagnosis. [ABSTRACT FROM AUTHOR]

Objective: To examine the impact of validation and temporal resolution of estimation of hCG increase, because patients' hCG values are not obtained at precise daily increments or always in the same laboratory.Design: Retrospective cohort study of women presenting with nondiagnosed symptomatic first-trimester pregnancies who had serial hCG level measurements over time.Setting: Not applicable.Patient(s): A total of 171 women presenting from September 2007 to February 2010 with first-trimester pregnancy pain and/or bleeding for whom a normal intrauterine pregnancy was ultimately confirmed.Interventions: None.Main Outcome Measure(s): Serial hCG values, time period between hCG measurements, hCG rise.Result(s): After data verification, 118 subjects contributing 327 values met inclusion criteria and passed data verification for analysis with improved temporal precision. The more precise data showed a steeper hCG rise, and the predicted 2-day hCG increase at the 1st percentile was slightly faster (1.68-fold vs. 1.56-fold) than the "raw" clinical data and previous models.Conclusion(s): Data verification and improved temporal precision suggested a faster hCG increase in early intrauterine gestation than previously demonstrated. Because laboratory variation and temporal imprecision are common, these data demonstrate that current modeling of the expected rise of hCG in a normal gestation is valid and appropriately conservative in the determination of a nonviable gestation. No change in the minimal threshold for potential viability is recommended. [ABSTRACT FROM AUTHOR]

Objective: To determine if the pattern of decline in hCG curves can discriminate spontaneous abortion (SAB) from ectopic pregnancy (EP). Design: Retrospective cohort study. Setting: University hospitals. Patient(s): A total of 1,551 women with symptomatic pregnancy of unknown location (PUL) and decreasing hCG values. Intervention(s): None. Main Outcome Measure(s): Percentage change in hCG; days and visits to final diagnosis. Result(s): Of the 1,551 women with a PUL and declining hCG, 146 were ultimately diagnosed with EP and 1,405 with SAB. An 85% hCG drop within 4 days or a 95% hCG drop within 7 days both ruled out an EP 100% of the time. Applying the 4-day cutoff to this population would have saved 16% of the SAB population (229/1,405) a total of 2,841 person-days and 277 clinical visits. Applying the 7-day cutoff would have saved 9% of the SAB population (126/1,405) a total of 1,294 person-days and 182 clinical visits. These cutoffs were separately validated on a group of 179 EPs collected from three university clinical centers. In that population, each cutoff separately ruled out EP 100% of the time. Conclusion(s): The decline in serum hCG is slower in EPs than in SAB and can be used to aid clinicians in the frequency and duration of follow-up. Costs and patient time may be saved by allowing women who meet one of these criteria to be followed less frequently. [ABSTRACT FROM AUTHOR]

Objective: To determine if Chlamydia trachomatis (C. trachomatis) seropositivity, as detected by the C. trachomatis elementary body (EB)-based enzyme-linked immunosorbent assay [EB ELISA] predicts pregnancy and pregnancy outcome among infertile women with documented tubal patency.Design: Cohort study.Setting: Outpatient clinics.Patient(s): In all, 1,250 infertile women with documented tubal patency enrolled in 1 of 2 randomized controlled trials: Pregnancy in Polycystic Ovary Syndrome II; and the Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation.Intervention(s): Sera were analyzed for anti-C. trachomatis immunoglobulin G (IgG)1 and IgG3 antibodies, using a research C. trachomatis EB ELISA. The optical density (OD)405 readings of ≥ 0.35 and ≥ 0.1 were considered positive for IgG1 and IgG3, respectively.Main Outcome Measure(s): Primary outcomes included pregnancy, live birth, and ectopic pregnancy. Log-linear regression was used to determine the relative risk after adjusting for age, race, treatment medication, smoking status, and current alcohol use.Result(s): A total of 243 (19%) women were seropositive for anti-C. trachomatis IgG3. They tended to be nonwhite and smokers. Anti-C. trachomatis IgG3 seropositive women were significantly less likely to conceive (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.52-0.83) or to have a live birth (RR 0.59, 95% CI 0.43-0.80); these associations were weakened after adjusting for number of hysterosalpingography-documented patent tubes (RR 0.73, 95% CI 0.56-0.97) and (RR 0.73, 95% CI 0.50-1.04), respectively. Anti-C. trachomatis IgG3 seropositive women who conceived had a ×2.7 risk (95% CI 1.40-5.34) of ectopic pregnancy.Conclusion(s): Even in the presence of tubal patency, anti-C. trachomatis IgG3 seropositivity is associated with a lower likelihood of pregnancy. Anti-C. trachomatis IgG3 seropositive women have as high as 3 times the risk of ectopic pregnancy.Clinical Trial Registration Number: PPCOSII: NCT00719186 and AMIGOS: NCT01044862. [ABSTRACT FROM AUTHOR]

Unlabelled: Many clinical investigators think that the burden of Institutional Review Board (IRB) requirements has been consistently increasing over recent years, although there are few objective data describing these trends. Over a period of 7 years, the Reproductive Medicine Network observed a significant increase in the size and requirements of IRB submissions and significant variability of IRB performance in reviewing multicenter trials. These additional regulatory and administrative demands represent substantial burdens to researchers and to the IRBs themselves. It is timely to consider whether these changes better protect the interests and safety of human research participants.Clinical Trial Registration: ClinicalTrials.gov NCT00068861 and NCT00719186. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether a combination of putative markers of inflammation and CA-125 could serve as a multiple-marker screening test for endometriosis in a heterogeneous population of patients.Design: Case-control evaluation of a diagnostic test.Setting: University medical center.Patient(s): Consenting women of reproductive age undergoing laparoscopy for indications of pain, infertility, elective tubal ligation, tubal reanastomosis, or other benign indications.Intervention(s): Diagnostic laparoscopy and peripheral venipuncture.Main Outcome Measure(s): Serum concentrations of interleukin-6, tumor necrosis factor-alpha, macrophage migration inhibitory factor, macrophage chemotactic protein-1, interferon-gamma, leptin, and CA-125 measured by using ELISA assays; surgical staging of endometriosis.Result(s): Concentrations of the seven markers were compared between the 63 women with surgically confirmed stage II-IV endometriosis and 78 women who were surgically confirmed to be free of endometriosis. The individual diagnostic performance of each of the markers, based on receiver operating characteristic curves, was poor. When combinations of markers were evaluated by using classification tree analysis, a three-marker panel of CA-125, macrophage chemotactic protein-1, and leptin could diagnose 51% of subjects as to the presence of endometriosis with 89% accuracy. A four-marker panel of CA-125, macrophage chemotactic protein-1, leptin, and macrophage migration inhibitory factor could diagnose 48% of subjects with 93% accuracy. The remaining subjects would have no definitive diagnosis on the basis of the algorithm and would need to undergo standard evaluation.Conclusion(s): This large study evaluates the combined use of putative serum markers for the diagnosis of endometriosis, rather than the use of each singly. Using the serum concentration of four markers in a two-tiered decision rule, nearly half of the subjects in this population would have been diagnosed (and could have avoided surgery) with 93% accuracy. [ABSTRACT FROM AUTHOR]

Based on a recent review of the medical literature, a clinical diagnosis of infertility may not agree with strict criteria. Standardized definitions of diagnostic categories are essential for accurate patient prognosis and future research. [Copyright &y& Elsevier]

Objective: To predict first trimester pregnancy outcome using biomarkers in a multicenter cohort.Design: Case-control study.Setting: Three academic centers.Patient(s): Women with pain and bleeding in early pregnancy.Intervention(s): Sera from women who were 5-12 weeks' gestational age with ectopic pregnancy (EP), viable intrauterine pregnancy (IUP), and miscarriage/spontaneous abortion (SAB) was analyzed by ELISA and immunoassay for activin A, inhibin A, P, A Disintegrin And Metalloprotease-12, pregnancy-associated plasma protein A (PAPP-A), pregnancy specific B1-glycoprotein (SP1), placental-like growth factor, vascular endothelial growth factor, glycodelin (Glyc), and hCG. Classification trees were developed to optimize sensitivity/specificity for pregnancy location and viability.Main Outcome Measure(s): Area under receiver operating characteristic curve, sensitivity, specificity, and accuracy of first trimester pregnancy outcome.Result(s): In 230 pregnancies, the combination of trees to maximize sensitivity and specificity resulted in 73% specificity (95% confidence interval (CI) 0.65-0.80) and 31% sensitivity (95% CI 0.21-0.43) for viability. Similar methods had 21% sensitivity (95% CI 0.12-0.32) and 33% specificity (95% CI 0.26-0.41) for location. Activin A, Glyc, and A Disintegrin And Metalloprotease-12 definitively classified pregnancy location in 29% of the sample with 100% accuracy for EP. Progesterone and PAPP-A classified the viability in 61% of the sample with 94% accuracy.Conclusion(s): Multiple marker panels can distinguish pregnancy location and viability in a subset of women at risk for early pregnancy complications. This strategy of combining markers to maximize sensitivity and specificity results in high accuracy in a subset of subjects. Activin A, ADAM12, and Glyc are the most promising markers for pregnancy location; P and PAPP-A for viability. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of endometriosis, alone or in combination with other infertility diagnoses, on IVF outcomes.Design: Population-based retrospective cohort study of cycles from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database.Setting: Not applicable.Patient(s): A total of 347,185 autologous fresh and frozen assisted reproductive technology cycles from the period 2008-2010.Intervention(s): None.Main Outcome Measure(s): Oocyte yield, implantation rate, live birth rate.Result(s): Although cycles of patients with endometriosis constituted 11% of the study sample, the majority (64%) reported a concomitant diagnosis, with male factor (42%), tubal factor (29%), and diminished ovarian reserve (22%) being the most common. Endometriosis, when isolated or with concomitant diagnoses, was associated with lower oocyte yield compared with those with unexplained infertility, tubal factor, and all other infertility diagnoses combined. Women with isolated endometriosis had similar or higher live birth rates compared with those in other diagnostic groups. However, women with endometriosis with concomitant diagnoses had lower implantation rates and live birth rates compared with unexplained infertility, tubal factor, and all other diagnostic groups.Conclusion(s): Endometriosis is associated with lower oocyte yield, lower implantation rates, and lower pregnancy rates after IVF. However, the association of endometriosis and IVF outcomes is confounded by other infertility diagnoses. Endometriosis, when associated with other alterations in the reproductive tract, has the lowest chance of live birth. In contrast, for the minority of women who have endometriosis in isolation, the live birth rate is similar or slightly higher compared with other infertility diagnoses. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the performance of a novel biomarker, a disintegrin and metalloprotease-12 (ADAM-12), to differentiate an ectopic pregnancy (EP) from normal intrauterine pregnancies (IUPs).Design: Case-control study.Setting: Three urban academic centers.Patient(s): Women who were seen in the emergency department with pain or bleeding in the first trimester of pregnancy.Intervention(s): Sera from women with diagnosed EP or IUP were evaluated via proteomics and an ADAM-12 dissociation-enhanced lanthanide fluoroimmunoassay.Main Outcome Measure(s): Differences between groups, area under the receiver operating curve, sensitivity, and specificity.Result(s): Via a proteomics evaluation, we found a statistically significant decrease in ADAM-12 in the sera of patients with EP, which we confirmed in a larger group of 199 patients (median IUP 18.6 ng/mL versus median EP 2.5 ng/mL with good discrimination between the groups as assessed by receiver operating characteristics [area under the curve = 0.82]). At a low cut-point, the sensitivity was 70% and specificity 84%, but, at a higher cut-point optimizing sensitivity, the ADAM-12 test demonstrated a sensitivity of 97%.Conclusion(s): ADAM-12 is a promising marker for the diagnosis of EP in women with symptoms in the first trimester, validating the proteomics findings. Further studies in additional patient populations and in combination with other biomarkers are needed. [ABSTRACT FROM AUTHOR]