Search

Persons with HIV (PWH) are at increased risk for bacterial infections, and previous publications document an increased risk for invasive meningococcal disease (IMD) in particular. This analysis provides evidence that PWH face a 6-fold increase in risk for IMD based on Active Bacterial Core surveillance data collected during 2009-2019., Competing Interests: Potential conflicts of interest. Lee H. Harrison reports reimbursement for travel to attend meetings for Merck, Pfizer, Sanofi, and GSK and participation on a Merck data safety monitoring board. Ruth Lynfield reports receiving payment for work as an associate editor for the American Academy of Pediatrics’ (AAP) Red Book, which was donated to the Minnesota Department of Health, support from the Council of State and Territorial Epidemiologists for travel to meetings as president and vice president, travel support to ID Week by the Infectious Diseases Society of America, and support from AAP for travel to a committee meeting on infectious diseases in her role as associate editor. William Schaffner reports payment from the National Foundation for Infectious Disease for a leadership or fiduciary role. No other potential conflicts of interest were disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Older age and chronic conditions are associated with severe influenza outcomes; however, data are only comprehensively available for adults ≥65 years old. Using data from the Influenza Hospitalization Surveillance Network (FluSurv-NET), we identified characteristics associated with severe outcomes in adults 18-49 years old hospitalized with influenza., Methods: We included FluSurv-NET data from nonpregnant adults 18-49 years old hospitalized with laboratory-confirmed influenza during the 2011-2012 through 2018-2019 seasons. We used bivariate and multivariable logistic regression to determine associations between select characteristics and severe outcomes including intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), and in-hospital death., Results: A total of 16 140 patients aged 18-49 years and hospitalized with influenza were included in the analysis; the median age was 39 years, and 26% received current-season influenza vaccine before hospitalization. Obesity, asthma, and diabetes mellitus were the most common chronic conditions. Conditions associated with a significantly increased risk of severe outcomes included age group 30-39 or 40-49 years (IMV, age group 30-39 years: adjusted odds ratio [aOR], 1.25; IMV, age group 40-49 years: aOR, 1.36; death, age group 30-39 years: aOR, 1.28; death, age group 40-49 years: aOR, 1.69), being unvaccinated (ICU: aOR, 1.18; IMV: aOR, 1.25; death: aOR, 1.48), and having chronic conditions including extreme obesity and chronic lung, cardiovascular, metabolic, neurologic, or liver diseases (ICU: range aOR, 1.22-1.56; IMV: range aOR, 1.17-1.54; death: range aOR, 1.43-2.36)., Conclusions: To reduce the morbidity and mortality associated with influenza among adults aged 18-49 years, health care providers should strongly encourage receipt of annual influenza vaccine and lifestyle/behavioral modifications, particularly among those with chronic medical conditions., Competing Interests: Potential conflicts of interest. D.U. reports that he is a contract employee of GDIT. K.Y.H. reports grants from the CDC for the Connecticut Emerging Infections Program. M.M. reports grants from the CDC for the Emerging Infections Program. P.R. reports funding support from the Emerging Infections Program Cooperative agreement. A.F. reports grants from the Michigan Department of Health and Human Services from the CSTE Federal Grand. S.K. reports grants from the Michigan Department of Health and Human Services from the CSTE Federal Grand. R.L. reports grants from the CDC Emerging Infections Cooperative Agreement to the MN Department of Health. S.K. reports salary and data collection for the manuscript supported by a grant received from the CDC Emerging Infections Program. K.A. reports salary and data collection for the manuscript supported by a grant received from the CDC Emerging Infections Program. N.B. reports an agreement to consult for the GSK. E.S. reports grant funding for the population-based Influenza Hospitalization Surveillance Project (IHSP) and COVID-Net activities, including support for personnel and equipment for data collection activities from the Council for State and Territorial Epidemiologists (CSTE). W.S. reports a grant from the CDC Emerging Infections Program. H.K.T. reports a grant from the CDC. A.G. reports a grant from the CSTE. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Nontypeable Haemophilus influenzae (NTHi) is the most common cause of invasive H. influenzae disease in the United States (US). We evaluated the epidemiology of invasive NTHi disease in the US, including among pregnant women, infants, and people with human immunodeficiency virus (PWH)., Methods: We used data from population- and laboratory-based surveillance for invasive H. influenzae disease conducted in 10 sites to estimate national incidence of NTHi, and to describe epidemiology in women of childbearing age, infants aged ≤30 days (neonates), and PWH living in the surveillance catchment areas. H. influenzae isolates were sent to the Centers for Disease Control and Prevention for species confirmation, serotyping, and whole genome sequencing of select isolates., Results: During 2008-⁠2019, average annual NTHi incidence in the US was 1.3/100 000 population overall, 5.8/100 000 among children aged <1 year, and 10.2/100 000 among adults aged ≥80 years. Among 225 reported neonates with NTHi, 92% had a positive culture within the first week of life and 72% were preterm. NTHi risk was 23 times higher among preterm compared to term neonates, and 5.6 times higher in pregnant/postpartum compared to nonpregnant women. More than half of pregnant women with invasive NTHi had loss of pregnancy postinfection. Incidence among PWH aged ≥13 years was 9.5 cases per 100 000, compared to 1.1 cases per 100 000 for non-PWH (rate ratio, 8.3 [95% confidence interval, 7.1-9.7]; P < .0001)., Conclusions: NTHi causes substantial invasive disease, especially among older adults, pregnant/postpartum women, and neonates. Enhanced surveillance and evaluation of targeted interventions to prevent perinatal NTHi infections may be warranted., Competing Interests: Potential conflicts of interest. L. H. H. has served as a member of data and safety monitoring boards for Merck and reports reimbursement for travel expenses from Merck and Pfizer. S. P. reports funding awarded by the Connecticut Department of Public Health by the CDC (Emerging Infections Cooperative Agreement). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: Influenza is a persistent public health problem associated with severe morbidity and mortality. Drug use is related to myriad health complications, but the relationship between drug use and severe influenza outcomes is not well understood. The study objective was to evaluate the relationship between drug use and severe influenza-associated outcomes., Methods: Data were collected by the Influenza Hospitalization Surveillance Network (FluSurv-NET) from the 2016-2017 through 2018-2019 influenza seasons. Among persons hospitalized with influenza, descriptive statistics and logistic regression models were used to analyze differences in demographic characteristics, risk and behavioral factors, and severe outcomes (intensive care unit [ICU] admission, mechanical ventilation, or death) between people who use drugs (PWUD), defined as having documented drug use within the past year, and non-PWUD., Results: Among 48,430 eligible hospitalized influenza cases, 2019 were PWUD and 46,411 were non-PWUD. PWUD were younger than non-PWUD and more likely to be male, non-Hispanic Black or Hispanic/Latino, smoke tobacco, abuse alcohol, and have chronic conditions including asthma, chronic liver disease, chronic lung disease, or immunosuppressive conditions. PWUD had greater odds of ICU admission and mechanical ventilation, but not death compared with non-PWUD; however, these findings were not statistically significant after adjustment. Opioid use specifically was associated with increased risk of ICU admission and mechanical ventilation., Conclusion: These results support targeted initiatives to prevent influenza in this population, including influenza vaccination, which remains one of the most important tools to prevent influenza infection and associated severe outcomes., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

From surveillance data of patients hospitalized with laboratory-confirmed influenza in the United States during the 2015-2016 through 2018-2019 seasons, initiation of antiviral treatment increased from 86% to 94%, with increases seen across all age groups. However, 62% started therapy ≥3 days after illness onset, driven by late presentation to care., Competing Interests: Potential conflicts of interest. E.A. has received received grants for clinical trials from Pfizer, Merck, PaxVax, Micron, Sanofi-Pasteur, Janssen, MedImmune, and GSK, has been a consultant for Sanofi-Pasteur, Pfizer, Medscape, Janssen, GSK, and Moderna, has been a member of the data safety monitoring board for Kentucky Bioprocessing and Sanofi-Pasteur, and has been a member of the endpoint adjudication committee for WCG and ACI Clinical. His institution has also received funding from the NIH to conduct clinical trials of COVID-19 vaccines. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Background: The normal pituitary production of human chorionic gonadotropin (hCG)alongside luteinizing hormone, and its presence in women after bilateral oophorectomy, during perimenopause and menopause, as measured in serum and urine, has been known for 30 years and is described in numerous publications. Last year our group discussed this finding in a correspondence to the editor in the March 15th issue of New England Journal of Medicine, yet the misinterpretation of low-level hCG in these women seems to have increased in magnitude., Methods: This is an outcomes study of 36 cases of menopausal hCG referred to the USA hCG Reference Service over a 1-year period, from March 2007 to March 2008., Results: Eight cases occurred in women after oophorectomy, 28 were women in menopause/perimenopause. Surgery was postponed in 5 (14%) of 36 cases, and in 3 cases (8%), chemotherapy was unnecessarily administered. In 2 cases, computed tomography scans were cancelled. The average hCG detected was 10 +/- 7.2 IU/L in cases receiving an oophorectomy and 9.8 +/- 6.7 in perimenopause and 11 +/- 6.2 IU/L in menopause cases., Conclusions: Low-level hCG production in woman in physiologic perimenopause, in menopause, or in women with prior bilateral oophorectomy is a normal biologic and biochemical phenomenon. Management protocols in all fields need to be changed to accept pituitary hCG as normal and recognize the clinical maneuvers that will secure the diagnosis. Understanding this physiology will avoid needless delays in necessary therapies such as organ transplant procedures and will limit the misadventure of prescribing unnecessary cancer treatments.

Background: The USA uniquely does not use quantitative urine human chorionic gonadotropin (hCG) tests despite being invaluable in pregnancy testing and in monitoring cancer patients. We look at current hCG tests and their detection of the degraded forms of hCG predominant in urine. We examine levels of urinary hCG, its usefulness in pregnancy testing, and advantages of urine testing in false positive hCG cases and cancer cases., Methods: hCG assays were blindly evaluated at 10 laboratories running different methodologies. Daily urine samples from 164 women were collected through 5 menstrual cycles or until pregnancy was achieved. Urines were assayed for total hCG. We also examined the use of quantitative urine hCG in confirming false positive serum hCG results in 80 clinical cases., Results: Only the Siemens Immulite test was shown to detect the degraded forms of hCG present in urine. This test equally recognized urine and serum hCG. We investigated background hCG in 9026 urines, the mean hCG level was 0.04 IU/L, and the 99th centile was 1.4 IU/L. In cycles where pregnancy was achieved, hCG could be detected in urine at 24.6 days of a 28.7 day menstrual cycle. At this time, the average hCG was 6.02 IU/L, setting a sensitivity level for quantitative urine hCG tests to detect pregnancy. Quantitative urinary hCG proved critical in detecting cancer in 3 of 80 cases complicated by false positive serum hCG., Conclusions: The need for a quantitative urine hCG assay is undeniable and we invite manufacturers to produce a quantitative urine hCG test.

Hyperglycosylated chorionic gonadotropin (CG-H) signals placental cytotrophoblast cell growth and invasion, and chorionic gonadotropin (CG) promotes uterine vascularization. A hypothesis is presented relating the evolution of these molecules to the evolution of human hemochorial implantation and that of the human brain. Deep placental invasion, vascularization and hemochorial placentation, under the influence of CG and CG-H, are a critical part of the nutrition and energy-generating mechanisms needed for human brain development and thus for the evolution of humans. Insufficient CG-H production and the resulting inappropriate implantation is associated with an unduly high incidence of pregnancy failures in humans. Low levels of CG-H and inappropriate hemochorial placentation also appear to be associated with subsequent preeclampsia. It is also of note that human CG-H drives invasion by gestational trophoblastic neoplasms that have been described only in humans.

Objective: To examine utility of measurement of proportions of free beta-subunit of human chorionic gonadotropin (hCG) in diagnosis of placental site trophoblastic tumor (PSTT) and nontrophoblastic neoplasm in patients with persistent low hCG levels and patients with history of gestational trophoblastic diseases., Study Design: The USA hCG Reference Service measured proportions of free beta-subunit in 128 cases, 45 with active invasive trophoblastic disease and 83 questionable cases with persistent low hCG levels, with or without history of gestational trophoblastic disease (GTD)., Results: High proportions of free beta-subunit (> 30% of total hCG) were identified in 18 of 128 cases, all suspected of having PSTT or nontrophoblastic neoplasm, which was reported to referring physicians. Within 2 months of testing, hysterectomy or tumor biopsy led to histologic proof of PSTT in 13 of the 18 cases and biopsy led to proof of nontrophoblastic neoplasm in 5 of the 18 cases., Conclusion: We confirm use of proportion of free beta-subunit (> 30%) as a seemingly absolute test for identifying PSTT and nontrophoblastic neoplasms. It should be used to identify and diagnose these malignancies in women presenting with persistent low hCG levels outside of pregnancy and in secondary evaluation of patients with a history of GTDs.

Objective: The normal pituitary production of human chorionic gonadotropin alongside luteinizing hormone, measurable in menopausal serum and urine was initially reported over 3 decades ago and has been described in numerous subsequent publications. Unfortunately, delays or cancellations of important medical procedures and use of needless chemotherapy still occurs because of the finding of human chorionic gonadotropin in perimenopausal and postmenopausal woman. We describe the problem and a concise approach to this management dilemma in menopausal women., Study Design: This is an outcomes study of 36 cases of perimenopausal and postmenopausal human chorionic gonadotropin evaluated in cases referred to the USA hCG Reference Service., Results: By report of the provided records, in 6 of 36 cases, unneeded chemotherapy was given for assumed recurrent gestational trophoblastic disease. In 9 cases, surgery was cancelled or postponed and in 3 cases renal transplantation was cancelled at the time of locating a matched donor kidney. In all cases the measured human chorionic gonadotropin was due to menopausal production of pituitary human chorionic gonadotropin. The average human chorionic gonadotropin detected in perimenopausal cases was 6.4 +/- 3.2 IU/L, and in postmenopausal cases was 11.6 +/- 7.0 IU/L or significantly higher. In 24 cases, therapeutic doses of high-estrogen birth control pill were used to confirm pituitary origin with 23 cases demonstrating successful human chorionic gonadotropin suppression., Conclusion: Low levels of human chorionic gonadotropin production in the perimenopausal and postmenopausal state is a normal physiologic phenomenon. Provider education is warranted and management protocols are suggested in all health-related fields to clarify the normality of low level pituitary human chorionic gonadotropin production. Understanding this physiology will avoid delays in necessary therapies such as organ transplants, and will limit the misadventure of prescribing unnecessary treatments for presumed gestational malignancy.

Hyperglycosylated hCG (hCG-H) is an over-glycosylated variant of hCG. While regular hCG is produced by differentiated syncytotrophoblast cells, hCG-H is independently secreted by stem cytotrophoblast cells. hCG-H has an independent function to regular hCG. It is the direct promoter of trophoblast invasion and malignancy. Invasion as in implantation of pregnancy and malignancy as in choriocarcinoma. Neither will occur in the absence of hCG-H. hCG-H measurements have multiple functions. Primarily or exclusively hCG-H is produced at the time of implantation of pregnancy and in the 2 weeks that follows. As such, a good pregnancy test should measure regular hCG and hCG-H equally. This is not commonly the case. Most tests poorly detect hCG-H. New pregnancy tests are needed, including those that measure only hCG-H. Considering that hCG-H is critical for implantation, hCG-H is also invaluable for determining pregnancy outcome and detecting failures. It makes a considerable more accurate test for detecting pregnancy failures and ectopic pregnancies than regular hCG. Down syndrome pregnancies are marked by poor trophoblast differentiation. As such, they are very well marked by using a combination of hCG-H measurements and other screening tests. hCG-H is also an absolute tumor marker for malignant or invasive gestational trophoblastic disease, it can discriminate active and inactive (quiescent) disease, and the need for chemotherapy.

Objective: Hyperglycosylated human chorionic gonadotropin (hCG-H) is a carbohydrate variant of hCG with double-sized oligosaccharide side chains. While hCG-H is produced exclusively by stem cytotrophoblast cells in gestational choriocarcinoma, by pregnancy cytotrophoblast at implantation and by the cytotrophoblast produced in testicular malignancies, regular hCG is produced only by differentiated syncytiotrophoblast cells., Study Design: hCG-H was measured using the Nichols Advantage hCG-H assay (Nichols Institute Diagnostics, San Clemente, California)., Results: hCG-H has a function separate from regular hCG. hCG-H, but not regular hCG, acts in vivo and in vitro to promote invasion, whether invasion through membranes or tumor formation. Invasion or tumorigenesis is completely blocked by administration of specific antibody to hCG-H. The same hCG-H-modulated invasion mechanisms are observed in early pregnancy, gestational choriocarcinoma and testicular cancers., Conclusion: hCG-H is a cytokinelike molecule, produced by cells different from those that make regular hCG and having a completely separate function. It appears to be the modulator of invasion as in implantation of pregnancy, gestational choriocarcinoma and testicular cancer malignancy.

Recent publications show that the measurements of particular human chorionic gonadotropin (hCG) variants are extremely beneficial in the diagnosis, monitoring and treatment of gestational trophoblastic disease (GTD). Here we review the possible sources of hCG and the use of commercial tests in the optimal management of GTD, quiescent GTD,false positive hCG results, placental site trophoblastic tumor (PSTT) detection, nontrophoblastic neoplasms and pituitary hCG. Hyperglycosylated hCG (hCG-H) measurements are ideal for discriminating active (invasive) from inactive (quiescent or benign) disease. hCG-H testing is also more sensitive than regular hCG in detecting recurrent or persistent disease. After excluding false positive hCG results, and in the absence of any radiographic evidence of tumor, hCG-H should be measured before starting chemotherapy or surgery in women presenting with low hCG (<1,000 mIU/mL) with or without a history of GTD. The hCG free beta assay is an invaluable test in discriminating PSTT from other GTDs, thereby aiding the determination of appropriate treatment options.

Objectives: To determine whether circulating hyperglycosylated human chorionic gonadotropin (hCG-H), a promoter of choriocarcinoma growth and tumorigenesis, is a reliable marker of active gestational trophoblastic neoplasia (GTN) or choriocarcinoma, and whether hCG-H can consistently discriminate quiescent gestational trophoblastic disease (GTD) from neoplasia., Methods: Patients were those referred to the USA hCG Reference Service for consultation. These included a total of 82 women with GTN, including 30 with histologic choriocarcinoma. They were compared with 26 patients with resolving hydatidiform mole and 69 with quiescent GTD (persistent positive low value of real hCG but no clinical evidence of disease). All were tested for total hCG and hCG-H. hCG-H was calculated as the percentage of total hCG (hCG-H(%))., Results: We compared the utility of total hCG and hCG-H(%) in detecting active GTN and quiescent GTD. There was no significant difference when measuring total hCG (includes regular and hyperglycosylated hCG), between women with quiescent GTD and self-resolving hydatidiform mole compared to choriocarcinoma/GTN cases (P > 0.05 and P > 0.05). In contrast, hCG-H(%) was significantly higher in choriocarcinoma/GTN cases (P < 0.000001, and P < 0.000001). The usefulness of hCG and hCG-H(%) testing was assessed for discriminating between the 69 quiescent GTD cases, which required no therapy, and choriocarcinoma/GTN which need treatment. While hCG would detect 62% and 24% of malignancies at a 5% false positive rate, hCG-H(%) would detect 100% and 84% of malignancies at this same false positive rate. Follow-up data were received and repeat consultations were performed in 23 cases in which active disease was subsequently demonstrated. In 12 of 23 cases, hCG-H(%) results were able to first identify active disease 0.5 to 11 months prior to rapidly rising hCG or detection of clinically active neoplasia. In the remaining 11 cases, hCG-H(%) active disease appeared at the same time as rising hCG or demonstrable clinical tumor., Discussion and Conclusion: hCG-H(%) appears to reliably identify active trophoblastic malignancy. It is a 100% sensitive marker for discriminating quiescent GTD from active GTN/choriocarcinoma. It is also a marker for the early detection of new or recurrent GTN/choriocarcinoma. The data presented appear sufficient to encourage the adoption of hCG-H as a tumor marker in trophoblastic disease. Further studies are now urgently required to confirm and extend our findings.

Objectives: Placental site trophoblastic tumor (PSTT) commonly presents with low and variable concentration of hCG immunoreactivity in serum which can be difficult to differentiate from early stage choriocarcinoma/gestational trophoblastic neoplasm (GTN) or quiescent gestational trophoblastic disease (quiescent GTD). Nontrophoblastic malignancies such as germ cell tumors or other tumors secreting low hCG must also be considered in the differential diagnosis. Because treatments for these conditions are different, a means of differentiating PSTT from other diagnoses is important. We investigate the usefulness of hCG-free beta-subunit to make this discrimination., Methods: Data collected on cases referred to the USA hCG Reference Service for consultation served as a basis for this retrospective analysis. There were 13 cases with histology proven PSTT and 12 with nontrophoblastic malignancy. hCG-free beta-subunit was measured by immunoassay and reported as a proportion of total hCG (hCG-free beta-subunit(%)). hCG-free beta-subunit(%) results were determined for all histologically proven cases of PSTT and for the nontrophoblastic malignancies. Comparisons of hCG-free beta-subunit(%) were made and compared with those of the 82 choriocarcinoma/GTN cases and 69 quiescent GTD cases. The accuracy of hCG-free beta-subunit(%) to discriminate these malignancies was analyzed by investigating the areas under receiver-operating characteristics curve +/- standard error., Results: hCG-free beta-subunit(%) was the predominant hCG form in cases of PSTT (mean +/- standard deviation, 60 +/- 19%) and nontrophoblastic malignancies (91 +/- 11%), thus discriminating these diagnoses from choriocarcinoma/GTN (9.3 +/- 9.2%) and from quiescent GTD (5.4 +/- 7.8%). The cutoff of >35% free beta-subunit is proposed. At this cutoff, 100% detection at 0% false-positive is achieved. The accuracy of hCG-free beta-subunit(%) for this discrimination is 100 +/- 0%. At a proposed cutoff of >80%, the free beta-subunit test will also distinguish PSTT from nontrophoblastic malignancy, with 77% detection at 23% false-positive or an accuracy of 92 +/- 3.2%., Conclusion: Measurement of the proportion hCG-free beta-subunit(%) was found to be useful in the diagnosis of PSTT using proposed cutoff values of >35% and >80%. While this finding needs to be confirmed by larger studies, it would be reasonable to measure hCG-free beta-subunit(%) whenever the diagnosis of PSTT is considered.

Objectives: A high proportion of women with persistent low levels of hCG, in the absence of pregnancy or any evidence of tumor, have received chemotherapy and hysterectomy for assumed malignancy. Such chemotherapy and surgery were ineffective and unwarranted. This study identifies the causes of persistent low level of hCG and provides guidelines for the management of these patients, preventing unnecessary treatment in the future., Methods: The USA hCG Reference Service has consulted on 170 women with low levels of hCG persisting for 3 months or longer. Serum total hCG was measured in the Diagnostic Products Corporation (DPC) Immulite assay and hyperglycosylated hCG in the Nichols Advantage test., Results: Among these 170 patients, the average persistent hCG result was 102 +/- 152 mIU/ml, with a range of 6.1-900 mIU/ml. Thirteen (7.6%) of the 170 patients had true malignancy, 5 had placental site trophoblastic tumor, 3 had other gestational trophoblastic neoplasms (GTN), and 5 had non-trophoblastic malignancies. The remaining 157 patients had false-positive hCG, quiescent gestational trophoblastic disease (quiescent GTD), or pituitary hCG (hCG of pituitary origin). Of 71 patients with false-positive hCG, 47 patients received chemotherapy and 9 had surgery that had no effect on the level of hCG. Five of these patients with false-positive hCG were being monitored for hydatidiform mole or GTN. The majority of these cases were first investigated following an incidental pregnancy test. Of 69 patients who had quiescent GTD, 41 received chemotherapy and 9 underwent hysterectomy. All these therapies were unnecessary and ineffective. While 21 patients with quiescent GTD followed incidental pregnancy tests, the majority were discovered while monitoring patients after treatment for hydatidiform mole or GTN/choriocarcinoma (n = 48). Seventeen cases of pituitary hCG were found among those women who were peri- or post-menopause. Two patients also received chemotherapy for assumed malignancy which was not present., Conclusion: Clinicians frequently assume that an elevated hCG implies that a patient is pregnant or has GTD or recurrent GTN, even when apart from the pregnancy test, no clinical evidence was found to support such a diagnosis. In most of these cases of persistent low hCG etiologies, all therapies were found unnecessary and ineffective. Guidelines are proposed for managing these patients. It is essential to demonstrate a malignancy clinically and with readily available biochemical tests before initiating therapy. This applies whether the patient is identified by an incidental pregnancy test or is actively being monitored for gestational trophoblastic disease.

Objectives: Current testing to determine a failing pregnancy requires two separate clinic visits to measure the hCG doubling rate. Diagnosing a failing pregnancy is often done in emergency departments where simplified and accelerated testing methods are needed. Here, we investigated hyperglycosylated hCG (hCG-H) for predicting pregnancy failure., Design and Methods: We studied two independent sets of patient samples collected in the early weeks of gestation. One set was urine samples, and the other was serum samples. In all cases, hCG and hCG-H were measured using automated chemiluminescence immunoassays. Concentrations of hCG and hCG-H were plotted on a scattergram, and levels in failing pregnancies were compared to those in continuing pregnancies., Results: Data indicated that a threshold level of hCG-H (13 microg/L) in both serum and urine samples defined the concentration below where pregnancies were likely to fail. This cut-off corresponded to 73% detection of failures at a 2.9% false positive rate using serum and 75% detection at a 15% false positive rate using urine. Using an hCG cut-off that corresponded to the same false positive rates, hCG detected only 42% of failures using serum and 43% of failures using urine., Conclusions: Our data indicate that hCG-H provides a much more accurate single test than hCG for assessing pregnancy outcome. Compatible with the use of serum or urine samples, a single hCG-H test might provide simpler, faster, and more accurate results for predicting the progress of a pregnancy than standard hCG testing.

Objective: To determine the sensitivity of seven over-the-counter pregnancy tests (OTC-PTs) using urine containing a mixture of human chorionic gonadotropin (hCG)-related molecules as found on the first day of missed menstrual period., Design: Blinded in vitro sensitivity analysis., Setting: Medical school laboratory., Participants: None., Interventions: Urine was tested with OTC-PT devices at titers of 100, 50, 25, 12.5, 6.3, and 0 mIU/mL hCG immunoreactivity, and laboratory workers rated their confidence in the test result based on whether the test result was a clear, sharp, and unquestionable band in the test window., Main Outcome Measures: Analytical sensitivity, defined as the urine concentration at which all OTC-PTs tested gave a positive result regardless of operator confidence score; clinical sensitivity of OTC-PTs, defined as the proportion of pregnancies likely to be detected on the first day of a missed period and calculated from the analytical sensitivity and a recently published regression curve for total urine hCG immunoreactivity in 25 urine samples from this period of gestation; percentage of tested devices showing a band in the test window at a specific hCG concentration measured devices positive; percentage faulty devices, defined as the proportion of tested devices failing to yield a band in the control window; and confidence score, determined from operator ratings for each device at each concentration of hCG., Results: First Response Early Result had an analytical sensitivity of 6.3 mIU/mL, which was estimated to detect greater than 95% of pregnancies on the day of missed period. The sensitivity of Clearblue Easy Earliest Results was 25 mIU/mL, which indicated detection of 80% of pregnancies. The sensitivity of the five other products was 100 mIU/mL or greater, indicating detection of 16% or less of pregnancies. Three of these last products included faulty devices., Conclusion: Universal claims for OTC-PTs of more than 99% laboratory accuracy and use as early as the first day of missed period, while cleared for use by the U.S. Food and Drug Administration, are ambiguous and inappropriate for many products, according to these data. The majority of products tested were found to detect only a small percentage of pregnancies on the first day of a missed menstrual period. Until more data become available on the actual clinical sensitivity of these products, pharmacists should advise consumers to be cautious in interpreting test results.

The USA hCG Reference Service is a consulting service with a specialized clinical laboratory aiding physicians in the interpretation of conflicting or nonrepresentative human chorionic gonadotropin (hCG) results. We have consulted on 189 cases with persistent low levels of hCG but no evidence of pregnancy or tumor. Quiescent gestational trophoblastic disease (GTD) was identified in 121 cases by the absence of invasive trophoblast antigen and nonresponse to chemotherapy (64 cases with a history of hydatidiform mole or gestational trophoblastic neoplasia (GTN) and 57 cases following antecedent pregnancy). Another 61 Reference Service cases hadfalse positive hCG, and we observed 7 cases with low levels of hCG of pituitary origin (hCG subsequently suppressed by estrogen-progesterone medication). Most disturbing is that the majority of these cases (68%) received needless therapy for assumed GTN/choriocarcinoma/placental site trophoblastic tumor before consultation with the Reference Service. One hundred twenty-eight of the 189 patients (77 of 121 with quiescent GTD, 48 of 61 withfalse positive hCG and 3 of 7 with pituitary hCG) underwent therapy ranging from single-agent chemotherapy (117 cases), to EMA-CO combination chemotherapy (etoposide, methotrexate, actinomycin D alternating with cyclophosphamide and vincristine) (16 cases), to hysterectomy and/or bilateral salpingo-oophorectomy (31 cases). False positive hCG and pituitary hCG would obviously not respond to these treatments, and no treated cases of quiescent GTD responded to chemotherapy orfully responded to hysterectomy. The continued needless treatment of patients with quiescent GTD, even after multiple publications, is entirely avoidable. Unfortunately, the number of needlessly treated cases referred to the Reference Service is increasing.

Background: False-positive hCG results can lead to erroneous diagnoses and needless chemotherapy and surgery. In the last 2 years, eight publications described cases involving false-positive hCG tests; all eight involved the AxSym test. We investigated the source of this abundance of cases and a simple fix that may be used by clinical laboratories., Methods: False-positive hCG was primarily identified by absence of hCG in urine and varying or negative hCG results in alternative tests. Seventeen false-positive serum samples in the AxSym test were evaluated undiluted and at twofold dilution with diluent containing excess goat serum or immunoglobulin., Results: We identified 58 patients with false-positive hCG, 47 of 58 due to the Abbott AxSym total hCGbeta test (81%). Sixteen of 17 of these "false-positive" results (mean 100 mIU/ml) became undetectable when tested again after twofold dilution., Conclusions: A simple twofold dilution with this diluent containing excess goat serum or immunoglobulin completely protected 16 of 17 samples from patients having false-positive results. It is recommended that laboratories using this test use twofold dilution as a minimum to prevent false-positive results.

Objective: The purpose of this study was to investigate the validity of home pregnancy tests (HPTs) around the time of the missed menses., Study Design: Levels of human chorionic gonadotropin (hCG) were determined in urine around the time of the missed menses, and 5th and 95th centiles were calculated. In a blind study evaluating 18 brands of HPTs, each was tested six times with five concentrations of hCG, 0 to 100 mIU/mL. Sensitivity was defined as the concentration at which six of six brands gave positive results, at the suggested reading time or at an extended time., Results: It was estimated that a sensitivity of 12.5 mIU/mL was needed to detect 95% of pregnancies at the time of missing menses. Only 1 of 18 HPTs had this sensitivity. If faintly discernible results considered, 2 of 18 brands gave false-positive or invalid results. Clear positive results were given by only 44% of the brands at 100 mIU/mL hCG. If one accepted faintly discernible and extended reading times, all brands responded at 100 mIU/mL. A test with 100 mIU/mL sensitivity would detect approximately 16% of pregnancies at the time of missed menses., Conclusion: The utility of HPTs is questioned. Clinicians need to be aware of the limitations of current HPT brands.

Objectives: Hyperglycosylated human chorionic gonadotrophin (hCG) is an hCG variant with extra-large O-linked oligosaccharides, produced by phenotypically invasive cytotrophoblast cells in choriocarcinoma and pregnancy. It is the principal form of hCG produced in the first weeks of gestation. We investigated the importance of hyperglycosylated hCG in pregnancy testing and its detection by current hCG tests., Design and Methods: We measured the concentration of hyperglycosylated hCG and total hCG in 512 pregnancies throughout gestation. We assessed and compared the abilities of 14 commonly used commercial laboratory hCG tests and 18 home pregnancy tests to detect regular and hyperglycosylated hCG., Results: Hyperglycosylated hCG is the principal source of hCG-related immunoreactivity in early pregnancy. In the week following missing menses, hyperglycosylated hCG measurements may be more sensitive than regular hCG measurements in detecting pregnancy. Of 14 commercial laboratory hCG tests, 3 appropriately detected hyperglycosylated hCG standard. Of 18 different home pregnancy products 11 poorly or very poorly detected this key antigen., Conclusions: Hyperglycosylated hCG may be the key molecule in the detection of early pregnancy. However, the majority of tests poorly detected or failed to detect this key antigen. New pregnancy tests are needed that either solely detect hyperglycosylated hCG or equally detect regular hCG and hyperglycosylated hCG.

Objective: This study was undertaken to evaluate the significance of persistent low-level human chorionic gonadotropin (hCG) titers (usually <50 IU/L) in the absence of clinical evidence of pregnancy or gestational trophoblastic disease., Study Design: The USA hCG Reference Service consulted on 114 cases with persistent low levels of hCG; 51 had false-positive hCG results. The remaining 63 cases had real hCG results and are presented here., Results: Antecedent gestational events included hydatidiform mole (27), pregnancy (35), and gestational trophoblastic neoplasm (1). Forty of the 63 (64%) cases received therapy, including chemotherapy (38), hysterectomy (2), or both (10). Despite treatment, in all cases, low hCG titers persisted. After 1 to 4.5 years of low titers, four women had a sudden rapid increase in hCG levels, and malignant disease was confirmed or clearly suggested (gestational trophoblastic neoplasm [3] and placental site trophoblastic tumor [1]). Invasive trophoblast antigen (ITA) is a marker of invasive cytotrophoblast cells. ITA was measured in 38 of the cases with persistent low hCG, in all cases ITA accounted for less than 25% of the hCG concentration. It was also determined in the 4 cases indicated with malignant disease, accounting for more than 80% of the hCG., Conclusion: The presence of persistent low-level hCG titers defines a subset of women with preinvasive or quiescent gestational trophoblastic disease. ITA effectively detected the presence or absence of invasive cells in these cases. The recommended management of the quiescent disease is close surveillance without therapy until malignant disease detected.

Background: Home pregnancy testing devices claim >99% diagnostic accuracy for pregnancy and utility on the first day of the missed menses or earlier. We investigated the forms of human chorionic gonadotropin (hCG) in early pregnancy urines, the diagnostic accuracy claim, and the abilities of 15 devices to detect the different forms of hCG., Methods: We measured the concentrations of regular hCG and hyperglycosylated hCG (H-hCG, a large hCG variant) in 592 urines. Fifteen home devices were tested according to manufacturers' instructions with regular hCG and H-hCG diluted in urine., Results: H-hCG was the principal hCG-related molecule in pregnancy urine in the 2 weeks following the missed menses (61% and 50% of total immunoreactivity in the 4th and 5th completed weeks of pregnancy, respectively). Of 15 home test devices, 2 had a detection limit of 6.3 IU/L for regular hCG, but poorer detection of H-hCG. Two devices detected 13 IU/L regular hCG, one with similar detection and one with poorer detection of H-hCG. Ten devices detected 25 IU/L regular hCG, 6 with poorer detection of H-hCG. One device detected 50 IU/L regular hCG, but better detected H-hCG. Overall, 9 of 15 devices did not detect H-hCG as well as regular hCG., Conclusions: H-hCG is the principal hCG immunoreactivity in early pregnancy urine. Home tests vary widely in detection limits for regular hCG (6.3-50 IU/L), and 9 of 15 devices (60%) had poorer detection limits for H-hCG than for hCG. The variation in analytical detection limits appears contradictory to the common claim for all devices of >99% detection of pregnancy on the first day of the missed menses or earlier. We suggest that manufacturers calibrate devices for both hCG and H-hCG and determine the detection rates for pregnancy rather than the proportion of positive results at arbitrary hCG concentrations.