The use of PAMG-1 testing in patients with preterm labor, intact membranes and a short sonographic cervix reduces the rate of unnecessary antenatal glucocorticoid administration.

OBJECTIVES: To assess the frequency of antenatal corticosteroid (ACS) administration in cases with shortened cervical length by addition of placental alpha-microglobulin-1 (PAMG-1) testing to sonographic examination. METHODS: Single centre retrospective cohort study. Rate of ACS administration was compared between cases with cervical length between 15 and 25 mm and cases with positive PAMG-1 testing and cervical length between 15 and 25 mm. We evaluated the following outcome parameters: Rate of ACS administration, gestational age at delivery, time to delivery, delivery within seven days, delivery <34 and <37 weeks' gestation, rate of admission to neonatal intensive care unit (NICU). RESULTS: In total, 130 cases were included. "PAMG-1 group" consisted of 68 women, 62 cases built the "historical control group". ACS administration was performed less frequently in the "PAMG-1 cohort" (18 (26%) vs. 46 (74%); p<0.001). The rate of delivery within seven days did not differ (2 (3%) vs. 4 (6.5%); p=0.4239). The rates of delivery <34 weeks' gestation (7 (10%) vs. 9 (15%); p=0.4643) and <37 weeks' gestation (19 (28%) vs. 26 (42%); p=0.0939) did not differ. Time to delivery interval was longer in the PAMG-1 group (61.5 vs. 43 days, p=0.0117). NICU admission occurred more often in the "historical control group" (22 (38%) vs. 28 (60%); p=0.0272). CONCLUSIONS: Addition of biomarker testing can help to avoid unnecessary ACS administrations in women with shortened cervical length.

Maternal Plasma Lipids During Pregnancy, Insulin-like Growth Factor-1, and Excess Fetal Growth.

CONTEXT: Maternal lipids during pregnancy and placental growth factors are associated with excess fetal growth. However, how these factors interact to increase the risk of delivering large-for-gestational-age (LGA) neonates remains unclear. In this study, we investigated the relationship between maternal plasma triglycerides (TGs) and free fatty acids (FFAs) during pregnancy, cord blood insulin-like growth factors (IGF), and LGA. OBJECTIVE: In a cell model, we studied the effect of different FAs on placental IGF-1 secretion. METHODS: This cohort study included pregnant women with term pregnancy and without diabetes or hypertensive disorders in pregnancy. Maternal fasting plasma TGs and FFAs were measured in the second trimester. Cord blood IGF-1, IGF-2, and IGF binding protein-1 and protein-3 were measured at the time of delivery. A human trophoblast cell line, 3A-sub-E, was used to evaluate the effect of different FFAs on placental IGF-1 secretion. RESULTS: We recruited 598 pregnant women-neonate pairs. Maternal plasma TG (180 mg/dL [152.5-185.5 mg/dL] vs 166 mg/dL [133-206 mg/dL], P = .04) and cord blood IGF-1 concentrations (72.7 ±â€…23.0 vs 54.1 ±â€…22.8 ng/mL, P < .001) were higher in the LGA group and were significantly associated with birth weight z score. Maternal plasma free palmitic acid (PA) and stearic acid (SA), but not oleic acid (OA) or linoleic acid (LA), were significantly associated with cord blood IGF-1 concentrations. In 3A-sub-E cells, treatment with PA, SA, and LA, but not OA, induced IGF-1 expression and secretion. CONCLUSION: Certain FFAs can induce placental IGF-1 secretion, which suggests a potential pathophysiology linking maternal plasma lipids and LGA.

The value of a vaginal sample for detecting PAMG-1 (Partosure®) in women with a threatened preterm delivery (the MAPOSURE Study): protocol for a multicenter prospective study.

BACKGROUND: Threatened preterm delivery (TPD) is the leading cause of inpatient admissions during pregnancy. The ability to predict the risk of imminent preterm delivery is thus a major priority in obstetrics. The aim of our study is to assess the diagnostic performance of the test to detect the placental alpha microglobulin 1 (PAMG-1) for the prediction of delivery within 7 days in women with TPD. METHODS: This is a prospective multicenter diagnostic study. Inclusion criteria are singleton pregnancy, gestational age between 24 + 0 and 33 + 6 weeks inclusive, cervical measurement 25 mm or less assessed by transvaginal ultrasound (with or without uterine contractions), clinically intact membranes and cervical dilatation < 3 cm assessed by digital examination. According to the current protocol, when a women presents with TPD and the diagnosis is confirmed by transvaginal ultrasound, a vaginal sample to test for genital infection is performed. At the same time, the midwife will perform the PartoSure® test. To perform this analysis, a sample of cervicovaginal secretions is taken with the vaginal swab furnished in the test kit. The primary outcome is the specificity of the PartoSure® test of women who gave birth more than 7 days after their hospitalization for TPD. The secondary outcomes are the sensitivity, PPV, and NPV of the Partosure® test and the factors associated with false positives (with a univariate logistic regression model). Starting with the hypothesis of an anticipated specificity of 89%, if we want to estimate this specificity with a confidence interval of ± 5%, we will require 151 women who do not give birth within 7 days. We therefore decided to include 400 women over a period of two years to have a larger number of events (deliveries within 7 days). DISCUSSION: The different tests already used such as fetal fibronectin and phIGFBP-1, are not sufficiently relevant to recommend their use in daily practice. The different studies of PAMG-1 described above thus provide support for the use of this substance, tested by PartoSure®. Nonetheless, other larger studies are necessary to validate its use in daily practice and our study could answer this question. TRIAL REGISTRATION: NCT03401255 (January 15, 2018).

Biomarker Modulation Study of Celecoxib for Chemoprevention in Women at Increased Risk for Breast Cancer: A Phase II Pilot Study.

In preclinical studies, celecoxib has been associated with reduced risk of breast cancer. In this study, the aim was to assess the biomodulatory effect of celecoxib on blood and benign breast tissue biomarkers in women at increased risk for breast cancer. Women at increased risk for breast cancer [5-year Gail risk score of >1.67%, history of atypical hyperplasia, lobular carcinoma in situ, or previous estrogen receptor (ER)-negative breast cancer] were treated with celecoxib at 400 mg orally twice daily for 6 months. Participants underwent random periareolar fine needle aspiration and blood draw at baseline and at 6 months for analysis of biomarkers: serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1 (IGFBP-1), and IGFBP-3; tissue expression of Ki-67 and ER; as well as cytology. Forty-nine patients were eligible for analysis. Median IGFBP-1 levels increased significantly from 6.05 ng/mL at baseline to 6.93 ng/mL at 6 months (P = 0.04), and median IGFBP-3 levels decreased significantly from 3,593 ng/mL to 3,420 ng/mL (P = 0.01). We also detected favorable changes in cytology of 52% of tested sites after 6 months of celecoxib therapy. No changes in tissue Ki-67 and ER expression levels were observed. No grade 3 or 4 toxicity was recorded. Celecoxib was well tolerated and induced favorable changes in serum biomarkers as well as cytology in this pilot phase II trial. A phase IIb placebo-controlled study with celecoxib could be considered for women at increased risk for breast cancer.

The effects of physical activity on physiological markers in breast cancer survivors: A meta-analysis.

BACKGROUND: To systematically evaluate the effects of physical activity on physiological markers in breast cancer survivors. METHODS: A systematic search of the PubMed, Wed of Science, Medline, CNKI and Wanfang Database was performed to identify eligible randomized controlled trials to explore physical activity on physiological markers in breast cancer survivors. STATA version 13.0 (Stata Corp LP, College Station, TX) was used for all statistical analyses. RESULTS: A total of 11 articles with 941 cases were eligible in this meta-analysis. The results of the meta-analysis showed that physical activity could decrease the levels of insulin (SMD = -1.90, 95%CI: -3.2 to -0.60; I = 92.3%, P < .001), insulin-like growth factor 1 (IGF-I) (WMD = -4.67, 95%CI: -23.14 to 13.79; I = 96.2%, P < .001), insulin-like growth factor binding protein-3 (IGFBP-3) (WMD = -20.09, 95%CI: -47.15 to 6.97; I = 93.3%, P < .001). However, compared with the control group, there was not the significant change of insulin-like growth factor 2 (IGF-II), insulin-like growth factor binding protein-1 (IGFBP-1), leptin, adiponectin, glucose, C-reactive protein (CRP), Interleukin-6 (IL-6), Interleukin-10 (IL-10), and tumor necrosis factor alpha (TNF-ɑ) levels after the intervention. CONCLUSIONS: Physical activity could improve the insulin function that might be associated with decreasing the levels of IGF-I, IGFBP-3 and insulin in breast cancer survivors.

Study protocol for a randomised trial for atosiban versus placebo in threatened preterm birth: the APOSTEL 8 study.

INTRODUCTION: Preterm birth complicates >15 million pregnancies annually worldwide. In many countries, women who present with signs of preterm labour are treated with tocolytics for 48 hours. Although this delays birth, it has never been shown to improve neonatal outcome. In 2015, the WHO stated that the use of tocolytics should be reconsidered and that large placebo-controlled studies to evaluate the effectiveness of tocolytics are urgently needed. METHODS AND ANALYSIS: We designed an international, multicentre, randomised, double-blinded, placebo-controlled clinical trial. Women with threatened preterm birth (gestational age 30-34 weeks), defined as uterine contractions with (1) a cervical length of < 15 mm or (2) a cervical length of 15-30 mm and a positive fibronectin test or (3) in centres where cervical length measurement is not part of the local protocol: a positive fibronectin test or insulin-like growth factor binding protein-1 (Actim-Partus test) or (4) ruptured membranes, will be randomly allocated to treatment with atosiban or placebo for 48 hours. The primary outcome is a composite of perinatal mortality and severe neonatal morbidity. Analysis will be by intention to treat. A sample size of 1514 participants (757 per group) will detect a reduction in adverse neonatal outcome from 10% to 6% (alpha 0.05, beta 0.2). A cost-effectiveness analysis will be performed from a societal perspective. ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Committee (REC) of the Amsterdam University Medical Centres, location AMC, as well as the REC's in Dublin and the UK. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results. TRIAL REGISTRATION NUMBER: Nederlands Trial Register (Trial NL6469).

The levonorgestrel-releasing intrauterine device induces endometrial decidualisation in women on tamoxifen.

There is conflicting literature on whether the levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena®) induces decidualisation in the tamoxifen-treated endometrium. The expression of the decidualisation marker IGFBP-1 was measured using immunohistochemistry in endometrial biopsies and in serum (using ELISA) of 20 postmenopausal women at the start of tamoxifen-treatment for breast cancer. Ten women were then fitted with LNG-IUS and the other ten received tamoxifen-treatment only and acted as controls. Samples were taken at baseline and after 12 months. At baseline, all endometrial samples were negative for IGFBP-1 and at 12 months, IGFBP-1 was only expressed in the endometria of women fitted with the LNG-IUS, confirming the observed histological features of decidualisation. By contrast, serum IGFBP-1 concentrations were increased by tamoxifen, but not in the group receiving LNG-IUS. In conclusion, tamoxifen induces a rise in serum IGFBP-1 suggesting a systemic, possibly hepatic effect, whilst LNG abrogates this in both the liver and endometrium. Impact statement What is already known on this subject? Previous reports of the use of LNG-IUS in women on tamoxifen have provided conflicting evidence as to whether the endometrium exhibited decidualisation or not. These reports were however based solely on histological examination and lacked supporting biochemical data. What do the results of this study add? After 12 months of treatment with LNG-IUS, the endometria of women on tamoxifen show histological features of decidualisation and the presence of the decidualisation marker IGFBP-1, suggesting that levonorgestrel protects the tamoxifen-treated uterus from additional pathology by causing decidualisation. Serum levels of IGFBP-1 were expected to be a reflection of uterine production, but contrary to expectations, higher levels were identified in women on tamoxifen alone. These data suggest that an inhibition of tamoxifen-induced serum IGFBP-1 production (possibly from a hepatic source) by LNG-IUS occurred and indicates independent systemic effects of both drugs in post menopausal breast cancer patients. What are the implications of these findings for clinical practice and/or further research? This research demonstrated a mechanism for endometrial protection in women on tamoxifen. It also alerts clinicians to the fact that both tamoxifen and LNG-IUS exert systemic effects in this patient group.

Unique Associations between Insulin-Like Growth Factor Binding Protein-1, Insulin-Like Growth Factor-1 and T Cell Immunoglobulin Mucin 3 in Successful Twin Pregnancies Conceived with Donor Oocytes.

Background and Objectives: To investigate if pregnancies conceived using an oocyte donor necessitate an alteration in immune regulation, we compared concentrations of insulin-like growth factor binding protein (IGFBP)-1, insulin-like growth factor (IGF)-1 and T cell immunoglobulin mucin-3 (Tim-3) in women with ongoing successful twin pregnancies conceived spontaneously, using assisted reproductive technologies that utilized homologous oocytes or with donor oocytes. Differences in levels of these immune modulatory proteins may be magnified and easier to detect in twin as compared to singleton pregnancies. Methods: In this prospective study IGFBP-1 and IGF-1 were measured in sera and Tim-3 in lysates of peripheral blood mononuclear cells (PBMCs) by ELISA. Results: Median IGFBP-1 levels were lower in women with donor oocytes (41.4 ng/ml) as compared to those with a spontaneous conception (51.2 ng/mL) or who conceived with various assisted reproduction protocols using homologous oocytes (52.4 ng/mL) (p < 0.001). IGF-1 and Tim-3 levels were comparable in each group. The IGFBP-1 level was inversely correlated to the IGF-1 concentration only in women with donor oocytes (p = 0.032). IGFBP-1 and Tim-3 levels were similarly negatively correlated in the donor oocyte group (p = 0. 012). Women in the assisted reproduction group who conceived following intracytoplasmic sperm injection were the only other group in which IGFBP-1 and Tim-3 were negatively correlated (p = 0.018). Conclusions: Down-regulation of IGFBP-1 production in pregnancies conceived with donor oocytes may reduce the extent of pro-inflammatory immunity and contribute to successful outcome in totally allogeneic pregnancies.

Impact of HIV-1 infection on the IGF-1 axis and angiogenic factors in pregnant Cameroonian women receiving antiretroviral therapy.

Although mother-to-child transmission of HIV has dramatically declined, the number of in utero HIV-exposed, uninfected infants is on the increase. HIV-exposed infants are at an increased risk of mortality, morbidity and slower early growth than their non-HIV exposed counterparts. Maternal HIV increases the risk of having preterm deliveries, intrauterine growth restriction and low birth weight babies. However, the mechanism underlying dysregulation of fetal growth in HIV-infected pregnant women is unknown. We sought to determine whether maternal HIV is associated with dysregulation of the insulin-like growth factor (IGF) axis, some angiogenic factors or other related biomarkers that regulate fetal growth. A total of 102 normotensive pregnant women were enrolled in a small cross-sectional study. Amongst these were thirty-one HIV-1 positive women receiving combination antiretroviral therapy (cART) (Mean age: 30.0 ± 5.1 years; % on ART: 83.9%; median plasma viral load: 683 copies/ml; median CD4 count: 350 cells/ul) and 71 HIV uninfected women (mean age: 27.3 ± 5.8) recruited at delivery. A panel of biomarkers including IGF1 and IGF binding proteins (IGFBP1, IGFBP3), angiopoietins (ANG) 1 and 2, matrix metalloproteinases (MMP) 2 and 9, and galectin 13, was measured in plasma collected from the placental intervillous space. The levels of IGF1, IGFBP1, ANG1, ANG2, MMP2, MMP9 and Gal-13 were not affected by maternal HIV, even when adjusted for maternal factors in linear regression models (all p>0.05). It was observed that HIV-infection in pregnancy did not significantly affect key markers of the IGF axis and angiogenic factors. If anything, it did not affect women. These findings highlight the importance of the use of ART during pregnancy, which maintains factors necessary for fetal development closer to those of healthy women. However, decrease in IGF1 levels might be exacerbated in women con-infected with HIV and malaria.

Comparison of the effectiveness of a PAMG-1 test and standard clinical assessment in the prediction of preterm birth and reduction of unnecessary hospital admissions.

PURPOSE: The purpose of this study is to first compare the performance of the PAMG-1 biomarker test to that of standard clinical assessment (SCA) for the risk assessment of spontaneous preterm delivery (sPTD) among women with symptoms of preterm labor (PTL) and then calculate the potential impact on unnecessary admission reduction. MATERIALS AND METHODS: Patients of gestational age 240/7-366/7 with PTL symptoms, cervical dilatation ≤3 cm, no intercourse within 24 h, and clinically intact membranes were recruited consecutively into this prospective observational study. Specificity (SP), sensitivity (SN), positive-predictive value (PPV), and negative-predictive value (NPV) for the PAMG-1 test and SCA, for which a positive result was defined as patient admission, for predicting spontaneous delivery ≤7 and ≤14 d of presentation were calculated. RESULTS: One hundred and forty-eight patients were included in the analysis, 132 of which had both SCA and PAMG-1 results available. For the prediction of sPTD ≤7 d for SCA and PAMG-1, the PPV and NPV were 10% and 100%, and 71% and 98%, respectively. For prediction of sPTD ≤14 d for SCA and PAMG-1, the PPV and NPV were 14% and 100%, and 86% and 96%, respectively. Sixty-one per cent (81/132) of patients were admitted for treatment and/or observation. CONCLUSION: Our study reinforces the critical role of the PAMG-1 biomarker test to aid in risk assessment of imminent spontaneous preterm delivery in patients with symptoms of PTL. The PAMG-1 test was found to be statistically superior to standard clinical assessment alone, with respect to specificity. Based on our data, the introduction of a PAMG-1 test result into clinical decision making could reduce up to 91% of unnecessary admissions for women presenting with threatened preterm labor.

Evaluation of the quantitative fetal fibronectin test and PAMG-1 test for the prediction of spontaneous preterm birth in patients with signs and symptoms suggestive of preterm labor.

Objective: The objective of this study is to compare the qualitative fFN test at 50 ng/ml threshold to novel methods for assessing risk of imminent sPTB in women with symptoms of preterm labor (PTL): (1) quantitative fetal fibronectin (qfFN) at four thresholds: 10, 50, 200, and 500 ng/ml; and (2) qualitative PAMG-1 test. Study design: Consecutive patients presenting with singleton pregnancies, signs of PTL, gestational age 23.1-34.6, intact membranes, no coitus within 24 h, and cervical dilation ≤3 cm. fFN was performed as standard of care, while clinicians were blinded to the qfFN and PAMG-1 test results. qfFN accuracy was evaluated at four thresholds of 10, 50, 200, and 500 ng/ml for its ability to predict imminent spontaneous preterm delivery (sPTD) ≤ 7 and ≤14 d from the time of sample collection. The PAMG-1 test was evaluated based on its qualitative result for the same delivery endpoints. Results: Seventy-two patients were analyzed. Fifty-seven percent of patients had an fFN concentration of <10 ng/ml fFN; 75% < 50 ng/ml; 92% < 200 ng/ml; 97% < 500 ng/ml. The SN, SP, PPV, and NPV for fFN at each of the four cutoffs for sPTB ≤7 d: 10 ng/ml: 67%, 58%, 6%, 98%; 50 ng/ml: 67%, 77%, 11%, 98%; 200 ng/ml: 33%, 93%, 17%, 97%; 500 ng/ml: 0%, 97%, 0%, 96%. The PAMG-1 test was positive in 7% of patients. SN, SP, PPV, and NPV for PAMG-1 for sPTD ≤7 d were 67%, 96%, 40%, and 99%, respectively. Conclusion: Compared with qfFN, the PAMG-1 test is a better predictor of spontaneous delivery within 7 d while maintaining a very high negative predictive value. The PAMG-1 test is an easy-to-use bedside test that provides rapid results, does not require a speculum examination, can be used after vaginal exam and coitus and does not require specialized equipment to analyze results. As to be expected, compared with the conventional cutoff of fFN (50 ng/ml), a higher fFN cutoff of 200 ng/ml does seem to increase the PPV of the test, but this comes at a cost to the fFN test's SN and NPV, rendering it of little to no advantage in clinical practice.

Performance indices of AmnioQuick Duo+ versus placental α-microglobulin-1 tests for women with prolonged premature rupture of membranes.

OBJECTIVE: To compare AmnioQuick Duo+ versus the placental α-microglobulin-1 (PAMG-1) test for diagnosis of prolonged premature rupture of membranes (PROM). METHODS: A multicenter prospective cohort study included women with suspected PROM at six tertiary institutions in southern Nigeria between January 1 and December 31, 2015. The inclusion criteria were features of PROM lasting at least 24 hours and a pregnancy duration of more than 24 weeks. AmnioQuick Duo+ (Biosynex, Strasbourg, France) and PAMG-1 (AmniSure International, Boston, USA) tests were used to diagnose PROM, which was confirmed after delivery by any two of the following criteria: delivery within 48 hours to 7 days, chorioamnionitis, membranes perceptibly ruptured at delivery, and adverse perinatal outcomes considerably associated with prolonged PROM. RESULTS: Of 100 women assessed for eligibility, 99 were included. Sensitivity, specificity, and accuracy were, respectively, 97.3%, 100%, and 95.9% for AmnioQuick Duo+, and 93.2%, 100%, and 90.4% for PAMG-1. The differences were not significant and the diagnostic discordant rate between the two tests was 3.1%. In equivocal cases (i.e., negative pooling test result), AmnioQuick Duo+ and PAMG-1 performed equally (diagnostic accuracy, 100% vs 97.7%; P>0.99). CONCLUSION: For diagnosis of PROM, AmnioQuick Duo+ was found to be non-inferior and comparable in accuracy to the PAMG-1 test, with a diagnostic discordance rate of 3.1%.

[Correlation between automated optical reading and double human reading for two tests of fetal membranes rupture]. / Concordance entre la lecture optique automatisée et la lecture visuelle double pour deux tests de rupture des membranes.

OBJECTIVES: To assess concordance between double human and automated optical reading (AOR) concerning two biological tests for rupture of membranes (ROM) METHODS: We conducted a monocentric, prospective, observational study comparing Actim Prom® (Alere SAS, Jouy-en Josas, France) and Hiprom Duo® (Fumouze, Levallois-Perret, France). Each test was performed simultaneously in patients with suspected ROM and read independently by 2 biologists and AOR device. ROM was clinically confirmed in case of recurrent leakage or spontaneous labour with no perceived membranes within 48hours. RESULTS: Concerning Actim Prom®, concordance was 100 %, 92.5 % and 91.6 % between biologists, biologists-AOR device and biologists or AOR vs. clinical presentation respectively. Concerning Hiprom Duo®, concordance was 97.2 % between biologists, 97.2 % between biologist 1 and AOR, 95.3 % between biologist 2 and AOR, 63.5 % between clinical presentation and human reading, 62.3 % between clinical presentation and AOR. False positive cases were significantly associated with modified cervix (21 % vs. 46 %, P=0.006). CONCLUSION: We demonstrated excellent correlation between biologists and good or excellent correlation between AOR and human reading supporting the use of AOR in clinical practice.

[Diagnosis of rupture of fetal membranes: CNGOF Preterm Premature Rupture of Membranes Guidelines]. / Diagnostic de la rupture des membranes. RPC Rupture prématurée des membranes avant terme CNGOF.

OBJECTIVE: To describe clinical and paraclinical tests diagnosing rupture of fetal membranes (ROM). METHODS: Bibliographic search over the period 1980-2017 considering articles in French and English as well as guidelines from national obstetrical societies. RESULTS: Typical amniotic fluid leakage occurs in ¾ of cases. In this situation, no additional test is required (Professional consensus). For ambiguous cases, a speculum examination can demonstrate pooling of amniotic fluid but suspicion can persist in 50% of cases (evidence level IV). In this context, we recommend to consider performing an IGFBP-1 or PAMG-1 test of vaginal fluid (evidence level III). Ability of these tests to reduce maternal or neonatal morbidity has never been demonstrated (Professional consensus). An isolated positive test should be considered cautiously as false positive does exist (Professional consensus). CONCLUSION: Symptoms suggestive of ROM and speculum examination demonstrating pooling of amniotic fluid are sufficient to diagnose ROM. If pooling is not observed, we recommend to consider performing an IGFBP-1 or PAMG-1 test of vaginal fluid.

Prediction of preterm delivery in symptomatic women using PAMG-1, fetal fibronectin and phIGFBP-1 tests: systematic review and meta-analysis.

OBJECTIVE: To assess the accuracy of placental alpha microglobulin-1 (PAMG-1), fetal fibronectin (fFN) and phosphorylated insulin-like growth factor-binding protein-1 (phIGFBP-1) tests in predicting spontaneous preterm birth (sPTB) within 7 days of testing in women with symptoms of preterm labor, through a systematic review and meta-analysis of the literature. The test performance of each biomarker was also assessed according to pretest probability of sPTB ≤ 7 days. METHODS: The Cochrane, MEDLINE, PubMed and ResearchGate bibliographic databases were searched from inception until October 2017. Cohort studies that reported on the predictive accuracy of PAMG-1, fFN and phIGFBP-1 for the prediction of sPTB within 7 days of testing in women with symptoms of preterm labor were included. Summary receiver-operating characteristics (ROC) curves and sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and positive (LR+) and negative (LR-) likelihood ratios were generated using indirect methods for the calculation of pooled effect sizes with a bivariate linear mixed model for the logit of sensitivity and specificity, with each diagnostic test as a covariate, as described by the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. RESULTS: Bivariate mixed model pooled sensitivity of PAMG-1, fFN and phIGFBP-1 for the prediction of sPTB ≤ 7 days was 76% (95% CI, 57-89%), 58% (95% CI, 47-68%) and 93% (95% CI, 88-96%), respectively; pooled specificity was 97% (95% CI, 95-98%), 84% (95% CI, 81-87%) and 76% (95% CI, 70-80%) respectively; pooled PPV was 76.3% (95% CI, 69-84%) (P < 0.05), 34.1% (95% CI, 29-39%) and 35.2% (95% CI, 31-40%), respectively; pooled NPV was 96.6% (95% CI, 94-99%), 93.3% (95% CI, 92-95%) and 98.7% (95% CI, 98-99%), respectively; pooled LR+ was 22.51 (95% CI, 15.09-33.60) (P < 0.05), 3.63 (95% CI, 2.93-4.50) and 3.80 (95% CI, 3.11-4.66), respectively; and pooled LR- was 0.24 (95% CI, 0.12-0.48) (P < 0.05), 0.50 (95% CI, 0.39-0.64) and 0.09 (95% CI, 0.05-0.16), respectively. The areas under the ROC curves for PAMG-1, fFN and phIGFBP-1 for sPTB ≤ 7 days were 0.961, 0.874 and 0.801, respectively. CONCLUSIONS: In the prediction of sPTB within 7 days of testing in women with signs and symptoms of preterm labor, the PPV of PAMG-1 was significantly higher than that of phIGFBP-1 or fFN. Other diagnostic accuracy measures did not differ between the three biomarker tests. As prevalence affects the predictive performance of a diagnostic test, use of a highly specific assay for a lower-prevalence syndrome such as sPTB may optimize management. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Increased Insulin-like Growth Factor Binding Protein-1 Phosphorylation in Decidualized Stromal Mesenchymal Cells in Human Intrauterine Growth Restriction Placentas.

Intrauterine growth restriction (IUGR) is often caused by placental insufficiency, which is believed to be associated with decreased delivery of oxygen and nutrients to the placental barrier. We recently reported that hypoxia and/or leucine deprivation triggered hyperphosphorylation of insulin-like growth factor binding protein-1 (IGFBP-1) in decidualized human immortalized endometrial stromal cells (HIESCs), resulting in decreased insulin-like growth factor-1 (IGF-1) bioactivity. To test the hypothesis that human IUGR is associated with increased decidual IGFBP-1 phosphorylation at discrete sites, we used IUGR and gestational age matched appropriate for gestational age (AGA) placentas ( n=5 each). We performed dual immunofluorescence immunohistochemistry (IHC) using IGFBP-1 and vimentin as decidual and mesenchymal markers, respectively. Employing a unique strategy with imaging software, we extracted signal intensity of IGFBP-1 expressed specifically from truly decidualized cells of the placenta. Relative IGFBP-1 was increased (85%; p=0.0001) and using custom phospho-site-specific antibodies, we found that IGFBP-1 phosphorylation (pSer101; +40%, p=0.0677/pSer119; +60%, p=0.0064/pSer169; +100%, p=0.0021) was markedly enhanced in IUGR. Together, our data links for the first time, increased decidual IGFBP-1 phosphorylation at discrete sites with human IUGR. These novel findings suggest that hyperphosphorylation of IGFBP-1 in decidualized stromal mesenchymal decidua basalis contributes to potentially elevated levels of phosphorylated IGFBP-1 in maternal circulation in IUGR pregnancies.

Delayed Diagnosis of Acromegaly in the Context of Post-Traumatic Stress Disorder due to Symptoms Mimicking Known Psychotropic Medication Side Effects.

BACKGROUND: Acromegaly is caused by elevated secretion of human growth hormone, which is frequently because of intracranial tumors. This diagnosis is fairly uncommon with an incidence of 3 to 4 cases per million patients per year. We are presenting a case of acromegaly diagnosed in an active duty Chief Petty Officer. MATERIALS AND METHODS: A 38-year-old male Chief Petty Officer with no previous mental health diagnosis experienced post-traumatic stress disorder (PTSD)-like symptoms in early 2012 after deploying to Iraq and Afghanistan from 2010 to 2011. Initially he self-managed his symptoms, but in July 2012 he required a reduction mammoplasty because of gynecomastia. The metabolic workup revealed elevated prolactin, but this was not further investigated. His recovery from anesthesia was complicated by intensified PTSD-like symptoms, which continued to worsen after the surgery. On self-referral to mental health, he was diagnosed with PTSD and managed for 6 months with cognitive behavioral therapy. Because of persistent and worsening symptoms, his therapy was augmented to include continued cognitive behavioral therapy, alpha-blockers, antidepressants, antihistamines, and sleep aids. Because of night sweats, the selective serotonin reuptake inhibitors doses were modified. Night sweats persisted, and the patient was re-evaluated for other potential etiologies. On evaluation, the patient endorsed a history of obstructive sleep apnea, cervicalgia, visual changes, depressed mood, as well as multiple physical symptoms including coarsened facial features, large hands/feet, and increased interdental distance. On laboratory analysis, insulin-like growth factor 1 was noted to be 3 times the upper limit of normal, and a prolactin level was five times the upper limit of normal. A brain magnetic resonance imaging revealed a cystic pituitary lesion with suprasellar extension, compression of the infundibulum without invasion of the cavernous sinus, or displacement of the optic chiasm. Based on clinical history, physical examination, laboratory data, and the pituitary lesion, this patient was diagnosed with acromegaly. He was referred to neurosurgery for further evaluation and management. RESULTS AND CONCLUSION: This case shows that side effects of medications can easily mimic some medical conditions. The possibility of unrecognized disease should not be overlooked simply because a patient's symptoms that develop after starting a medication correspond well the side effect profile of the prescribed medications. This is especially true if side effects do not stop with alteration of medication dose, cessation of the medication, or changing to another medication. Pituitary adenomas are rare in patients treated for PTSD. However, attribution of PTSD patient's symptoms to the side effects of selective serotonin reuptake inhibitors therapy without considering a broader differential may lead to a missed diagnosis of an endocrine disease. In this case, the presence of an undiagnosed pituitary lesion resulted in ineffective medical management of PTSD in the patient. Mental health providers should remain allied with their primary care counterparts and consider directing patients to primary care for periodic physical re-evaluation to provide the most effective approach to symptom evaluation and management.

Use of cervicovaginal PAMG-1 protein as a predictor of delivery within seven days in pregnancies at risk of premature birth.

BACKGROUND: To investigate the utility of vaginal placental alpha microglobulin-1 (PAMG-1) protein as a predictor of preterm delivery within 7 days in pregnancies at risk of premature birth. METHODS: This prospective study was performed in women at risk of premature birth. The levels of vaginal PAMG-1 and foetal fibronectin (fFN) and the transvaginal cervical length measurement (CLM) were investigated and compared. RESULTS: Seventy-two pregnant women were included in this study. The sensitivities of PAMG-1, fFN and CLM were 73.3, 73.6%, and 52.9%, respectively, while the specificities of PAMG-1, fFN and CLM were 92.9%, 94.3%, and 90.9%, respectively. The positive predictive values of PAMG-1, fFN and CLM were 73.3%, 82.3%, and 64.2%, respectively, and the negative predictive values of PAMG-1, fFN and CLM were 92.9%, 90.9%, and 86.2%, respectively. CONCLUSION: The diagnostic accuracy of PAMG-1 is similar to that of fFN in terms of preterm labour detection within 7 days.

Combined value of placental alpha microglobulin-1 detection and cervical length via transvaginal ultrasound in the diagnosis of preterm labor in symptomatic patients.

AIM: We aimed to evaluate the combined value of placental alpha microglobulin-1 (PAMG-1) and cervical length (CL) via transvaginal ultrasound for assessing risk of imminent spontaneous preterm delivery in patients presenting with threatened preterm labor (PTL). METHODS: Clinical exam, PAMG-1 test, cardiotocography, and CL measurement via transvaginal ultrasound were performed on all patients meeting inclusion criteria. Ninety-nine patients at 22+0 -36+6 gestational weeks with the symptoms of PTL were included. The interval between sample collection and delivery was measured for each method. RESULTS: Performance metrics were calculated for PAMG-1 test, CL < 25 mm, and contractions ≥ 8/h. The sensitivity, specificity, positive predictive value, and negative predictive value for the PAMG-1 test were 100%, 95%, 75%, 100% and 100%, 98%, 88%, 100% for 7 and 14 days, respectively; the respective values for CL < 25 mm were 83%, 59%, 22%, 96% and 79%, 59%, 24%, 94% for 7 and 14 days; and those for contractions ≥ 8/h were 42%, 38%, 8%, 83% and 43%, 38%, 10%, 80% for 7 and 14 days. Specificity for the PAMG-1 test was statistically significant (P < 0.001) in pairwise comparisons for all other methods. Patients were divided into four groups for analysis of PAMG-1 test performance as follows: CL < 15 mm (100%, 100%, 100%, 100% and 100%, 100%, 100%, 100% for 7 and 14 days, respectively); CL < 25 mm (100%, 94%, 83%, 100% and 100%, 97%, 92%, 100% for 7 and 14 days, respectively); CL of 15-30 mm (100%, 95%, 64%, 100% and 100%, 97%, 82%, 100% for 7 and 14 days, respectively); and CL ≥ 30 mm (100%, 100%, 100%, 100% and 100%, 100%, 100%, 100% for 7 and 14 days, respectively). CONCLUSION: The use of the PAMG-1 test in patients with a CL of 15-30 mm is highly predictive of imminent spontaneous preterm delivery in women presenting with threatened PTL and could save hospital resources.