Identification of Putative Biomarkers in Cerebral Palsy: A Meta-Analysis and Meta-Regression.

BACKGROUND: Cerebral palsy (CP) is a neurological disorder that impairs motor abilities. Identifying maternal biomarker derangements can facilitate further evaluation for early diagnosis, potentially leading to improved clinical outcomes. This study investigates the association between maternal biomarker derangements and CP development during the antenatal period. METHODS: A systematic search was conducted in MEDLINE, EMBASE, and Cochrane databases, following MOOSE guidelines. Data on participants exceeding biomarker thresholds (95th and 5th percentiles) were extracted for combined odds ratio estimation. Geometric mean differences, reported as multiples of the median (MoMs), were used to analyze changes in marker levels. Trimesterwise subgroup analysis and metaregression assessed the impact of variables on outcomes. RESULTS: Five observational studies (1552 cases, 484,985 controls) revealed lower maternal pregnancy-associated plasma protein A levels were associated with CP (pooled odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.22 to 2.09; I = 0%), with a -0.04 MoM geometric mean difference. Lower maternal beta-human chorionic gonadotropin (HCG) levels in first and second trimesters indicated a pooled OR = 1.18 (95% CI = 0.85 to 1.63; I = 57%). Sensitivity analysis showed an OR = 1.40 (95% CI = 1.08 to 1.82; I = 0%), with a -0.07 MoM geometric mean difference. Metaregression identified primigravida status as negatively influencing beta-HCG levels. Elevated nuchal translucency values and CP presented a pooled OR = 1.06 (95% CI = 0.77 to 1.44; I = 0%). CONCLUSION: Lower maternal pregnancy-associated plasma protein A levels during the first trimester and lower beta-HCG levels in the first and second trimesters are associated with CP development in children. Future research should validate the predictive utility of these biomarkers and explore novel ones through large-scale cohort studies.

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

PURPOSE: To compare Expectant management to systemic methotrexate in the management of persistent pregnancy of unknown location with beta-hCG levels below the discrimination zone. METHODS: A retrospective cohort study was conducted on 71 women with persistent pregnancy of unknown location. They were divided into two groups according to the applied management; Group 1, (n = 40) who were managed expectantly and Group 2 (n = 31) who were given a single dose of methotrexate. Data variables were collected and analyzed to evaluate whether expectant management was as effective as methotrexate. RESULTS: There was no significant difference between the two groups regarding age, parity, gestational age, body mass index and day seven beta-hCG. Success rates were (32 patients (80%) and 28 patients (90.3%) in expectant management and methotrexate groups, respectively (P > 0.05). The mean values for day zero and day four beta-hCG were significantly higher and the mean duration for complete recovery was statistically shorter in the methotrexate group (P < 0.05). There were no significant differences between the two groups regarding prior ectopic, percentage of beta-hCG level drop on day four and day seven, success rate, occurrence of sequelae and patient satisfaction that area under the curve (AUC) for group 1 (expectant management) is 0.566 at 95% Confidence Interval of (0.388: 0.745). CONCLUSION: Expectant management is an effective and safe alternative to single-dose methotrexate for persistent PUL with beta-hCG levels below the discrimination zone.

Extragonadal Nongestational Choriocarcinoma With a Widespread Metastasis in a Young Female: A Case Report and Literature Analysis With a Focus on Unmet Needs.

Choriocarcinoma is a highly aggressive malignant tumor that occurs due to the formation of an abnormal trophoblast. Choriocarcinoma is classified into gestational (GC) and nongestational (NGC) subtypes. The majority of nongestational diseases are limited to ovaries. Extragonadal NGC is a sporadic occurrence and a diagnostic and therapeutic dilemma. Here, we present a young 24-year-old female who presented with a widespread metastatic disease to the brain, bilateral kidneys, lungs, liver, pancreas, and small bowel. She was diagnosed with extragonadal NGC, probably originating from her kidneys. She responded poorly to standard first-, second-, and third-line chemotherapies. Detailed literature analysis with various aspects of pathogenesis, diagnostic criteria, clinical presentation, and treatment options are discussed. There is an unmet need for further research and consensus on many aspects of this rare disease.

Increase in the level of ß-HCG after uterine artery embolization in the context of partial molar pregnancy: A case report.

This report documents the case of a patient with a previously diagnosed partial molar pregnancy evacuated by dilation and suction curettage with appropriately declining post-operative levels of beta-human chorionic gonadotropin (beta-hCG), who, one month later, underwent uterine artery embolization in the setting of acute bleeding and imaging concerning for arteriovenous malformation. After embolization, beta-hCG levels increased, prompting concern for gestational trophoblastic neoplasia and referral to gynecologic oncology. With further workup, the elevation was found to be transient and benign - a phenomenon not previously described.

Thyrotoxicosis in the Setting of Hydatidiform Mole with Subsequent Development of Takotsubo Cardiomyopathy Complicated by COVID-19.

We present a rare case of hydatidiform molar pregnancy, which led to the development of thyroid storm, followed by a rare complication of takotsubo cardiomyopathy in the setting of a COVID-19 infection. A 21-year-old female of 22 weeks gestational age presented with heavy vaginal blood loss, brown emesis, tachycardia, and lethargy. Through clinical presentation and ultrasound confirmation, a molar pregnancy was diagnosed. Laboratory data and clinical presentation of thyrotoxicosis supported a diagnosis of thyroid storm. Test for COVID-19 was positive. The patient was treated with dilation and curettage, antithyroid medication, and blood transfusions, resulting in symptom resolution. Thereafter, echocardiography confirmed takotsubo cardiomyopathy. It is suspected that the homology in structure between the human chorionic gonadotropin (hCG) and thyroid stimulating hormone subunits resulted in thyroid storm secondary to receptor cross-reactivity. We speculate that subsequent cardiovascular stress of b-hCG-induced thyroid storm with superimposed COVID-19 infection facilitated the development of Takotsubo cardiomyopathy.

High initial ß-hCG predicts IVF outcomes accurately and precludes the need for repeated measurements.

This study evaluated ß-human chorionic gonadotropin (hCG) changes during the early period of pregnancy in an attempt to predict successful pregnancy outcomes in ART. It determined the median values of the ß-hCG and the 2-day ß-hCG increments of clinical vs biochemical pregnancies. The results of fresh day 3 embryo, frozen day 3 embryo, and frozen day 5 embryo transfers were evaluated. The cutoff values of ß-hCG and the 2-day increments predicting clinical pregnancy and delivery were determined. All women who underwent embryo transfer and had a singleton pregnancy from January 2017 to December 2019 were included. As expected, clinical pregnancies had higher initial median ß-hCG values compared to biochemical pregnancies (fresh day 3 (400 vs 73 mIU/mL), frozen day 3 (600 vs 268.5 mIU/mL) and frozen day 5 (937 vs 317 mIU/mL)). Nonetheless, the abortion rate was significantly lower in the group with ß-hCG above the cutoff values in fresh (141 mIU/mL) and frozen (354.5 mIU/mL) cleavage stage transfers (17.2% vs 44%, P < 0.001 and 18.5% vs 38%, P = 0.003, respectively). Blastocyst transfers resulted in higher median initial ß-hCG compared to cleavage embryo transfers (937 vs 600 mIU/mL), and the initial ß-hCG values from frozen cleavage embryos were higher compared to fresh cleavage embryos (600 vs 400 mIU/mL). Earlier implantation in frozen cycles may be caused by freezing-thawing procedures. Moreover, in fresh cycles, negative effects of the hormonal milieu of fresh cycles may delay implantation. These results indicate that high initial ß-hCG and high 2-day ß-hCG increments demonstrated better outcomes, including more clinical pregnancies and fewer abortions.

Testicular neoplasms: the interrelationships of serum levels of microRNA-371a-3p (M371) and classical tumor markers with histology, clinical staging, and age-a statistical analysis.

PURPOSE: In testicular neoplasms, the interrelationship of elevations of the novel serum tumor marker microRNA-371a-3p (M371) and traditional markers with other clinical features is still incompletely understood. The present study evaluated marker expression rates in relation to various other clinical parameters. METHODS: The following data were retrospectively registered from 641 consecutive patients with testicular neoplasms: histology, such as seminoma (n = 365), nonseminoma (n = 179), benign tumor (n = 79), other malignant tumor (n = 18); patients age (years); clinical stage (CS1, CS2a/b, CS2c, CS3); and preoperative elevation of beta HCG, AFP, LDH, M371 (yes/no). Descriptive statistical methods were employed with comparisons of various subgroups to disclose associations of marker expression rates with age, histology and CS, and of age with histology. RESULTS: The histologic subgroups revealed significantly different expression rates of tumor markers. M371 performed best with expression rates of 82.69% and 93.58% in seminoma and in nonseminoma, respectively. In germ cell tumors, all markers had significantly higher expression rates in metastasized stages than in localized disease. All markers except LDH have significantly higher expression rates in younger than in older patients. Nonseminoma is most prevalent in the youngest age category, seminoma predominates in patients > 40 years, other malignancies were restricted to patients > 50 years. CONCLUSION: The study documented significant associations of serum marker expression rates with histology, age and clinical staging, with highest rates in nonseminomas, young age and advanced clinical stages. M371 showed significantly higher expression rates than other markers suggesting its superior clinical usefulness.

Epithelioid trophoblastic tumor: A case series.

An epithelioid trophoblastic tumor (ETT) is an extremely rare gestational trophoblastic tumor. Cases of ETT present with abnormal vaginal bleeding in women of reproductive age group with marginally elevated beta human chorionic gonadotrophin (B-hCG) levels. Here, we describe a series of four patients (all were females) including histomorphology, immunoprofiles, and diagnostic difficulty of this rare entity. All cases were in their reproductive age group. The mean pre-treatment hCG level was 665.24 (mIU/mL). Microscopically, all cases had a tumor showing an epithelioid appearance arranged in large nests and sheets. Individual tumor cells were round to polygonal with abundant eosinophilic cytoplasm, with central vesicular nuclei and prominent nucleoli. Areas of hemorrhage, necrosis, and intercellular hyaline-like material deposition were identified in all cases (100%). Immunohistochemically, tumor cells in all cases showed diffuse positivity for AE1/AE3 and p63 (100%). GATA3 was available in one case (25%), which was positive in the tumor cells. In one case (25%), hPL was focally positive, and in one case (25%), it was negative. SALL4 was performed in two cases (50%) and was negative in tumor cells. The mean Ki67 labeling index was 19.2 (range 10-30%). All four patients underwent surgical intervention and were treated with hysterectomy. The mean follow-up in this series was 39.4 months (range 6-70), and all patients are alive to date with a mean survival of 32.8 months (range, 4-67).

Clinical consequences of maternal serum PAPP-A and free beta hCG levels above 2.0 multiple of median in the first trimester screening.

INTRODUCTION: Extreme levels of either PAPP-A or free ß-hCG may be a serious clinical concern. A multicentre study was carried out to determine the frequency and clinical consequences of high (minimum 2,0 MoM) maternal (PAPP)-A and free beta hCG. METHODS: A total number of 8591 patients with singleton pregnancies between 11 + 0-13 + 6 weeks of gestation were enrolled. A total number of 612 cases with first trimester serum level of PAPP-A corresponding to ≥ 2,0 MoM and/or free ß-hCG to ≥ 2,0 MoM were included in the statistical analysis. All serum samples were analysed with Roche (Cobas) or Kryptor (Brahms) devices. A retrospective analysis of perinatal outcomes was conducted. RESULTS: Values of PAPP-A ≥ 2,0 MoM and free ß-hCG < 2.0 MoM were detected in 48,5% of patients (n = 297), free ß-hCG ≥ 2,0 MoM and PAPP-A concentration < 2,0 MoM in 38,1% of patients (n = 233) and both PAPP-A and free ß-hCG ≥ 2,0 multiple of median in 13,4% of patients (n = 82). The highest PAPP-A and free ß-hCG concentrations were 19,2 MoM and 16,3 MoM respectively. Patients with both PAPP-A and free ß-hCG above 2,0 MoM had a slightly higher (but statistically not significant) prevalence of history of low birthweight (8,3%). DISCUSSION: Pregnancy outcomes in women with normal ultrasound findings and high PAPP-A /free ß-hCG concentration are good. Higher prevalence of pregnancy complications was not detected in either extremely high PAPP-A and free ß-hCG concentration groups. In cases of normal ultrasound and isolated high (even extreme) biochemical markers levels the counselling should be comforting.

Successful Management of Persistent Gestational Trophoblastic Neoplasia: A Comprehensive Review and Case Analysis.

Gestational trophoblastic disease comprises hydatidiform mole (HM) (complete or partial) and gestational trophoblastic neoplasia (GTN). Complete and partial moles have different karyotypes, gross and microscopic histopathology, clinical presentation, prognosis, and chances of progress to GTN. Ultrasonography (USG) and human chorionic gonadotropin (hCG) quantification are commonly used to diagnose molar pregnancy and further follow-up until resolution. Our case reports two patients, one with a complete mole and another with a partial mole, who were evaluated and followed up with serial beta hCG as per protocol and were found to have persistent disease and referred for chemotherapy until complete resolution. Fifteen to 20% of the patients with complete moles and about 1-5% of patients with partial moles developed GTN, which is primarily invasive. Hence, proper follow-up and chemotherapy assure 100% curability.

Predictors of Successful Medical Management With Methotrexate in Unruptured Tubal Ectopic Pregnancy.

Introduction Medical treatment with methotrexate (MTX) is a safe and effective alternative to surgery in carefully selected cases of ectopic pregnancies diagnosed early prior to rupture. Aim To determine the optimal pre-treatment levels of beta human chorionic gonadotropin (𝛽-hCG) and its changing trends most likely to have a successful outcome with medical management. Material and methods A prospective observational study was conducted in a tertiary teaching hospital from December 2018 to May 2021. "Single-dose" MTX regime was used for medical management of ectopic pregnancy in patients fulfilling the selection criteria. The 𝛽-hCG levels were recorded at baseline and on day 4 and day 7 of MTX injection. Thereafter, at weekly intervals till complete resolution or surgical intervention due to failure of medical management. In addition, receiver operating characteristic (ROC) curve analysis for a pre-treatment 𝛽-hCG cut-off value and changing trends in post-treatment 𝛽- hCG levels most likely to have a successful outcome with MTX treatment were determined. Results Fifty patients fulfilling the inclusion criteria were included in the study, with successful medical management in 33 (66%). The mean pre-treatment 𝛽-hCG levels in women with successful medical management were 3270.97 (+/- 901) compared to 5249.17 (+/-808.02) for those with treatment failure (p=0.00001). The mean 𝛽-hCG level in the failed treatment group was significantly higher on day 4 than the pre-treatment levels (6742.56 +/- 572 vs. 5249.17+/- 808.02; p<0.05). Inadequate reduction of 𝛽-hCG level on day 7 (<15% of day 4 levels) requiring repeat dosage of MTX was more likely to have an unsuccessful outcome (p=0.00001). The area under curve (AUC) value of 0.905 (95% CI: 0.814-0.996) depicted that pre-treatment 𝛽-hCG level of 4000 mIU/ml taken as the cut-off value was able to predict levels ≤4000 mIU/ml had a greater likelihood of successful outcome with MTX, having a sensitivity of 84.5%, specificity of 83.3%, positive predictive value (PPV) of 90.3%, and negative predictive value (NPV) of 75% (p< 0.05). Demographic variables or previous clinical history, considered risk factors for ectopic pregnancy, did not affect the outcome of medical management in this study. Conclusion Medical management of ectopic pregnancy is a viable first-line treatment option in carefully selected patients. In this study, the most important predictors for the successful outcome of medical management were the pre-treatment ß-hCG levels and their fall on day 4 and day 7 after MTX therapy.

Hook effect in gestational trophoblastic disease: An emergency department case presentation.

Gestational trophoblastic disease is a process that affects ≈1 of 1000 pregnancies. If left untreated, this can progress to potentially life-threatening complications with malignancy such as choriocarcinoma.  The emergency physician must be aware of the presentation and complications of this disease process, including the difficulties in diagnosis.  In this case presentation, the authors discuss the presentation and diagnostic process of a patient in the emergency department as well as the phenomenon known as the hook effect, which may complicate the decision-making process.

Conservative Management of Interstitial Pregnancy With Beta-hCG of Over 39,000 mIU/mL: A Case Report.

Interstitial ectopic pregnancy can be a life-threatening condition as the myometrial tissue around the gestational sac is thin. Furthermore, the interstitial aspect of the fallopian tubes is highly vascularized. Thus, a rupture in this area can result in catastrophic hemorrhage, hemoperitoneum, and shock. Therefore, surgical management is often the preferred mode of therapy. This report identifies the successful medical management of a patient with interstitial ectopic pregnancy with ß-hCG of more than 39,000 utilizing methotrexate.

A Rare Case of Gestational Choriocarcinoma with Lung and Vaginal Metastases with Obstructive Jaundice.

Choriocarcinoma is a rare highly malignant neoplasm which may present with early metastases as it has a propensity of rapid haematogenous spread. However the neoplasm is chemosensitive and has a good prognosis even in advanced stages. We are presenting a case of a 26 years old female with early pregnancy presented with lung and vaginal metastases with obstructive jaundice. [International Federation of Gynaecology and Obstetrics (FIGO) stage III; World Health Organization score, 14]. Serum beta-hCG was 3,61,131 mIU/ml. Radiological evaluation suggested marked lung metastases with vaginal metastases. Patient was started on single agent chemotherapy doxorubicin in view of deranged liver function test. Patient was given 5 cycles of doxorubicin with liver function test and beta hcg monitoring. After liver function test normalized, patient was shifted to EMACO regimen for 6 cycles of treatment dose and 2 cycles of maintenance dose.

Elevated Beta-Human Chorionic Gonadotropin in a Non-pregnant Female With Altered Kidney Function.

Elevated beta-human chorionic gonadotropin (beta-hCG) levels in postmenopausal women is a finding known in the literature; however, it still commonly leads to unnecessary and extensive diagnostic workup. We present the case of a 48-year-old African-American postmenopausal female with acute kidney injury on chronic kidney disease (CKD) stage 5 and an incidental finding of elevated serum beta-hCG. Abdominal and transvaginal ultrasound showed no evidence of intrauterine or ectopic pregnancy or gestational trophoblastic disease. Menopausal status was confirmed with follicle-stimulating hormone (FSH) measurement, and following the improvement of renal status, beta-hCG levels were normalized to expected values for the patient's age group. The etiology of elevated beta-hCG was suspected to be from the pituitary as previous literature has shown decreasing beta-hCG levels in postmenopausal women following the administration of gonadotropin-releasing hormone (GnRH) antagonist.

Primary Pulmonary Choriocarcinoma Treated With Neoadjuvant Chemotherapy and Lobectomy: A Case Report.

Primary pulmonary choriocarcinomas (PPC) are a rare form of extragonadal germ cell tumors (GCT). They present as lung nodules and secrete beta-human chorionic gonadotropin (ß-HCG). This is a rare case of PPC that presented insidiously in a postmenopausal woman. Clinical suspicion arose due to markedly elevated serum ß-HCG and lung tumor biopsy immunohistochemical staining negative for markers of small cell and non-small cell carcinomas of the lung. The diagnosis of PPC was made after staining positive for markers of GCTs including ß-HCG in the absence of a primary tumor in the reproductive organs. The patient was treated with neoadjuvant vincristine, ifosfamide, and cisplatin (VIP) chemotherapy, followed by video-assisted thoracoscopic surgery (VATS) with lobectomy and mediastinal lymph node dissection. This is the first reported case of PPC treated with VIP induction chemotherapy. The patient initially had complete pathologic response and remission; however, she presented with relapse at a nine-month follow-up with new pulmonary nodules and metastatic disease to the brain.

Second trimester prediction of gestational diabetes: maternal analytes as an additional screening tool.

OBJECTIVES: Early diagnosis of gestational diabetes can lead to greater optimization of glucose control. We evaluated associations between maternal serum analytes (alpha-fetoprotein [AFP], free beta-human chorionic gonadotropin [beta-hCG], inhibin, and estriol) and the development of gestational diabetes mellitus (GDM). METHODS: This retrospective cohort study identified single-ton pregnancies with available second trimester serum analytes between 2009 and 2017. GDM was identified by ICD-9 and -10 codes. We examined the associations between analyte levels and GDM and to adjust for potential confounders routinely collected during genetic serum screening (maternal age, BMI, and race) using logistic regression. Optimal logistic regression predictive modeling for GDM was then performed using the analyte levels and the above mentioned potential confounders. The performance of the model was assessed by receiver operator curves. RESULTS: Out of 5,709 patients, 660 (11.6%) were diagnosed with GDM. Increasing AFP and estriol were associated with decreasing risk of GDM, aOR 0.76 [95% CI 0.60-0.95] and aOR 0.67 [95% CI 0.50-0.89] respectively. Increasing beta-hCG was associated with a decreasing risk for GDM(aOR 0.84 [95% CI 0.73-0.97]). There was no association with inhibin. The most predictive GDM predictive model included beta-hCG and estriol in addition to the clinical variables of age, BMI, and race (area under the curve (AUC 0.75), buy this was not statistically different than using clinical variables alone (AUC 0.74) (p=0.26). CONCLUSIONS: Increasing second trimester AFP, beta-hCG, and estriol are associated with decreasing risks of GDM, though do not improve the predictive ability for GDM when added to clinical risk factors of age, BMI, and race.

Hyperemesis Gravidarum Presenting as Severe Hypokalemic Periodic Paralysis and Type II Respiratory Failure: A Different Form of Thyroid Storm?

Hyperthyroidism in pregnancy is a condition that results from an excess of beta-human chorionic gonadotropin hormone resulting in gestational thyrotoxicosis. This thyrotoxicosis of pregnancy might be linked with hyperemesis gravidarum and is usually a self-limiting disease. Hyperthyroidism can cause hypokalemic periodic paralysis, which presents as pure motor areflexic flaccid paralysis. In severe cases, it may involve respiratory muscles and cause hypercapnic respiratory failure requiring invasive ventilation. A positive feed-forward cycle of hypokalemia could be triggered by the loss of function of inward rectifier potassium channel 18 (Kir2.6) along with the increased activity of sodium, potassium-adenosine triphosphatase (Na⁺/K⁺-ATPase). Hyperthyroid periodic paralysis is characterized by biochemical hyperthyroidism, normal urine potassium excretion, and electrocardiography abnormalities. We report a case of a 23-year-old female (G2P0L0A1) who had severe hyperemesis gravidarum and later on developed flaccid quadriplegia. Her thyroid profile revealed hyperthyroidism. She later developed hypercapnic respiratory failure and was managed by potassium replacement and invasive ventilation.

Can Pretreatment Serum Beta-hCG be Used for Predicting Thyrotoxicosis in Gestational Trophoblastic Disease?

BACKGROUND: Gestational trophoblastic disease (GTD) comprises a diverse spectrum of entities of abnormal cellular proliferations originating in placental trophoblasts. The specific marker of GTD is beta-hCG which has a similar structure to the TSH molecule, interfering level of thyroid hormones. How and when to check for thyroid function test during this period remain challenging. OBJECTIVE: To assess values of pretreatment beta-hCG and its benefit for predicting thyrotoxicosis among patients with diagnoses of GTD. METHODS: Retrospective analytical study included all women diagnosed with GTD at Lampang Hospital from January 2010 to May 2020. The patients' pretreatment beta-hCG and thyroid function were collected. Sensitivity and specificity for detecting laboratory hyperthyroidism were reported and classified by pretreatment beta-hCG levels. RESULTS: Forty-four women with diagnoses of GTD were recruited. The range of pretreatment beta-hCG levels were classified  into 4 groups: beta-hCG > 50,000 IU/ml (group 1), beta-hCG > 100,000 IU/ml (group 2), beta-hCG > 150,000 IU/ml (group 3), beta-hCG > 200,000 IU/ml (group 4). The sensitivity for prediction of high fT4 were 100%, 94.1%, 94.1% and 88.2% in group 1,2,3 and 4, respectively, while the specificity were 12%, 20%, 32% and 44% in group 1,2,3 and 4, respectively. CONCLUSION: Pretreatment beta-hCG > 100,000 uIU/ml has the high sensitivity and acceptable specificity for predicting hyperthyroidism. So we don't need to check or wait for thyroid function test in patients who had beta-hCG < 100,000 IU/ml.