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.

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).

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.

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.

Insulin-like growth factor binding protein 1, Bishop score, and sonographic cervical length: tolerability and prediction of vaginal birth and vaginal birth within 24 hours following labour induction in nulliparous women.

OBJECTIVE: To evaluate the tolerability of cervical insulin-like growth factor binding protein 1 (IGFBP-1) and its value as a predictor of successful labour induction, compared with Bishop score and transvaginal ultrasound (TVUS) cervical length. DESIGN: A prospective study. SETTING: A tertiary hospital in Malaysia. POPULATION: A cohort of 193 term nulliparous women with intact membranes. METHODS: Prior to labour induction, cervical fluid was obtained via a vaginal speculum and tested for IGFBP-1, followed by TVUS and finally Bishop score. After each assessment the procedure-related pain was scored from 0 to 10. Cut-off values for Bishop score and cervical length were obtained from the receiver operating characteristic (ROC) curve. Multivariable logistic regression analysis was performed. MAIN OUTCOMES MEASURES: Vaginal delivery and vaginal delivery within 24 hours of starting induction. RESULTS: Bedside IGFBP-1 testing is better tolerated than Bishop score, but is less well tolerated than TVUS [median (interquartile range) of pain scores: 5 (4-5) versus 6 (5-7) versus 3 (2-3), respectively; P < 0.001]. IGFBP-1 independently predicted vaginal delivery (adjusted odds ratio, AOR 5.5; 95% confidence interval, 95% CI 2.3-12.9) and vaginal delivery within 24 hours of induction (AOR 4.9; 95% CI 2.1-11.6) after controlling for Bishop score (≥4 or ≥5), cervical length (≤29 or ≤27 mm), and other significant characteristics for which the Bishop score and TVUS were not predictive of vaginal delivery after adjustment. IGFBP-1 has 81% sensitivity, 59% specificity, positive and negative predictive values of 82 and 58%, respectively, and positive and negative likelihood ratios of 2.0 and 0.3 for vaginal delivery, respectively. CONCLUSION: IGFBP-1 better predicted vaginal delivery than BS or TVUS, and may help guide decision making regarding labour induction in nulliparous women. TWEETABLE ABSTRACT: IGFBP-1: a stronger independent predictor of labour induction success than Bishop score or cervical sonography.

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.

Comparison of the duo of insulin-like growth factor binding protein-1/alpha fetoprotein (Amnioquick duo+®) and traditional clinical assessment for diagnosing premature rupture of fetal membranes.

PURPOSE: To determine the diagnostic accuracy of insulin-like growth factor binding protein-1/alpha fetoprotein (Amnioquick duo+®) compared with traditional clinical assessment (TCA) of nitrazine, ferning and pooling for the diagnosis of prelabor rupture of membranes (PROM). METHODS: A double-blinded, multicenter clinical study was conducted between February 2015 and August 2015 among pregnant women presenting with symptoms or features suggestive of PROM between 24 and 42 weeks gestation. Confirmation of PROM was done after delivery based on the presence of any two of these criteria: delivery within 48 h to 7 days, evidence of chorioamnionitis, membranes explicitly ruptured at delivery and adverse perinatal outcomes strongly correlated with prolonged PROM. Sensitivity, specificity and accuracy were outcome measures assessed. RESULTS: Two hundred and thirty-six women were recruited. Three women were excluded from the final analysis due to lack of follow-up data and failure to meet inclusion criteria. Two hundred and thirty-three women had complete data for analysis. The specificity and sensitivity values for TCA were 76.2% and 85.2%, which were lower than those of Amnioquick duo+, which were 97.6% and 97.9%, respectively. The accuracy of Amnioquick duo+ was statistically higher (97.9% vs. 83.7%; RR=1.17; 95%CI=1.10-1.24; P<0.001). In equivocal cases (pooling=negative), the accuracy of Amnioquick duo+ vs. TCA was 98.4% vs. 69.4% (RR=1.42; 95%CI=1.20-1.68; P<0.001) at ≥34 weeks gestation and 100.0% vs. 71.4% (RR=1.40; 95%CI=1.07-1.83; P=0.021) at <34 weeks gestation. CONCLUSION: The performance matrix of Amnioquick duo+® was superior to that of TCA for diagnosing PROM even in equivocal cases.

Accuracy of a combined insulin-like growth factor-binding protein-1/interleukin-6 test (Premaquick) in predicting delivery in women with threatened preterm labor.

PURPOSE: To determine values of combinations of interleukin-6 (IL-6)/cervical native insulin-like growth factor-binding protein-1 (IGFBP-1)/total IGFBP-1 (Premaquick©) in predicting spontaneous deliveries and spontaneous exclusive preterm deliveries in women with threatened preterm labor. METHODS: Women with singleton pregnancies between gestation age (GA) of 24 weeks and 36 weeks and 6 days with preterm labor were recruited during a prospective multicenter study. Premaquick© was positive when at least two of three biomarkers were positive. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were estimated for both prediction of spontaneous deliveries and spontaneous exclusive preterm deliveries. RESULTS: Ninety-seven (99.0%) out of 98 women enrolled were analyzed. Based on delivery status 7/14 days post-enrollment of general study population, Premaquick© had a sensitivity of 87.1/85.7%, a specificity of 92.4/96.8%, a PPV of 84.4/93.8% and a NPV of 93.9/92.3% for prediction of spontaneous delivery. Predictive accuracy of Premaquick© test in relation to days of enrollment were: 90.7% (≤7 days) and 92.8% (≤14 days). For women enrolled at GA <35 weeks, Premaquick© had a sensitivity of 100.0/87.5%, a specificity of 94.1/96.9%, a PPV of 70.5/87.5%, a NPV of 100.0/96.9% and an accuracy of 95.0/95.0% for prediction of preterm delivery within 7/14 days of enrollment, respectively. PPV was most significantly different in both groups when outcomes were compared between 2 days and 14 days post-enrollment (P<0.001). CONCLUSION: This novel triple biomarker model of native and total IGFBP-1 and IL-6 appears to be an accurate test in predicting spontaneous deliveries and spontaneous exclusive preterm deliveries in threatened preterm labor in singleton pregnancies.

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.

Cervical phosphorylated insulin-like growth factor binding protein-1 test for the prediction of preterm birth: a systematic review and metaanalysis.

OBJECTIVE: To assess the accuracy of the cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) test to predict preterm birth in women with and without symptoms of preterm labor through the use of formal methods for systematic reviews and metaanalytic techniques. DATA SOURCES: PubMed, Embase, Cinahl, Lilacs, and Medion (all from inception to June 30, 2015), reference lists, conference proceedings, and Google scholar. STUDY ELIGIBILITY CRITERIA: Cohort or cross-sectional studies that reported on the predictive accuracy of the cervical phIGFBP-1 test for preterm birth. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers independently selected studies, assessed the risk of bias, and extracted the data. Summary receiver-operating characteristic curves, pooled sensitivities and specificities, and summary likelihood ratios were generated. RESULTS: Forty-three studies met the inclusion criteria, of which 15 provided data on asymptomatic women (n = 6583) and 34 on women with an episode of preterm labor (n = 3620). Among asymptomatic women, the predictive accuracy of the cervical phIGFBP-1 test for preterm birth at <37, <34, and <32 weeks of gestation was minimal, with pooled sensitivities and specificities and summary positive and negative likelihood ratios ranging from 14% to 47%, 76% to 93%, 1.5 to 4.4, and 0.6 to 1.0, respectively. Among women with an episode of preterm labor, the test had a low predictive performance for delivery within 7 and 14 days of testing, and preterm birth at <34 and <37 weeks of gestation with pooled sensitivities and specificities and summary positive and negative likelihood ratios that varied between 60% and 68%, 77% and 81%, 2.7 and 3.5, and 0.4 and 0.5, respectively. A negative test result in women with an episode of preterm labor had a low to moderate accuracy to identify women who are not at risk for delivering within the next 48 hours (summary negative likelihood ratio of 0.28 in all women and 0.23 in women with singleton gestations). CONCLUSION: Cervical phIGFBP-1 has the potential utility to identify patients with an episode of preterm labor who will not deliver within 48 hours. However, its overall predictive ability for the identification of symptomatic and asymptomatic women at risk for preterm birth is limited.

INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 1 PREDICTS INSULIN SENSITIVITY AND INSULIN AREA-UNDER-THE-CURVE IN OBESE, NONDIABETIC ADOLESCENTS.

OBJECTIVE: To compare fasting insulin-like growth factor binding protein 1 (IGFBP-1) to other fasting indices as a surrogate marker of insulin sensitivity and resistance calculated from a 3-hour oral glucose tolerance test (oGTT). METHODS: Fasting IGFBP-1 and oGTT were performed at 0 (n = 77), 52 (n = 54), and 100 (n = 38) weeks in a study investigating metformin treatment of obesity in adolescents. Insulin area-under-the-curve (IAUC) and the composite insulin sensitivity index (CISI) calculated from the oGTT were compared to fasting IGFBP-1, homeostasis model assessment-insulin resistance, and corrected insulin release at the glucose peak (CIRgp). RESULTS: IGFBP-1 and the ratio of IGFBP-1 to fasting insulin were significantly correlated with indices based on timed sampling, including IAUC, CISI, and CIRgp. In addition, a significant effect of IGFBP-1, but not IGFBP-1 to insulin at time zero, was observed for IAUC and CISI. CONCLUSION: Our results indicate that fasting IGFBP-1 may be a useful marker of insulin sensitivity and secretion.

Proliferation and decidualization of endometrial stromal cells during embryo-attachment stage in bonnet monkeys (Macaca radiata).

We report embryo-induced alterations occurring in endometrial stromal cells (ESCs) during the embryo-attachment stage in bonnet monkeys (Macaca radiata). Laser micro-dissected ESCs obtained from pregnant and non-pregnant animals were compared for levels of selected proliferation and decidualization-associated factors by analysis with quantitative real-time polymerase chain reaction or immunohistochemistry. Stromal cells exhibited extensive cellular proliferation, as indicated by cellular compaction and significantly higher (P < 0.05) levels of proliferating cell nuclear antigen and of estrogen receptor 1, c-Myc, and Cyclin D1 transcripts in pregnant animals as compared with non-pregnant animals. A significant decrease (P < 0.05) was observed in the transcript levels of stromal interleukin-6 (IL-6) in pregnant animals. Cell proliferation was accompanied by a significant increase (P < 0.001) in the levels of decidualization-associated molecules such as IL-1ß in the luminal and glandular epithelium and of stromal insulin-like growth-factor-binding protein-1 (IGFBP-1) and prostaglandin-endoperoxide synthase-2 (PTGS-2) proteins. In pregnant animals, proliferation was evident throughout the gestational stroma, whereas decidualization was more pronounced in the embryo-attachment zone than in the non-attachment zone. To our knowledge, this is the first report of alterations in the endometrial stroma during the embryo-attachment stage in a non-human primate model.

Markers of Insulin Sensitivity in 12-Year-Old Children Born from Preeclamptic Pregnancies.

OBJECTIVE: To determine whether maternal preeclampsia influences insulin sensitivity (IS) or its biochemical markers in offspring. STUDY DESIGN: Sixty children born from a preeclamptic pregnancy (PRE) and 60 matched control subjects born from a normotensive pregnancy (non-PRE) were studied at age 12 years. IS was estimated using the Quantitative Insulin Sensitivity Check Index (QUICKI), and serum concentrations of adiponectin, leptin, insulin-like growth factor (IGF)-1, IGF-2, IGF-binding protein-1 (IGFBP-1), sex hormone-binding globulin, lipids, and casual blood pressure (BP) were measured. RESULTS: The mean values of QUICKI, serum adiponectin, leptin, IGF-1, IGF-2, IGFBP-1, and sex hormone-binding globulin did not differ between the PRE group and non-PRE group (P > .05 for all). The PRE subjects with the lowest IS (the lowest QUICKI tertile; n = 20) had significantly higher mean serum leptin (P = .007), triglyceride (P = .008), and IGF-1 (P = .005) levels and systolic BP (P = .019), and lower serum IGFBP-1 level (P = .007) compared with PRE subjects with higher QUICKI values (n = 40). Similarly, in logistic regression analysis, higher serum leptin (OR, 1.2; P = .009), triglyceride (OR, 1.2; P = .040), and IGF-1 (OR, 1.1; P = .031) levels and systolic BP (OR, 5.8; P = .024) were associated with low QUICKI in the PRE group. CONCLUSION: Maternal preeclampsia did not produce decreased IS in offspring by age of 12 years. However, the offspring with the lowest IS had higher mean serum triglyceride level and systolic BP, suggesting that components of the metabolic syndrome may cluster in this subgroup.

Effect of blood on ROM diagnosis accuracy of PAMG-1 and IGFBP-1 detecting rapid tests.

Vaginal bleeding may be present in up to 30% of patients presenting with signs and symptoms of a rupture of the fetal membranes (ROM). The presence of blood may lead to false positive results with biochemical markers. The data presented in this study came from a multi-centric prospective observational clinical study that, for the first time, systematically evaluated the performance of placental alpha microglobulin-1 (PAMG-1) and insulin-like growth factor binding protein-1 (IGFBP-1) detecting tests in 151 women with vaginal bleedings as well as signs and symptoms indicative of ROM. Our data showed better performance for the PAMG-1 compared with the IGFBP-1 detecting tests in all quality parameters evaluated. In detail, sensitivity (SN) was 97.8% (91.0%), specificity (SP) was 91.5% (75.0%), positive predictive value (PPV) was 94.6% (83.5%) and negative predictive value (NPV) was 96.4% (85.7%) for PAMG-1 tests (and IGFBP-1 tests, respectively). A major difference between both tests was related to the number of non-evaluable test results (e.g., hidden bands due to blood smear on the test strips). While 2% of all results were not evaluable for PAMG-1 tests, this artifact appeared in 11% of the results obtained with IGFBP-1 tests. This difference and also those in Specificity and PPV were statistically significant, demonstrating superiority of PAMG-1 over IGFBP-1 detecting tests. In conclusion, the PAMG-1 detecting test was significantly less susceptible to interference by blood than the IGFBP-1 detecting test.

Accuracy and cost-analysis of placental alpha-microglobulin-1 test in the diagnosis of premature rupture of fetal membranes in resource-limited community settings.

AIM: To determine accuracy and costs of placental α-microglobulin-1 (PAMG-1) test compared to standard clinical assessment (SCA) for diagnosing rupture of membranes (ROM). METHODS: A multicenter double-blind study of consecutive women with symptoms and signs of ROM in Nnamdi Azikiwe University Teaching Hospital, Nnewi and University of Nigeria Teaching Hospital, Enugu, both in south-east Nigeria using SCA for ROM and the PAMG-1 test was done. ROM was diagnosed if two out of three methods from SCA (pooling, positive nitrazine test or ferning) were present and confirmed post-delivery based on presence of any two of these clinical criteria: delivery in 48 h to 7 days, evidence of chorioamnionitis, membranes overtly ruptured at delivery and adverse perinatal outcomes strongly correlated with prolonged PROM. A cost-analysis was also done. The outcome measures included sensitivity, specificity, accuracy and costs for the two tests. RESULTS: Accuracy, sensitivity and specificity for the PAMG-1 test were 97.2%, 97.4% and 96.7%, higher than for SCA which were 83.7%, 87.9% and 70.5%, respectively (P < 0.001). Accuracy of SCA was higher at less than 34 weeks than 34 weeks or more (88.3% vs 81.4%) while the PAMG-1 test performed equally at both gestational age categories (96.1% vs 97.7%). In women without pooling, accuracy of the PAMG-1 test was 96.7%, while it was 40.0% with SCA. Analysis showed that the overall cost of SCA was 45% higher than the PAMG-1 test. CONCLUSION: This study confirms that the PAMG-1 test has a consistently high diagnostic accuracy at all gestational ages and with equivocal cases of ROM. The PAMG-1 test appears less costly than SCA.

[COMBINED APPLICATION OF FETAL FIBRONECTIN AND INSULIN-LIKE GROWTH FACTOR IN PRETERM DELIVERY DIAGNOSIS--OUR RESULTS].

The insulin-like growth factor IGFBP-1 is a binding protein (IBP-1), also known as placental protein (PP12), is encoded in people as IGFBP-1 gene. The IGFBP-1 is an especially vital hormone in the female reproductive physiology. The presence of it in large quantities in the amniotic fluid can be used as a biochemical marker for preterm birth and premature rupture of membranes. Fetal fibronectin is a high-molecular glycoprotein, that is produced during pregnancy and has a role as biological glue, binding the foetus membranes to the endometrium. fFN can be found in the cervicovaginal secretions until 22nd gestational week and later on during the last trimester (1 to 3 weeks before birth). fFN is usually absent between 24th and 34th gestational week. Thirty sixth (30%) of all the 120 females tested had positive fFN test results and were, therefore, at high risk for preterm delivery. Despite the implemented tocolytic therapy, 15 (12.5%) of them delivered before the 37th gestational week. The results from the investigation for the presence of pLGFBP-1 in 120 pregnant women show that 35.8% (43 women) were positive and 15(12,5%) of them delivered before the 37th gestational week despite the implemented tocolytic therapy In both tests, the average gestational age of the premature fetus was 32.5 ÷ 2.8 gestational weeks.

Meta-analysis of studies on biochemical marker tests for the diagnosis of premature rupture of membranes: comparison of performance indexes.

BACKGROUND: Premature rupture of the membranes (PROM) is most commonly diagnosed using physical examination; however, accurate decision making in ambiguous cases is a major challenge in current obstetric practice. As this may influence a woman's subsequent management, a number of tests designed to assist with confirming a diagnosis of PROM are commercially available. This study sought to evaluate the published data for the accuracy of two amniotic fluid-specific biomarker tests for PROM: insulin-like growth factor binding protein-1 (IGFBP-1 - Actim® PROM) and placental alpha microglobulin-1 (PAMG-1 - AmniSure®). METHODS: Main analysis included all PubMed referenced studies related to Actim® PROM and AmniSure® with available data to extract performance rates. To compare accuracy, a comparison of pooled indexes of both rapid tests was performed. Studies in which both tests were used in the same clinical population were also analysed. Membrane status, whether it was known or a suspected rupture, and inclusion or not of women with bleeding, were considered. RESULTS: All the available studies published in PubMed up to April 2013 were reviewed. Data were retrieved from 17 studies; 10 for Actim® PROM (n = 1066), four for AmniSure® (n = 1081) and three studies in which both biomarker tests were compared directly. The pooled analysis found that the specificity and positive predictive value were significantly higher for AmniSure® compared with Actim® PROM. However, when 762 and 1385 women with known or suspected rupture of membranes, respectively, were evaluated, AmniSure® only remained significantly superior in the latter group. Furthermore, when the two tests were compared directly in the same study no statistically significant differences were observed. Remarkably, women with a history or evidence of bleeding were excluded in all four studies for AmniSure®, in two Actim® PROM studies and in two of the three studies reporting on both tests. CONCLUSIONS: No differences were observed in the performance of the two tests in studies where they were used under the same clinical conditions or in women with known membrane status. Although AmniSure® performed better in suspected cases of PROM, this may need further analysis as exclusion of bleeding may not be representative of the real clinical presentation of women with suspected PROM.

Usefulness of the insulin-like growth factor binding protein-1 bedside test for ruptured fetal membranes.

OBJECTIVE: We evaluated whether phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) in blood or from other sources interferes with the vaginal IGFBP-1 dipstick test in rupture of fetal membranes (ROM). DESIGN: Cross-sectional study. SETTING: Antenatal Clinic, University Hospital. POPULATION: A total of 247 pregnant women consulting the emergency obstetric unit with self-reported amniotic fluid leakage. METHODS: Vaginal samples were tested with the IGFBP-1 dipstick test and the concentrations of different IGFBP-1 isoforms were measured by two immunoenzymometric assays. MAIN OUTCOME MEASURE: IGFBP-1 dipstick test result in the presence or absence of blood and different phosphoisoforms of IGFBP-1. RESULTS: The dipstick test was positive in 37.2% of women and negative in 62.8% of women. Vaginal bleeding was present in 19.4%. In women with a positive test and clinical evidence of ROM, both IGFBP-1 and phIGFBP-1 concentrations in vaginal fluid were lower in women with than in women without bleeding (p = 0.025 and p = 0.031, respectively). No difference was found in concentrations of IGFBP-1 and phIGFBP-1 in women with a positive dipstick test without ROM, with or without vaginal bleeding. In women with a negative test the concentrations of IGFBP-1 and phIGFBP-1 remained below the cut-off for the test, regardless of bleeding. IGFBP-1 concentration did not differ by cervical status, but phIGFBP-1 concentration was higher in women with a ripe cervix (p = 0.001). CONCLUSIONS: Rapid vaginal dipstick test can be used in the detection of ROM irrespective of the presence or absence of blood. Positive tests near term indicate either ROM or leakage of less phIGFBP-1 associated with onset of delivery.

Comparative study of placental α-microglobulin-1, insulin-like growth factor binding protein-1 and nitrazine test to diagnose premature rupture of membranes: a randomized controlled trial.

AIM: The aim of this study was to compare the accuracy of placental α-microglobulin-1 (PAMG-1), insulin-like growth factor binding protein-1 (IGFBP-1) and nitrazine test to diagnose premature rupture of membranes. MATERIAL AND METHODS: A total of 120 pregnant women between 11 and 42 weeks with signs/symptoms of membrane rupture were eligible for our study. These women were evaluated with the PAMG-1, IGFBP-1, and nitrazine tests. RESULTS: In the 120 women, the sensitivity, specificity, positive predictive value, and negative predictive value of PAMG-1, IGFBP-1 and nitrazine test were 100%, 100%, 100%, and 100%, 93.33%, 98.89%, 96.55% and 97.80%, and 93.33%, 94.44%, 84.85%, and 97.7%, respectively. In a comparison of the PAMG-1 test and the nitrazine test, positive coincidence rate was 84.85%, negative coincidence rate was 97.70%, total coincidence rate was 94.17%, and kappa value was 0.85. In a comparison of the PAMG-1 test and the IGFBP-1 test, the positive coincidence rate, negative coincidence rate and total coincidence rate were 96.55%, 97.80%, and 97.50%, and kappa value was 0.93. CONCLUSION: PAMG-1 assay was the most accurate method to diagnose premature rupture of membranes with the highest sensitivity, specificity, positive predictive value and negative predictive value.