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

INTRODUCTION: There is no global agreement on how to best determine pregnancy of unknown location viability and location using biomarkers. Measurements of progesterone and ß human chorionic gonadotropin (ßhCG) are still used in clinical practice to exclude the possibility of a viable intrauterine pregnancy (VIUP). We evaluate the predictive value of progesterone, ßhCG, and ßhCG ratio cut-off levels to exclude a VIUP in women with a pregnancy of unknown location. MATERIAL AND METHODS: This was a secondary analysis of prospective multicenter study data of consecutive women with a pregnancy of unknown location between January 2015 and 2017 collected from dedicated early pregnancy assessment units of eight hospitals. Single progesterone and serial ßhCG measurements were taken. Women were followed up until final pregnancy outcome between 11 and 14 weeks of gestation was confirmed using transvaginal ultrasonography: (1) VIUP, (2) non-viable intrauterine pregnancy or failed pregnancy of unknown location, and (3) ectopic pregnancy or persisting pregnancy of unknown location. The predictive value of cut-off levels for ruling out VIUP were evaluated across a range of values likely to be encountered clinically for progesterone, ßhCG, and ßhCG ratio. RESULTS: Data from 2507 of 3272 (76.6%) women were suitable for analysis. All had data for ßhCG levels, 2248 (89.7%) had progesterone levels, and 1809 (72.2%) had ßhCG ratio. The likelihood of viability falls with the progesterone level. Although the median progesterone level associated with viability was 59 nmol/L, VIUP were identified with levels as low as 5 nmol/L. No single ßhCG cut-off reliably ruled out the presence of viability with certainty, even when the level was more than 3000 IU/L, there were 39/358 (11%) women who had a VIUP. The probability of viability decreases with the ßhCG ratio. Although the median ßhCG ratio associated with viability was 2.26, VIUP were identified with ratios as low as 1.02. A progesterone level below 2 nmol/L and ßhCG ratio below 0.87 were unlikely to be associated with viability but were not definitive when considering multiple imputation. CONCLUSIONS: Cut-off levels for ßhCG, ßhCG ratio, and progesterone are not safe to be used clinically to exclude viability in early pregnancy. Although ßhCG ratio and progesterone have slightly better performance in comparison, single ßhCG used in this manner is highly unreliable.

Systematic review of immunoglobulin use in paediatric neurological and neurodevelopmental disorders.

AIM: A systematic literature review of intravenous immunoglobulin (IVIG) treatment of paediatric neurological conditions was performed to summarize the evidence, provide recommendations, and suggest future research. METHOD: A MEDLINE search for articles reporting on IVIG treatment of paediatric neuroinflammatory, neurodevelopmental, and neurodegenerative conditions published before September 2015, excluding single case reports and those not in English. Owing to heterogeneous outcome measures, meta-analysis was not possible. Findings were combined and evidence graded. RESULTS: Sixty-five studies were analysed. IVIG reduces recovery time in Guillain-Barré syndrome (grade B). IVIG is as effective as corticosteroids in chronic inflammatory demyelinating polyradiculoneuropathy (grade C), and as effective as tacrolimus in Rasmussen syndrome (grade C). IVIG improves recovery in acute disseminated encephalomyelitis (grade C), reduces mortality in acute encephalitis syndrome with myocarditis (grade C), and improves function and stabilizes disease in myasthenia gravis (grade C). IVIG improves outcome in N-methyl-d-aspartate receptor encephalitis (grade C) and opsoclonus-myoclonus syndrome (grade C), reduces cataplexy symptoms in narcolepsy (grade C), speeds recovery in Sydenham chorea (grade C), reduces tics in selected cases of Tourette syndrome (grade D), and improves symptoms in paediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (grade B). INTERPRETATION: IVIG is a useful therapy in selected neurological conditions. Well-designed, prospective, multi-centre studies with standardized outcome measures are required to compare treatments.

Do women with pain and bleeding in early pregnancy require a vaginal speculum examination as part of their assessment?

AIMS: To investigate whether a vaginal speculum examination (VSE) prior to a transvaginal scan (TVS) alters the diagnosis or management of women who complain of bleeding in early pregnancy. METHODS: A prospective study. Women were asked to describe their bleeding as heavy, moderate or light and to consent to VSE prior to TVS. TVS was performed to obtain a final diagnosis of pregnancy outcome. RESULTS: 221 consecutive women were included in the study. In 14.5% (n = 32) complaining of heavy bleeding, blood was seen in all but two VSE and 84% (n = 27) had a miscarriage diagnosed by TVS. Products of conception were removed in 18.8% (n = 6), but this did not alter the subsequent immediate management of any cases. 65.2% (n = 144) of women complained of light bleeding, blood was seen on VSE in 53% (n = 77). Of these women, 25% (n = 19) of those where blood was seen had a miscarriage, compared to 6% (n = 4) of women where blood was not seen. A cervical ectropion was visualised in 11.7% (n = 26) and 2.3% (n = 5) had a cervical polyp. No other clinically significant pathology was detected. CONCLUSION: The amount of bleeding reported by women in early pregnancy relates well with VSE findings. Performing a VSE did not alter the subsequent management of these patients. This study demonstrates that routine objective assessment of blood by a clinician performing VSE prior to a TVS is unnecessary.

Accurate prediction of pregnancy viability by means of a simple scoring system.

STUDY QUESTION: What is the performance of a simple scoring system to predict whether women will have an ongoing viable intrauterine pregnancy beyond the first trimester? SUMMARY ANSWER: A simple scoring system using demographic and initial ultrasound variables accurately predicts pregnancy viability beyond the first trimester with an area under the curve (AUC) in a receiver operating characteristic curve of 0.924 [95% confidence interval (CI) 0.900-0.947] on an independent test set. WHAT IS KNOWN ALREADY: Individual demographic and ultrasound factors, such as maternal age, vaginal bleeding and gestational sac size, are strong predictors of miscarriage. Previous mathematical models have combined individual risk factors with reasonable performance. A simple scoring system derived from a mathematical model that can be easily implemented in clinical practice has not previously been described for the prediction of ongoing viability. STUDY DESIGN, SIZE AND DURATION: This was a prospective observational study in a single early pregnancy assessment centre during a 9-month period. PARTICIPANTS/MATERIALS, SETTING AND METHODS: A cohort of 1881 consecutive women undergoing transvaginal ultrasound scan at a gestational age <84 days were included. Women were excluded if the first trimester outcome was not known. Demographic features, symptoms and ultrasound variables were tested for their influence on ongoing viability. Logistic regression was used to determine the influence on first trimester viability from demographics and symptoms alone, ultrasound findings alone and then from all the variables combined. Each model was developed on a training data set, and a simple scoring system was derived from this. This scoring system was tested on an independent test data set. MAIN RESULTS AND THE ROLE OF CHANCE: The final outcome based on a total of 1435 participants was an ongoing viable pregnancy in 885 (61.7%) and early pregnancy loss in 550 (38.3%) women. The scoring system using significant demographic variables alone (maternal age and amount of bleeding) to predict ongoing viability gave an AUC of 0.724 (95% CI = 0.692-0.756) in the training set and 0.729 (95% CI = 0.684-0.774) in the test set. The scoring system using significant ultrasound variables alone (mean gestation sac diameter, mean yolk sac diameter and the presence of fetal heart beat) gave an AUC of 0.873 (95% CI = 0.850-0.897) and 0.900 (95% CI = 0.871-0.928) in the training and the test sets, respectively. The final scoring system using demographic and ultrasound variables together gave an AUC of 0.901 (95% CI = 0.881-0.920) and 0.924 (CI = 0.900-0.947) in the training and the test sets, respectively. After defining the cut-off at which the sensitivity is 0.90 on the training set, this model performed with a sensitivity of 0.92, specificity of 0.73, positive predictive value of 84.7% and negative predictive value of 85.4% in the test set. LIMITATIONS, REASONS FOR CAUTION: BMI and smoking variables were a potential omission in the data collection and might further improve the model performance if included. A further limitation is the absence of information on either bleeding or pain in 18% of women. Caution should be exercised before implementation of this scoring system prior to further external validation studies WIDER IMPLICATIONS OF THE FINDINGS: This simple scoring system incorporates readily available data that are routinely collected in clinical practice and does not rely on complex data entry. As such it could, unlike most mathematical models, be easily incorporated into normal early pregnancy care, where women may appreciate an individualized calculation of the likelihood of ongoing pregnancy viability. STUDY FUNDING/COMPETING INTEREST(S): Research by V.V.B. supported by Research Council KUL: GOA MaNet, PFV/10/002 (OPTEC), several PhD/postdoc & fellow grants; IWT: TBM070706-IOTA3, PhD Grants; IBBT; Belgian Federal Science Policy Office: IUAP P7/(DYSCO, `Dynamical systems, control and optimization', 2012-2017). T.B. is supported by the Imperial Healthcare NHS Trust NIHR Biomedical Research Centre. TRIAL REGISTRATION NUMBER: Not applicable.

Improved modeling of clinical data with kernel methods.

OBJECTIVE: Despite the rise of high-throughput technologies, clinical data such as age, gender and medical history guide clinical management for most diseases and examinations. To improve clinical management, available patient information should be fully exploited. This requires appropriate modeling of relevant parameters. METHODS: When kernel methods are used, traditional kernel functions such as the linear kernel are often applied to the set of clinical parameters. These kernel functions, however, have their disadvantages due to the specific characteristics of clinical data, being a mix of variable types with each variable its own range. We propose a new kernel function specifically adapted to the characteristics of clinical data. RESULTS: The clinical kernel function provides a better representation of patients' similarity by equalizing the influence of all variables and taking into account the range r of the variables. Moreover, it is robust with respect to changes in r. Incorporated in a least squares support vector machine, the new kernel function results in significantly improved diagnosis, prognosis and prediction of therapy response. This is illustrated on four clinical data sets within gynecology, with an average increase in test area under the ROC curve (AUC) of 0.023, 0.021, 0.122 and 0.019, respectively. Moreover, when combining clinical parameters and expression data in three case studies on breast cancer, results improved overall with use of the new kernel function and when considering both data types in a weighted fashion, with a larger weight assigned to the clinical parameters. The increase in AUC with respect to a standard kernel function and/or unweighted data combination was maximum 0.127, 0.042 and 0.118 for the three case studies. CONCLUSION: For clinical data consisting of variables of different types, the proposed kernel function--which takes into account the type and range of each variable--has shown to be a better alternative for linear and non-linear classification problems.

Ectopic pregnancy: using the hCG ratio to select women for expectant or medical management.

OBJECTIVE: To identify variables that can be used to select women with an ectopic pregnancy for expectant or medical management with systemic methotrexate. DESIGN: Cohort study. SETTING: Early Pregnancy Unit of a London teaching hospital. POPULATION: Women with a tubal ectopic pregnancy managed non-surgically. METHODS: The diagnosis of tubal ectopic pregnancy was made using transvaginal sonography. Human chorionic gonadotrophin (hCG) levels had to be taken at 0 hour and 48 hours pre-treatment. Other recorded variables include presenting complaints, gestational age, progesterone levels, size of the ectopic mass and appearance of the ectopic on transvaginal sonography. Women were followed up until the outcome (success or failure) of management was known. MAIN OUTCOME MEASURES: Univariable analysis was performed to identify the variables associated with successful management using area under curves and relative risks. RESULTS: Thirty-nine women underwent expectant management (overall success rate 71.8%) and 42 had medical management (overall success rate 76.2%). The pre-treatment hCG ratio (hCG 48 hours/hCG 0 hour) was related to the failure of both expectant (area under curve 0.86, 95% CI 0.67-0.94) and medical (area under curve 0.79, 95% CI 0.58-0.90) management. History of ectopic pregnancy was related to failure of expectant management only (relative risk 0.46, 95% CI 0.16-0.92). CONCLUSIONS: The most important variable for predicting the likelihood of successful non-surgical management was the pre-treatment hCG ratio. New studies are required to validate the use of this variable and of history of ectopic pregnancy to predict the likelihood of successful non-surgical management in clinical practice.

Is serum human chorionic gonadotrophin follow-up necessary after suspected spillage of trophoblast at the time of laparoscopic surgery for ectopic pregnancy?

BACKGROUND: Persistent trophoblast is a recognised complication of salpingostomy for the treatment of ectopic pregnancy, with reported rates of 3-20%; hence, women are advised to have serum human chorionic gonadotrophin (hCG) levels monitored post-operatively. Although much less common, there are also reports of disseminated trophoblastic peritoneal implants after laparoscopic salpingectomy. The aim of this study was to assess whether monitoring of post-operative serum hCG levels is necessary in women undergoing salpingectomy, where intra-operative spillage of trophoblast is thought to have occurred. METHODS: This was a retrospective study of women who underwent serum hCG follow-up after salpingectomy. Serum hCG levels were monitored if: (1) the ectopic pregnancy was found to be ruptured; (2) there was a significant haemoperitoneum (>500 ml); (3) there was thought to be spillage of trophoblast at the time of salpingectomy or (4) a tubal miscarriage was diagnosed. Serum hCG levels were taken at days 1-2, days 3-4, days 6-8 or days 13-15 post-surgery. Women were followed up until the serum hCG level was <15 IU/l. Persistent trophoblast was defined as a failure of the serum hCG level to decrease spontaneously after surgery. RESULTS: 105 women underwent serum hCG follow-up after a laparoscopy for a tubal ectopic pregnancy. Of these women, 92 had a laparoscopic salpingectomy and 13 were diagnosed with a tubal miscarriage at the time of laparoscopy. In all women the serum hCG decreased spontaneously. CONCLUSION: It does not appear necessary to routinely monitor serum hCG levels post-operatively in women diagnosed with tubal miscarriages, in those undergoing salpingectomy for a ruptured ectopic pregnancy or in cases of salpingectomy, where there is thought to be spillage of trophoblast.

Pregnancies of unknown location.

A 'pregnancy of unknown location' is a descriptive term used to classify a pregnancy when a woman has a positive pregnancy test, but no pregnancy can be visualised on transvaginal ultrasound (TVS). Women should be followed up until the final pregnancy outcome is known which includes: failing PUL, intra-uterine pregnancy, ectopic pregnancy and persisting PUL. Expectant management has been shown to be safe and surgical intervention in the form of uterine curettage and diagnostic laparoscopy should not be undertaken routinely. Serum human chorionic gonadotrophin levels, progesterone levels and mathematical models all have a role in the prediction of PUL outcome. This review discusses the various aspects of management of women with a PUL.

Why are some ectopic pregnancies characterized as pregnancies of unknown location at the initial transvaginal ultrasound examination?

OBJECTIVE: To compare the appearance and behavior of ectopic pregnancies (EPs) initially classified as pregnancies of unknown location (PULs) to those visualized on the initial transvaginal ultrasound scan (TVS). METHODS: An observational study over a four-year period on women undergoing a TVS prior to diagnosis of a tubal EP. Demographic details, presenting symptoms, TVS findings, serum hCG and progesterone levels were recorded at the time of the initial TVS and at the time of diagnosis of the EP in those initially classified as a PUL. RESULTS: 411 women with a tubal EP underwent a TVS prior to treatment. In 85.9% (353/411) the EP was visualized on the initial TVS while 14.1%(58/411) were initially classified as PULs. Those initially classified as PULs had significantly lower mean gestational age and mean initial human chorionic gonadotrophin (hCG) levels, and significantly higher mean progesterone level at presentation than those where the EP was visualized on the initial TVS. Of those with a PUL, 60.3% (35/58) had the EP subsequently visualized on TVS. At the time of diagnosis these EPs were significantly smaller (p<0.0001); the appearance of the EPs, serum hCG and progesterone levels at the time of visualization on TVS were not significantly different from those visualized on the initial TVS. CONCLUSION: In women with EPs who are initially classified as PULs, failure of visualization of the EP on the initial TVS is likely to be due to the fact that they are too small and probably too early in the disease process.

The simple outpatient management of Bartholin's abscess using the Word catheter: a preliminary study.

INTRODUCTION: Bartholin's cysts/abscess affects 2% of women. Conventional treatment is marsupialisation under general anaesthetic. We evaluated a conservative approach in a non-randomised prospective interventional study over 12 months. METHOD: Women with a Bartholin's abscess were counselled and those who opted for the Word catheter (WC) had it inserted under local anaesthetic (follow up at one week and four weeks, when catheter was removed). Women recorded pain scores and completed a qualitative questionnaire and had telephone follow up at six months. Outcome measures were abscess resolution and acceptability of treatment. RESULTS: Fifty-eight women attended with a Bartholin's abscess requiring drainage. Twenty-three of 58 (40%) elected for marsupialisation. Thirty-five of 58 (60%) women had a WC inserted. Twenty-seven of 35 (77%) women retained their catheter for four weeks (three catheters fell out within 24 h of insertion, three catheters fell out within one week, one fell out after 11 days and there was one failed insertion). One woman had a recurrence six months after treatment. Abscess resolution occurred in 34 of 35 (97%). No woman reported significant discomfort at one week. Twenty-four of 27 women (89%) said that if they suffered a recurrence, they would have another WC inserted. Three of 27 (11%) women had intercourse within the second week of catheter insertion and reported that it was not uncomfortable. Fourteen women who had marsupialisation were traced and none had suffered a recurrence six months after treatment. CONCLUSIONS: The WC is a safe and effective treatment for a Bartholin's abscess. It may be considered as an alternative to marsupialisation.

Hyperemesis gravidarum: is an ultrasound scan necessary?

BACKGROUND: Traditionally, in cases of hyperemesis gravidarum (HG), an ultrasound evaluation is recommended to confirm viability and to exclude multiple pregnancies and gestational trophoblastic disease (GTD). Our aim was to perform a case-control study to evaluate the incidence of these findings. METHODS: Each case of HG was matched for gestational age with the next ultrasound examination performed in an asymptomatic pregnancy. The findings were compared between the two groups. RESULTS: Two hundred and eighty-six cases of HG were matched with 286 asymptomatic women. The total number of viable pregnancies was higher in the HG group (280/286, 97.9%) than that in the control group (265/286, 92.6%; P = 0.006). The incidence of twins was 3.1% in each group (P > 0.999). The incidence of early pregnancy failure was 0.7% in women with HG compared to 7.0% in asymptomatic women (odds ratio 0.09, 95% CI 0.01-0.04, P < 0.0001). The one case of GTD was in the HG group; however, this case also presented with vaginal bleeding. CONCLUSIONS: Pregnancies complicated by HG had a similar risk of twin pregnancy, and a lower risk of early pregnancy failure compared to controls. In the absence of vaginal bleeding, there was no increase in GTD in women with HG. We conclude that an ultrasound scan is not clinically necessary in women presenting with HG, other than for maternal reassurance.