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The levonorgestrel 52-mg intrauterine device significantly improved heavy menstrual bleeding in a population that included participants with severe obesity and nulliparous participants. OBJECTIVE: To evaluate heavy menstrual bleeding treatment outcomes with levonorgestrel 52-mg intrauterine device (IUD) use in participants without body mass index (BMI) or parity restrictions. METHODS: Investigators included participants aged 18–50 years with no pelvic or systemic pathology causing heavy menstrual bleeding at 29 U.S. centers in a prospective trial. Participants had up to three screening cycles with menstrual product collection for alkaline hematin blood-loss measurements. Investigators enrolled those with two menses with blood loss of 80 mL or more (values averaged for baseline blood loss), placed the IUD, and followed participants for up to six 28-day cycles. Participants collected any menstrual products used during cycles 3 and 6 for blood-loss measurement. We evaluated outcomes in participants with at least one follow-up assessment for the primary outcome of median absolute blood-loss change and, secondarily, treatment success , defined as the proportion with a final measured blood loss less than 80 mL and at least 50% reduction from baseline. We evaluated exploratory outcomes of differences in blood-loss changes by BMI and parity using Wilcoxon rank sum test. RESULTS: Of 105 enrolled participants, 47 (44.8%) had obesity (BMI 30.0 or higher) and 29 (27.6%) were nulliparous. Baseline mean blood loss ranged from 73 to 520 mL (median 143 mL, interquartile range 112–196 mL). Eighty-nine (84.8%) had at least one evaluable follow-up evaluation. Participants had median (interquartile range) absolute blood-loss decreases at cycles 3 (n=86) and 6 (n=81) of 93.3% (86.1–97.7%) and 97.6% (90.4–100%), respectively. At cycle 6, participants without obesity (n=43) and with obesity (n=38) had similar median [interquartile range] decreases (97.6% [91.8–100%] and 97.5% [90.3–100%], respectively; P =.89), with comparable findings for nulliparous (n=25) and parous (n=56) participants (97.0% [91.7–99.1%] and 98.1% [89.9–100%], respectively; P =.43). Treatment success occurred in 81.8% (95% CI 74.2–89.4%) of 99 participants, excluding those with no outcomes due to lost to follow-up or consent withdrawal, and did not vary by BMI or parity. The most common adverse events leading to discontinuation were bleeding or cramping (n=6 [5.7%]) and expulsion (n=5 [4.8%]). CONCLUSION: This levonorgestrel 52-mg IUD reduces blood loss by more than 90% over 6 months compared with baseline for most users with heavy menstrual bleeding. FUNDING SOURCE: Medicines360. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03642210. [ABSTRACT FROM AUTHOR]

Importance: Women with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities.Objective: To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed.Design, Setting, and Participants: This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019).Interventions: Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82).Main Outcomes and Measures: The primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of -12%.Results: Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, -8.4% to ∞]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%).Conclusions and Relevance: Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results.Trial Registration: ClinicalTrials.gov Identifier: NCT02152696. [ABSTRACT FROM AUTHOR]

Background: When managing a nonviable pregnancy of unknown location (PUL), a debate has emerged in the literature whether to perform uterine curettage for definitive diagnosis of pregnancy location or administer methotrexate for a presumed ectopic pregnancy. The purpose of this study is to describe the treatment patterns when managing a PUL.Methods: A prospective, anonymous Internet based-electronic survey of PUL case scenarios was administered to a random sample of physicians across the United States.Results: A total of 214 physicians responded. When presented with a PUL by ultrasound and a βhCG measurement of 3,270 mIU/mL, which is above the discriminatory level, 88.3% (188) would choose an additional βhCG measurement before recommending any intervention. When presented with a PUL by ultrasound and serial βhCG measurements demonstrating an inappropriate trend for a viable gestation, 36.5% would offer uterine curettage and 31.3% would offer methotrexate. Resident and private clinicians had a fourfold lower adjusted odds of choosing uterine curettage compared to academic physicians.Conclusions: Based on our findings, there does not appear to be a consensus regarding the management of a PUL. [ABSTRACT FROM AUTHOR]

Abstract Objective Pregnancy of unknown location (PUL) is not a diagnosis but a transient state used to classify a woman when she has a positive pregnancy test without definitive evidence of an intra-uterine or extra-uterine pregnancy on transvaginal ultrasonography. Management of a persisting PUL varies substantially, including expectant or active management. Active management can include uterine cavity evacuation or systemic administration of methotrexate. To date, no consensus has been reached on whether either management strategy is superior or non-inferior to the other. Design Randomized controlled trial. Setting Academic medical centers. Patients We plan to randomize 276 persisting PUL-diagnosed women who are 18 years or older from Reproductive Medicine Network clinics and additional interested sites, all patients will be followed for 2 years for fertility and patient satisfaction outcomes. Interventions Randomization will be 1:1:1 ratio between expectant management, uterine evacuation and empiric use of methotrexate. After randomization to initial management plan, all patients will be followed by their clinicians until resolution of the PUL. The clinician will determine whether there is a change in management, based on clinical symptoms, and/or serial human chorionic gonadotropin (hCG) concentrations and/or additional ultrasonography. Main outcome The primary outcome measure in each of the 3 treatment arms is the uneventful clinical resolution of a persistent PUL without change from the initial management strategy. Secondary outcome measures include: number of ruptured ectopic pregnancies, number and type of re-interventions (additional methotrexate injections or surgical procedures), treatment complications, adverse events, number of visits, time to resolution, patient satisfaction, and future fertility. Conclusion This multicenter randomized controlled trial will provide guidance for evidence-based management for women who have persisting pregnancy of unknown location. [ABSTRACT FROM AUTHOR]

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]

Objective: To identify the current and future state of the practice of reproductive medicine.Design: Cross-sectional survey.Setting: Not applicable.Patient(s): None.Intervention(s): Not applicable.Main Outcome Measure(s): The survey included 57 questions designed to assess practice patterns/metrics and professional satisfaction and morale.Result(s): A total of 336/1,100 (31%) responded, and they were 38% women, 61% men, and 76% Caucasian, with a mean age of 54. Respondents averaged 2.3 jobs and averaged 53 hours of work per week: 44% work in academia and 50% in private groups. Average practice size was 5.5, with an average of 470 fresh IVF cycles performed per year. Percent effort included 63% infertility, 10% endocrinology, 10% surgery, and 9% research. Respondents performed an average of 13 major surgeries, 69 minor surgeries, and 128 oocyte retrievals per year. A total of 60% were salaried, and 40% were equity partners. Compensation was highly skewed. Greater than 84% had a positive morale and had a positive view of the future, and 92% would again choose REI as a career. The most satisfying areas of employment were patient interactions, intellectual stimulation, interactions with colleagues, and work schedule. The least satisfying areas were work schedule and financial compensation. Training was felt to be too focused on female factor infertility and basic research with insufficient training on embryology, genetics, male factor infertility, and clinical research. In the next 5 years, 57% suggested that the need for specialists would stay the same, while 20% predicted a decrease. A total of 58% felt we are training the correct number of fellows (37% felt we are training a surplus). Compared with academia, those in private practice reported higher compensation, less major surgery, more IVF, less endocrinology, and less research. Men worked more hours, conducted more surgery and IVF cycles, and had higher compensation than women. Morale was similar across age, gender, practice type, and geography.Conclusion(s): Our subspecialty has an extremely high morale. We are a middle-aged subspecialty with disparate compensation and a focused practice. Some respondents sense a need for a change in our training, and most anticipate only mild growth in our field. [ABSTRACT FROM AUTHOR]

The proposed human chorionic gonadotropin threshold model optimizes the balance between identifying viable intrauterine pregnancies and minimizing rates of misdiagnosis of nonviable pregnancies. OBJECTIVE: To evaluate the performance of a new human chorionic gonadotropin (hCG) threshold model to classify pregnancies as viable or nonviable using a longitudinal cohort of individuals with pregnancy of unknown viability. The secondary objective was to compare the new model with three established models. METHODS: This is a single-center, retrospective cohort study of individuals seen at the University of Missouri from January 1, 2015, until March 1, 2020, who had at least two consecutive quantitative hCG serum levels with an initial level greater than 2 milli-international units/mL and 5,000 milli-international units/mL or less, with the first interval between laboratory draws no greater than 7 days. Prevalence of correct classification of viable intrauterine pregnancies, ectopic pregnancies, and early pregnancy losses was evaluated with a new proposed hCG threshold model and compared with three established models describing minimum expected rates of hCG rise for a viable intrauterine pregnancy. RESULTS: Of an initial cohort of 1,295 individuals, 688 patients met inclusion criteria. One hundred sixty-seven individuals (24.3%) had a viable intrauterine pregnancy; 463 (67.3%) had an early pregnancy loss; and 58 (8.4%) had an ectopic pregnancy. A new model based on the total additive percent rise of hCG at 4 and 6 days after initial hCG (70% or greater and 200% or greater rise, respectively) was created. The new model was able to correctly identify 100% of viable intrauterine pregnancies while minimizing incorrect classification of early pregnancy losses and ectopic pregnancies as normal pregnancies. At 4 days after initial hCG, 14 ectopic pregnancies (24.1%) and 44 early pregnancy losses (9.5%) were incorrectly classified as potentially normal pregnancies. At 6 days after initial hCG, only seven ectopic pregnancies (12.1%) and 25 early pregnancy losses (5.6%) were incorrectly classified as potentially normal pregnancies. In established models, up to nine intrauterine pregnancies (5.4%) were misclassified as abnormal pregnancies and up to 26 ectopic pregnancies (44.8%) and 58 early pregnancy losses (12.5%) were incorrectly classified as potentially normal pregnancies. CONCLUSION: The proposed new hCG threshold model optimizes a balance between identifying potentially viable intrauterine pregnancies and minimizing misdiagnosis of ectopic pregnancies and early pregnancy losses. External validation in other cohorts is needed before widespread clinical use. [ABSTRACT FROM AUTHOR]

Abstract: Antithrombin (AT) is a 65kDa glycoprotein belonging to a group of inhibitory factors known as serpins (serine protease inhibitors). It plays a critical role in the inhibition of coagulation and inflammation processes within the environment of the vascular endothelium. Inadequate levels of functional AT in plasma results in an increased risk of thrombotic events, both venous and arterial. AT deficiency can be inherited or acquired. Congenital AT deficiency is the most severe inherited thrombophilic condition with an odds ratio of 20 for the increased risk of venous thrombosis. Acquired AT deficiency occurs in a variety of physiologic and pathologic medical conditions with similar risks of increased thrombosis. In this article, we review clinical settings characterized by an acquired AT deficiency largely or partly subsequent to protein microvascular leakage. Other different mechanisms of AT depletion are implied in some clinical conditions together with endothelial loss, and, therefore, outlined. In addition, we provide a description of the current knowledge on the specific mechanisms underlying endothelial AT leakage and on the consequences of this protein decrease, specifically looking at thrombosis. We identify potential directions of research that might prove useful in patients with acquired AT deficiency. [Copyright &y& Elsevier]

Well-designed and -conducted clinical trials are needed to further advance the field for reproductive medicine. However, current reporting of outcomes of trials is ambiguous and disparate. In this review it is offered that the preferred outcome for clinical trials in reproductive medicine should be live birth. Multiple births should be listed, and it should be specified whether this is multiple births per couple or multiple births per conception. The unit of measure should be women (or couples) and not cycles. The duration of exposure should also be clearly identified (i.e., treatment was one cycle, a prespecified number of cycles, or a period of time). Pregnancy loss should be specified, and the denominator should be those who conceived. Although live birth is the primary outcome, complications should be defined and reported, including multiple births and other objective markers, such as preterm delivery, small-for-gestational age, or stillbirth. [Copyright &y& Elsevier]

Early pregnancy failure is the most common complication of pregnancy, and 1% to 2% of all pregnancies will be ectopic. As one of the leading causes of maternal morbidity and mortality, diagnosing ectopic pregnancy and determining the fate of a pregnancy of unknown location are of great clinical concern. Several serum and plasma biomarkers for ectopic pregnancy have been investigated independently and in combination. The following is a review of the state of biomarker discovery and development for ectopic pregnancy and pregnancy of unknown location. [ABSTRACT FROM AUTHOR]

A biomarker can be used for early diagnosis of a disease, identification of individuals for disease prevention, as a potential drug target, or as a potential marker for a drug response. A biomarker may also limit the use of drug (and therefore costs) to the population of patients for which the drug will be safe and efficacious. A biomarker in reproduction could be used to improve assessment of exposure, identify subgroups susceptible to treatment, predict outcome, and/or differentiate subgroups with potentially different etiologies of disease. Despite many potential uses there is low participation in reproductive biology to develop molecular biomarkers, which may be directly related to the low number of new molecular entities entering clinical trials. As the number of candidate markers in reproductive medicine is increasing, it is important to understand the pathway of development from discovery to clinical utility and recognize that the vast majority of potential markers will not be clinically useful, owing to a variety of pitfalls. Extensive testing, validation, and modification needs to be performed before a biomarker is demonstrated to have clinical utility. New opportunities and partnerships exist and should hasten the development of biomarkers in reproduction. As more biomarkers are moved into practice, a better-educated biomarker consumer will enhance the possibility that biomarker(s) will realize their great potential. [ABSTRACT FROM AUTHOR]

Interrogating the association between assisted reproductive technologies (ART) and perinatal outcome is complicated but very important. This is an introduction to a series of articles that review this potential association with an eye toward etiology of risk, and what aspects of in vitro fertilization (IVF) can be modified to reduce this risk. When an association is not due to chance (i.e., statistically significant), one must also consider how the association may be affected due to bias or confounding. Despite lack of the perfect study, perinatal consequences of ART are apparent, even though the vast majority of children conceived with ART are healthy. Pregnancy after IVF is altered as evidenced by risk of preterm delivery, low birth weight among infants, and an alerted prevalence of preeclampsia. The long-term clinical implications of ART, such as childhood development and metabolism, have not been established and ongoing study is proceeding. The risk attributed to multiple births is iatrogenic and needs to be minimized. Optimizing the environment at the time a woman conceives will likely have an effect on gestation as well as the health of children. Reproduction effects health and health effects reproduction. [ABSTRACT FROM AUTHOR]

Objective: To assess a scoring system to triage women with a pregnancy of unknown location. Design: Validation of prediction rule. Setting: Multicenter study. Patient(s): Women with a pregnancy of unknown location. Intervention(s): None. Main Outcome Measure(s): Scores assigned to factors identified at clinical presentation, total score calculated to assess risk of ectopic pregnancy (EP) in women with a pregnancy of unknown location, and a proposed three-tiered clinical action plan. Result(s): The cohort of 1,400 women (284 ectopic pregnancies, 759 miscarriages, and 357 intrauterine pregnancies) was more diverse than the original cohort used to develop the decision rule. The recommendations of the action plan were low risk, intermediate risk, and high risk; the recommendation based on the model score was compared with clinical diagnosis. A total of 29.4% intrauterine pregnancies were identified for less frequent follow-up observation, and 18.4% nonviable gestations were identified for more frequent follow-up observation (to rule out an ectopic pregnancy) compared with intermediate risk (i.e., monitor in current standard fashion). For a decision of possible less frequent monitoring, the specificity was 90.8% (89.0–92.6) with negative predictive value of 79.0% (76.7–81.3). For a decision of more intense follow-up observation, the specificity was 95.0% (92.7–97.2). Test characteristics using the scoring system were replicated in the diverse validation cohort. Conclusion(s): A scoring system based on symptoms at presentation has value to stratify risk and influence the intensity of outpatient surveillance for women with pregnancy of unknown location but does not serve as a diagnostic tool. [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 National Institute of Child Health and Human Development has conducted a series of vision workshops to set an ambitious but tenable broad agenda, transcending traditional organizational and disciplinary boundaries. This presentation sets forth a vision regarding how the aspects of a woman’s reproductive lifespan are interrelated, likely starting from childhood all the way to the later reproductive years. As a woman propagates, this circular interaction is then transmitted to the next generation. We need an understanding of the clinical processes, the time course, the natural history, and disruptors of these processes. With that understanding, we can then bring tools to bear to assess these issues, whether these tools are epidemiology, demography, social science, molecular biology, proteomics, genomics, or epigenomics. Our future research agenda should investigate how reproduction affects health and how health affects reproduction. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined the factors that influence the accuracy of initial ultrasonography in patients with symptomatic first-trimester pregnancy. The study compared ultrasound diagnosis in the emergency department with an ultimate clinical diagnosis in women. Study authors found that misdiagnosis is prevalent when using ultrasound diagnosis of intrauterine pregnancy or ectopic pregnancy.

The article discusses the case of a 29-year-old woman who had an ectopic pregnancy. The patient was taken to the hospital after experiencing vaginal spotting and abdominal pain. There are several factors that contribute to the risk of such pregnancy including a history of ectopic pregnancy, previous tubal surgery, and damage to the fallopian tubes. Various signs of shock are also experienced by patients with a ruptured ectopic pregnancy including rebound tenderness, tachycardia, and hypotension.

Objectives: To provide an overview of the studies that have evaluated the return to fertility following cessation of oral contraceptives (OCs), including recent evidence in women discontinuing extended-cycle and continuous-use regimens. Design: Comprehensive review. Patient(s): None. Intervention(s): Relevant articles were identified through a PubMed literature search (1960–2007) and a cross-reference of published data. Main Outcome Measure(s): Time to fertility following contraceptive use. Result(s): Numerous studies have demonstrated some delay in the time to conception in previous users of OCs who discontinued use in order to conceive, but this impairment appears to be temporary and typically limited to the early months following cessation of OC use. Reported 12-month conception rates in former cyclic OC users range from 72%–94% and are similar to those observed in women discontinuing intrauterine devices (71%–92%), progestin-only contraceptives (70%–95%), condoms (91%), and natural family planning (92%). There is a limited amount of data on the time to conception in women stopping extended-cycle and continuous-use OCs, but the data suggest that subsequent return to fertility is generally comparable to that of cyclic OCs. Conclusion(s): A comprehensive survey of reported data indicates that the return of fertility in former OC users (both cyclic and extended/continuous regimens) in women who stop use in order to conceive is comparable to that observed with other contraceptive methods. [Copyright &y& Elsevier]

The article assesses three strategies for diagnosing women at risk for ectopic pregnancy based on information collected at initial presentation. The strategies used were logistic regression, a numeric scoring system and a classification and regression tree. The researchers found that a scoring system based on five factors, namely age, ectopic history, bleeding, prior miscarriage and human chorionic gonadotropin level, is effective in predicting outcomes of women at risk for ectopic pregnancy.

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.

Abstract: NuvaRing®, a combined contraceptive vaginal ring 54 mm in diameter, offers many advantages over oral contraceptives. To better delineate in vivo placement, we performed MRI to confirm its anatomical position. Two healthy users, one nulliparous and one parous, underwent a series of MRI: preinsertion, immediately postinsertion and after ambulation. Three-dimensional imaging of the human vagina demonstrates that in vivo, NuvaRing® is located superior to the urogenital diaphragm (UGD), surrounding the cervix. The superior-most aspect of the ring lies behind (posterior) the cervix, at a level superior to the external os. The inferior aspect of the ring also lies in the vaginal canal above the UGD. The entire cervix rests inside the ring. The preambulation image in the nulliparous woman was the only exception. In this case, the upper portion of the ring was at the level of the lower-mid cervix and the lower aspect below the UGD. After ambulation, the ring moved cephalad and surrounded the cervix. In all instances, ambulation resulted in lower aspect of NuvaRing® moving away from the introitus. In vivo, NuvaRing® is compressed laterally forming a gentle oval in the anterior–posterior direction (5–7 mm longer than wide), an effect that is seen more in nulliparous women. [Copyright &y& Elsevier]

Abstract: This was a blinded crossover study to determine the in vivo distribution of 2.5 and 3.5 mL of 6% cellulose sulfate gel. This potential vaginal microbicide was mixed with dilute gadolinium chelate and inserted into the vagina. Magnetic resonance imaging was performed at baseline and repeated after 5, 20, 35 and 50 min with subjects either resting or ambulating between data acquisitions. Use of 2.5 mL with no ambulation gave low linear spread (53.1% of vaginal length) and surface contact (61.7%) at 50 min. Using 3.5 mL of gel with ambulation improved linear spread (84.5%) and surface contact (85.9%) of the gel in the same time interval without significant leakage. Most linear spreading took place in the first 5 min after insertion, although lateral spreading continued to increase with time especially when ambulation took place. Leakage and gel was not a significant problem at either volume. [Copyright &y& Elsevier]

Abstract: C31G (Savvy™) has been developed as a topical vaginal microbicide with broad-spectrum antibacterial and antiviral properties. The objective of this study was to evaluate the distribution of a 1.0% concentration of (3.5 mL) C31G vaginal gel in the human pelvis using magnetic resonance imaging (MRI). Gel delivery with a standard applicator was primarily to the upper vagina and was well tolerated. Vaginal mucosal coverage at 18 min was excellent with 92% linear coverage and 75% surface contact coverage of the vagina. The upper vagina was almost completely covered and gel was also noted in the lower vagina. Coverage 6 h after application was substantially decreased, with 60% of maximal linear coverage and 41% surface contact. There was a very minimal coverage of the vaginal mucosa noted 24 h following insertion. Simulated intercourse resulted in relatively little change in overall distribution at all three time points. Repeat application of the gel may be necessary if intercourse has not occurred within the first few hours after initial insertion. [Copyright &y& Elsevier]

OBJECTIVE: To analyze the change in serial human chorionic gonadotropin (hCG) levels in women symptomatic with pain or bleeding who presented with nondiagnostic ultrasonography but were ultimately confirmed to have a viable intrauterine pregnancy. METHODS: The rise in serial hCG measures were modeled over time, with the start point defined in 2 ways: by last menstrual period and by date of presentation for care. Both semiparametric (spline) curves and linear random-effects models were explored. The slope and projected increase of hCG were calculated to define 99% of viable intrauterine pregnancies. RESULTS: A total of 287 subjects met inclusion criteria and contributed 861 measurements of hCG. On average, these subjects contributed 3.00 observations and were followed up for 5.25 days. A linear increase in log hCG best described the pattern of rise. Curves derived from last menstrual period and day of presentation do not differ substantially. The median slope for a rise of hCG after 1 day was 1.50, (or a 50% increase); 2.24 after 2 days (or a 124% rise), and 5.00 after 4 days. The fastest rise was 1.81 at 1 day, 3.28 at 2 days, and 10.76 at 4 days. The slowest or minimal rise for a normal viable intrauterine pregnancy was 24% at 1 day and 53% at 2 days. CONCLUSION: These data define the slowest rise in serial hCG values for a potentially viable gestation and will aid in distinguishing a viable early pregnancy from a miscarriage or ectopic pregnancy. The minimal rise in serial hCG values for women with a viable intrauterine pregnancy is ‘slower’ than previously reported, suggesting that intervention to diagnosis and treat an abnormal gestation should be more conservative. [ABSTRACT FROM AUTHOR]

: ObjectiveTo evaluate serial hormone concentrations in subjects treated with vaginally administered misoprostol for early pregnancy failure.: DesignAs part of a randomized clinical trial, serum was collected on treatment days 1, 3, 8, and 15.: SettingMulticenter clinical trial.: Patient(s)Women with a nonviable first-trimester pregnancy.: Intervention(s)Serum concentrations of human chorionic gonadotropin (hCG), progesterone, and sex hormone binding globulin (SHBG) were evaluated.: Main outcome measure(s)A logistic regression model was constructed to assess the associations of percent and complete expulsion of the gestational sac and/or successful management.: Result(s)The percent change from the day of treatment until the first follow-up visit was predictive for complete expulsion for progesterone (P) (P<.005) and hCG (P<.005), but not for SHBG. The actual value was not significantly associated with complete expulsion or successful management. A decrease (day 1–3) of 79% for both hCG and P was associated with a 90% probability of complete passage of the gestational sac. A 90% probability of successful management was noted if P decreased by 78% on day 3 or 59% on day 7, or hCG decreased by 74% on day 3 or 78% on day 7 compared with pretreatment values.: Conclusion(s)Percent change, but not absolute change, in serial hormone values are strongly associated with both the complete expulsion of the gestational sac with one dose of misoprostol and ultimate success. [Copyright &y& Elsevier]

: ObjectiveThe diagnosis of ectopic pregnancy (EP) is often confirmed at presentation (acute), but often requires serial β-hCG levels to confirm the diagnosis (chronic). The purpose of this study is to analyze whether these clinical presentations represent a spectrum of disease.: DesignThe retrospective cohort study of 452 patients diagnosed with EP at the University of Pennsylvania in the years 1990–1999.: SettingUniversity of Pennsylvania, Philadelphia, Pennsylvania.: Patient(s)Four hundred fifty-two patients diagnosed with EP. Patients diagnosed with EP were divided into two groups according to the time of diagnosis.: Main outcome measure(s)A total of 37 parameters were examined including historic and demographic factors, findings at presentation, and treatment and outcome variables.: Result(s)The two groups were similar in terms of historic EP risk factors. Multivariable analysis demonstrates that women with a chronic presentation were less likely to have received fertility medications (odds ratio [OR] 0.23; 95% confidence interval [CI] 0.06–0.84), less likely to present with pain (OR 0.29; 95% CI 0.12–0.71), have a lower β-hCG level at presentation (9,849 mIU/mL ± 16,726 vs. 1,787 mIU/mL ± 4,717), lower chance of rupture (OR 0.19; 95% CI 0.05–0.73), and less frequently have blood type 0.: Conclusion(s)Women diagnosed with ectopic pregnancy can be categorized into two groups, those with an acute presentation and those with a chronic presentation. Differences in risk factors, presentation, and outcome may reflect differences in trophoblast viability or invasive potential. [Copyright &y& Elsevier]

: ObjectiveMedical management of an unruptured ectopic pregnancy with intramuscular methotrexate is common and cost-effective. Two treatment protocols, the “single dose” and the “multidose,” have been advocated and independently reported in the medical literature. This analysis systematically compares the success and prevalence of side effects of these two regimens.: Data sourcesPublished data on women with an ectopic pregnancy medically managed were identified using a MEDLINE search from 1966 to 2001 using key words and review of the references of each manuscript.: Methods of study selectionStudies were selected based on dosing regimen, number of subjects, and study quality. Data regarding outcome, number of doses administered, side effects, and baseline characteristics were extracted. Data were summarized, and the associations of failed management and the presence of side effects with treatment protocol were calculated. Baseline serum chorionic gonadotropin values and the presence of embryonic fetal actively were controlled for with multivariable logistic regression.: Tabulation, integration, and resultsThe overall success rate for women treated with methotrexate for an ectopic pregnancy was 89% (1181 of 1327). The single dose was much more commonly used. The use of single dose was associated with a significantly greater chance of failed medical management than the use of the multidose in both crude (odds ratio [OR] 1.71; 1.04, 2.82) and adjusted analyses (OR 4.74; 1.77, 12.62). The single-dose regimen was associated with fewer side effects (OR 0.44; 0.31, 0.63). Women who experienced side effects were more likely to have successful treatment regardless of regimen.: ConclusionThe multidose regimen is more effective than the single-dose regimen. [Copyright &y& Elsevier]

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]

The article comments on a randomized clinical trial of endometrial scratching as an adjuvant technique in in vitro fertilization (IVF). Topics discussed include the purposeful disruption of the endometrium which leads to immunologic response, inflammation and repair, the association of live-birth rates with endometrial scratching, and a comparison of outcome in women who underwent endometrial scratching and those who did not.

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]

The majority of perinatal morbidity after in vitro fertilization (IVF) is due to multiple pregnancy; however, even singleton infants are at an increased risk for adverse outcomes. We have summarized data that evaluates adverse outcomes in IVF infants and recent attempts to delineate the underlying causes of this risk. We submit that practitioners of reproductive medicine should remain at the forefront of this investigation. [Copyright &y& Elsevier]

The science of contraceptive medicine and reproductive medicine are similar. At present contraceptive medicine has moved beyond understanding the mechanism of action of steroid hormones with the introduction of many safe and effective methods. Long-acting reversible contraceptives are increasing in acceptance and providing very high efficacy. The science has pivoted toward optimization of family planning in selected high-risk populations, such as those with a high-risk of thrombosis, as well as addressing the challenge of obesity. The pipeline for male and female related methods will continue to advance the science and public health impact. [ABSTRACT FROM AUTHOR]

Approximately 25 years ago, our team initiated studies to determine whether outcome results from a large medical record database would yield valid results. We utilized the data in the United Kingdom (UK) General Practice Research Database (GPRD) to replicate the randomized controlled trial (RCT) study result and compared them to confirm the database results. The initial studies compared favorably, but some subsequent studies did not. This prompted development of a new strategy to determine and correct for unrecognized confounding in the database. This strategy divided outcome rates prior to initiation of therapy in the database study (which should include both identified and unidentified confounders) into the outcome rates during the treatment interval. When they differed from Cox‐adjusted results, it reflected unrecognized confounding. We called this strategy Prior Event Rate Ratio (PERR)–adjusted outcome. One of our previously published observational studies replicated the Women's Health Initiative (WHI) RCT study of hormone therapy in post‐menopausal women. Our study results replicated the WHI RCT results except it did not exhibit an increase in heart attack in contrast to the RCT. Furthermore, we could not evaluate death reliably since our analytic approach to overcome unrecognized confounding does not work for this outcome. In Volume 1, Issue 1 of the Learning Health Systems open access journal, we published a new study (titled "A new method to address unmeasured confounding of mortality in observational studies") that reported a novel death method, based on our prior methodology, that could analyze unrecognized confounding of the death outcome. This new methodology, termed Post Treatment Event Rate Ratio (PTERR), permitted a reliable examination of mortality in post‐menopausal women undergoing hormone therapy. These results are reported in this manuscript. The study used the data from our previous observational study. It demonstrates that estrogen therapy markedly reduced death in post‐menopausal women. This work also illuminates principles of database construction and correspondingly demonstrates the use of novel methodologies for obtaining valid results, which can be applied to enable learning from such databases. Work to advance such methodologies is essential to advancing the scientific integrity Core Value underpinning learning health systems (LHSs). Indeed, in the absence of such efforts to develop and refine methodologies for learning trustworthy lessons from real‐world data, we risk inadvertently creating mis‐learning systems. [ABSTRACT FROM AUTHOR]

Determining early pregnancy location and viability can be cumbersome, often requiring serial evaluations. This study aimed to identify novel biomarker candidates for pregnancy location and viability using a pseudodiscovery high-throughput technique. This was a case-control study among patients presenting for early pregnancy assessment, including ectopic pregnancies, early pregnancy losses, and viable intrauterine pregnancies. For pregnancy location, ectopic pregnancy was considered "case" and non-ectopic considered "control." For pregnancy viability, viable intrauterine pregnancy was considered "case" and early pregnancy loss + ectopic pregnancy were considered "control." Using Proximity Extension Assay technology from Olink Proteomics, serum levels of 1012 proteins were compared separately for pregnancy location and viability. Receiver operator characteristic curves were generated to determine a biomarker's discriminative abilities. Analysis included 13 ectopic pregnancies, 76 early pregnancy losses, and 27 viable intrauterine pregnancies. For pregnancy location, 18 markers had an area under the curve (AUC) ≥0.80, with three being expressed more in ectopic compared to non-ectopic pregnancies: thyrotropin subunit beta, carbonic anhydrase 3, and DEAD (Asp-Glu-Ala-Asp) box polypeptide 58. For pregnancy viability, two markers had an AUC ≥0.80: lutropin subunit beta and serpin B8. While some of the markers had previously been implicated in early pregnancy physiology, others were from pathways not previously explored. Using a high-throughput platform, a large number of proteins were screened as potential biomarkers for pregnancy location and viability, and twenty candidate biomarkers were identified. Further exploration of these proteins may facilitate validation as diagnostic tools for establishing early pregnancy diagnoses. [ABSTRACT FROM AUTHOR]