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BACKGROUND: Maternal gestational diabetes (GDM), small (SGA) and large (LGA) for gestational age neonates are associated with increased morbidity in both mother and child. We studied how different levels of first trimester pregnancy associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotropin (fß-hCG) were associated with SGA and LGA in GDM pregnancies and controls. METHODS: Altogether 23 482 women with singleton pregnancies participated in first trimester combined screening and delivered between 2014 and 2018 in Northern Finland and were included in this retrospective case-control study. Women with GDM (n = 4697) and controls without GDM (n = 18 492) were divided into groups below 5th and 10th or above 90th and 95th percentile (pc) PAPP-A and fß-hCG MoM levels. SGA was defined as a birthweight more than two standard deviations (SD) below and LGA more than two SDs above the sex-specific and gestational age-specific reference mean. Odds ratios were adjusted (aOR) for maternal age, BMI, ethnicity, IVF/ICSI, parity and smoking. RESULTS: In pregnancies with GDM the proportion of SGA was 2.6% and LGA 4.5%, compared to 3.3% (p = 0.011) and 1.8% (p < 0.001) in the control group, respectively. In ≤ 5th and ≤ 10th pc PAPP-A groups, aORs for SGA were 2.7 (95% CI 1.5-4.7) and 2.2 (95% CI 1.4-3.5) in the GDM group and 3.8 (95% CI 3.0-4.9) and 2.8 (95% CI 2.3-3.5) in the reference group, respectively. When considering LGA, there was no difference in aORs in any high PAPP-A groups. In the low ≤ 5 percentile fß-hCG MoM group, aORs for SGA was 2.3 (95% CI 1.8-3.1) in the control group. In fß-hCG groups with GDM there was no association with SGA and the only significant difference was ≥ 90 percentile group, aOR 1.6 (95% CI 1.1-2.5) for LGA. CONCLUSION: Association with low PAPP-A and SGA seems to be present despite GDM status. High PAPP-A levels are not associated with increased LGA risk in women with or without GDM. Low fß-hCG levels are associated with SGA only in non-GDM pregnancies.
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Gonadotropina Coriónica Humana de Subunidad beta , Diabetes Gestacional , Macrosomía Fetal , Recién Nacido Pequeño para la Edad Gestacional , Primer Trimestre del Embarazo , Proteína Plasmática A Asociada al Embarazo , Humanos , Femenino , Embarazo , Proteína Plasmática A Asociada al Embarazo/análisis , Proteína Plasmática A Asociada al Embarazo/metabolismo , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Primer Trimestre del Embarazo/sangre , Adulto , Estudios de Casos y Controles , Estudios Retrospectivos , Diabetes Gestacional/sangre , Diabetes Gestacional/epidemiología , Recién Nacido , Macrosomía Fetal/sangre , Macrosomía Fetal/epidemiología , Finlandia/epidemiología , Factores de Riesgo , Peso al NacerRESUMEN
Background: Gestational diabetes mellitus (GDM) can result in adverse maternal and neonatal outcomes. Predicting those at high risk of GDM and early interventions can reduce the development of GDM. The aim of this study was to examine the associations between first-trimester prenatal screening biomarkers and maternal characteristics in relation to GDM in Chinese women. Methods: We conducted a retrospective cohort study of singleton pregnant women who received first-trimester aneuploidy and preeclampsia screening between January 2019 and May 2021. First-trimester prenatal screening biomarkers, including pregnancy-associated plasma protein A (PAPP-A), free beta-human chorionic gonadotropin, and placental growth factor (PLGF), along with maternal characteristics, were collected for analysis in relation to GDM. Receiver operating characteristic (ROC) curve and logistic regression analyses were used to evaluate variables associated with GDM. Results: Of the 1452 pregnant women enrolled, 96 developed GDM. PAPP-A (5.01 vs. 5.73 IU/L, P < 0.001) and PLGF (39.88 vs. 41.81 pg/mL, P = 0.044) were significantly lower in the GDM group than in the non-GDM group. The area under the ROC curve of combined maternal characteristics and biomarkers was 0.73 (95% confidence interval [CI] 0.68-0.79, P < 0.001). The formula for predicting GDM was as follows: P = 1/[1 + exp (-8.148 + 0.057 x age + 0.011 x pregestational body mass index + 1.752 x previous GDM history + 0.95 x previous preeclampsia history + 0.756 x family history of diabetes + 0.025 x chronic hypertension + 0.036 x mean arterial pressure - 0.09 x PAPP-A - 0.001 x PLGF)]. Logistic regression analysis revealed that higher pregestational body mass index (adjusted odds ratio [aOR] 1.03, 95% CI 1.01 - 1.06, P = 0.012), previous GDM history (aOR 9.97, 95% CI 3.92 - 25.37, P < 0.001), family history of diabetes (aOR 2.36, 95% CI 1.39 - 4.02, P = 0.001), higher mean arterial pressure (aOR 1.17, 95% CI 1.07 - 1.27, P < 0.001), and lower PAPP-A level (aOR 0.91, 95% CI 0.83 - 1.00, P = 0.040) were independently associated with the development of GDM. The Hosmer-Lemeshow test demonstrated that the model exhibited an excellent discrimination ability (chi-square = 3.089, df = 8, P = 0.929). Conclusion: Downregulation of first-trimester PAPP-A and PLGF was associated with the development of GDM. Combining first-trimester biomarkers with maternal characteristics could be valuable for predicting the risk of GDM.
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Biomarcadores , Diabetes Gestacional , Primer Trimestre del Embarazo , Proteína Plasmática A Asociada al Embarazo , Humanos , Femenino , Embarazo , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/epidemiología , Diabetes Gestacional/sangre , Primer Trimestre del Embarazo/sangre , Adulto , Biomarcadores/sangre , Estudios Retrospectivos , Proteína Plasmática A Asociada al Embarazo/metabolismo , Proteína Plasmática A Asociada al Embarazo/análisis , China/epidemiología , Factor de Crecimiento Placentario/sangre , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Diagnóstico Prenatal/métodos , Preeclampsia/epidemiología , Preeclampsia/diagnóstico , Preeclampsia/sangre , Pueblos del Este de AsiaRESUMEN
Objective: This study aimed to investigate the effects of the presence of subchorionic hematoma (SH) in early pregnancies with threatened miscarriage (TM) on levels of first-trimester maternal serum markers, pregnancy-associated plasma protein-A (PAPP-A), and free ß-human chorionic gonadotropin (ß-hCG) levels. Methods: The data of TM cases with SH in the first trimester between 2015 and 2021 were evaluated retrospectively. The data of age and gestational age-matched TM cases without SH were also assessed to constitute a control group. Demographic characteristics, obstetric histories, ultrasonographic findings, and free ß-hCG and PAPP-A levels of the groups were compared. Results: There were 119 cases in the study group and 153 cases in the control group. The median vertical and longitudinal lengths of the SH were 31 mm and 16 mm. The median age of both groups was similar (p=0.422). The MoM value of PAPP-A was 0.088 (.93) in the study group and 0.9 (0.63) in the control group (p=0.519). Similarly, the MoM value of free ß-hCG was 1.04 (0.78) in the study group and 0.99 (0.86) in the control group (p=0.66). No significant relationship was found in the multivariate analysis between free ß-hCG MoM, PAPP-A MoM, age, gravida, and vertical and longitudinal lengths of the hematoma (p>0.05). Conclusion: The level of PAPP-A and free ß-hCG were not affected by the SH. Therefore, these markers can be used reliably in TM cases with SH for the first-trimester fetal aneuploidy screening test.
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Gonadotropina Coriónica Humana de Subunidad beta , Hematoma , Primer Trimestre del Embarazo , Proteína Plasmática A Asociada al Embarazo , Humanos , Femenino , Embarazo , Proteína Plasmática A Asociada al Embarazo/análisis , Primer Trimestre del Embarazo/sangre , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Hematoma/sangre , Hematoma/diagnóstico por imagen , Adulto , Estudios Retrospectivos , Biomarcadores/sangre , Estudios de Casos y Controles , Amenaza de Aborto/sangre , Corion/diagnóstico por imagenRESUMEN
Background: Due to the incomplete standardization of the etiology and diagnostic criteria for fetal growth restriction (FGR), there has been uncertainty in the early prediction of FGR. The comprehensive estimation of FGR was mainly based on various factors, such as maternal characteristics and medical history, nuchal translucency (NT), and serum biochemical markers [pregnancy-associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotropin (free ß-hCG)]. Herein, we performed a retrospective cohort study to investigate the correlation and diagnostic value of maternal markers such as PAPP-A, free ß-hCG, and NT in the first trimester with maternal characteristics, so as to provide theoretical basis for perinatal care and the application of low-dose aspirin. Methods: A retrospective cohort study was conducted to analyze the data of an FGR group and a non-FGR group. Chi-square test and Mann-Whitney U test were used for univariate analysis of qualitative or quantitative data, respectively. Modified Poisson regression calculated the relative risk (RR) and 95% confidence interval (CI) of perinatal variables; P<0.05 was considered statistically significant. Results: The multiple of median (MoM) of PAPP-A level and NT in the FGR group were lower than those of the non-FGR group [0.63 (0.12-2.08) vs. 1.01 (0.28-2.41) MoM, 1.30 (0.80-2.07) vs. 1.40 (0.80-2.20) cm, P<0.05]. The weight, score, and length of newborns in the FGR group were lower than those in the non-FGR group (all P<0.001). Modified Poisson regression analysis showed that gestational hypertension (GH) [RR =1.836 (95% CI: 1.188-2.836)], oligohydramnios [1.420 (95% CI: 1.022-1.973)], premature rupture of membranes (PROM) [0.641 (95% CI: 0.425-0.969)], female infant [1.539 (95% CI: 1.098-2.157)], low infant length [5.700 (95% CI: 3.416-9.509)], low birth weight [1.609 (95% CI: 1.012-2.559), and increased PAPP-A MoM [0.533 (95% CI: 0.369-0.769)] were associated with FGR. The cut-off value of PAPP-A + free ß-hCG + NT for predicting FGR was 0.190, with a sensitivity of 0.547 and a specificity of 0.778. Conclusions: Early screening markers combined with perinatal characteristics have better diagnostic value in predicting FGR and provide a scientific basis for the clinical use of low-dose aspirin to prevent FGR.
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INTRODUCTION: To determine the expression and clinical significance of maternal serum pregnancy-associated plasma protein A (PAPP-A) in pregnant women with different degrees of preeclampsia at 11-14 weeks of gestation. MATERIAL AND METHODS: The clinical data of 65 pregnant women with preeclampsia admitted to our hospital from January 2020 to October 2022 were retrospectively analysed. Another 45 normal pregnant women who came to our hospital for prenatal examination and delivery during the same period were selected as the healthy control group. The serum contents of PAPP-A, a-fetoprotein (AFP) and free estriol (uE3) in each group were compared. The correlation between PAPP-A and AFP as well as uE3 was analysed by Pearson analysis. The clinical value of serological indexes in diagnosing preeclampsia was analysed using ROC curve. RESULTS: The levels of PAPP-A and uE3 in pregnant women in the preeclampsia group were lower, while the contents of AFP were higher than these in the healthy control group ( p < 0.01). The pregnant women with severe preeclampsia had lower levels of PAPP-A and uE3 with higher levels of AFP compared to these with mild preeclampsia ( p < 0.001). Pearson correlation analysis showed that serum PAPP-A was negatively correlated with AFP ( r = -0.246, p < 0.05) and positively correlated with uE3 ( r = 0.398, p < 0.01) in preeclampsia patients. ROC curve analysis demonstrated that the area under the curve (AUC) of PAPP-A, AFP and uE3 to assist in the diagnosis of preeclampsia was 0.740, 0.738 and 0.806, respectively. The AUC of the combination of PAPP-A, AFP and uE3 to assist in the diagnosis was 0.912, with a sensitivity of 90.38% and a specificity of 80.33%. The clinical assisted diagnostic value of combined detection was high. CONCLUSIONS: The serum level of PAPP-A in pregnant women with preeclampsia in the early pregnancy was significantly lower and related to the severity of the disease. The combination of routine detection for AFP and uE3 had a good predictive value for preeclampsia, which was helpful to take relevant interventions to reduce the incidence of preeclampsia as early as possible, and had a positive impact on protecting maternal and infant health.
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BACKGROUND: Small-for-gestational-age (SGA), commonly caused by poor placentation, is a major contributor to global perinatal mortality and morbidity. Maternal serum levels of placental protein and angiogenic factors are changed in SGA. Using data from a population-based pregnancy cohort, we estimated the relationships between levels of second-trimester pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF), and serum soluble fms-like tyrosine kinase-1 (sFlt-1) with SGA. METHODS: Three thousand pregnant women were enrolled. Trained health workers prospectively collected data at home visits. Maternal blood samples were collected, serum aliquots were prepared and stored at -80â. Included in the analysis were 1,718 women who delivered a singleton live birth baby and provided a blood sample at 24-28 weeks of gestation. We used Mann-Whitney U test to examine differences of the median biomarker concentrations between SGA (< 10th centile birthweight for gestational age) and appropriate-for-gestational-age (AGA). We created biomarker concentration quartiles and estimated the risk ratios (RRs) and 95% confidence intervals (CIs) for SGA by quartiles separately for each biomarker. A modified Poisson regression was used to determine the association of the placental biomarkers with SGA, adjusting for potential confounders. RESULTS: The median PlGF level was lower in SGA pregnancies (934 pg/mL, IQR 613-1411 pg/mL) than in the AGA (1050 pg/mL, IQR 679-1642 pg/mL; p < 0.001). The median sFlt-1/PlGF ratio was higher in SGA pregnancies (2.00, IQR 1.18-3.24) compared to AGA pregnancies (1.77, IQR 1.06-2.90; p = 0.006). In multivariate regression analysis, women in the lowest quartile of PAPP-A showed 25% higher risk of SGA (95% CI 1.09-1.44; p = 0.002). For PlGF, SGA risk was higher in women in the lowest (aRR 1.40, 95% CI 1.21-1.62; p < 0.001) and 2nd quartiles (aRR 1.30, 95% CI 1.12-1.51; p = 0.001). Women in the highest and 3rd quartiles of sFlt-1 were at reduced risk of SGA delivery (aRR 0.80, 95% CI 0.70-0.92; p = 0.002, and aRR 0.86, 95% CI 0.75-0.98; p = 0.028, respectively). Women in the highest quartile of sFlt-1/PlGF ratio showed 18% higher risk of SGA delivery (95% CI 1.02-1.36; p = 0.025). CONCLUSIONS: This study provides evidence that PAPP-A, PlGF, and sFlt-1/PlGF ratio measurements may be useful second-trimester biomarkers for SGA.
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Biomarcadores , Recién Nacido Pequeño para la Edad Gestacional , Factor de Crecimiento Placentario , Insuficiencia Placentaria , Segundo Trimestre del Embarazo , Proteína Plasmática A Asociada al Embarazo , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Humanos , Femenino , Embarazo , Factor de Crecimiento Placentario/sangre , Biomarcadores/sangre , Estudios Prospectivos , Adulto , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre , Proteína Plasmática A Asociada al Embarazo/análisis , Proteína Plasmática A Asociada al Embarazo/metabolismo , Insuficiencia Placentaria/sangre , Recién Nacido , Segundo Trimestre del Embarazo/sangre , Bangladesh/epidemiología , Adulto Joven , Edad Gestacional , Factores de RiesgoRESUMEN
OBJECTIVES: To evaluate associations between serum analytes used for genetic screening and obstetric complications among twin pregnancies. METHODS: This cohort included twins delivered at a tertiary care hospital from 2009 to 2017. Abnormal levels of pregnancy associated plasma protein (PAPP-A), first and second trimester human chorionic gonadotropin (hCG), alpha fetoprotein (AFP), estriol, and inhibin, reported as multiples of the median (MoM), were defined as <5â¯%ile or >95â¯%ile for our cohort. Associations between abnormal analytes and preterm delivery, small for gestational age, and pregnancy-associated hypertension were calculated using Fisher's exact test. RESULTS: A total of 357 dichorionic/diamniotic and 123 monochorionic/diamniotic twins were included. Among dichorionic/diamniotic twins, elevated AFP (>3.70 MoM) was associated with increased preterm delivery <34 weeks (44.4 vs. 16.5â¯%, p=0.007), while elevated inhibin (>4.95 MoM) was associated with increased preterm delivery<37 weeks (94.1 vs. 58.8â¯%, p=0.004). For monochorionic/diamniotic twins, elevated inhibin (>6.34 MoM) was associated increased preterm delivery <34 weeks (66.7 vs. 24.8â¯%, p=0.04) and hypertension (66.7 vs. 21.4â¯%, p=0.03). CONCLUSIONS: Selected abnormal analyte levels were associated with increased rates of adverse outcomes in twin pregnancies, which differed by chorionicity. Our findings assist providers in interpreting abnormal analyte levels in twin pregnancies and may help to identify those at increased risk for adverse outcomes.
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Aneuploidia , Inhibinas , Embarazo Gemelar , Nacimiento Prematuro , alfa-Fetoproteínas , Humanos , Femenino , Embarazo , Embarazo Gemelar/sangre , Adulto , Inhibinas/sangre , Nacimiento Prematuro/sangre , Nacimiento Prematuro/diagnóstico , Nacimiento Prematuro/epidemiología , alfa-Fetoproteínas/análisis , alfa-Fetoproteínas/metabolismo , Gonadotropina Coriónica/sangre , Proteína Plasmática A Asociada al Embarazo/análisis , Proteína Plasmática A Asociada al Embarazo/metabolismo , Estriol/sangre , Resultado del Embarazo/epidemiología , Recién Nacido , Hipertensión Inducida en el Embarazo/sangre , Hipertensión Inducida en el Embarazo/diagnóstico , Hipertensión Inducida en el Embarazo/epidemiología , Pruebas Genéticas/métodos , Estudios Retrospectivos , Recién Nacido Pequeño para la Edad Gestacional , Estudios de CohortesRESUMEN
Background: Pre-eclampsia (PE) is a multiorgan disorder that affects 2-5% of all pregnant women. Present recommendations for when to start aspirin in high-risk women are after 11 wk of gestation. Objective: We present a protocol to investigate the effectiveness of aspirin use from early pregnancy, which is a randomized controlled trial to assess whether prescribed low-dose aspirin from early pregnancy reduces the prevalence of early and late-onset PE. Additionally, to compare the effectiveness of aspirin administration before and after 11 wk in reducing the occurrence of PE? Materials and Methods: All pregnancies at risk of PE, according to demographic and midwifery history, who are referred to the Maternal-Fetal Clinic of Tehran University hospital, Tehran, Iran were invited to take part in the trial. The outcomes of pregnancy and newborns will be gathered and analyzed. The first registration for the pilot study was in January 2023, and the participants were recognized as high-risk for PE. In addition, enrollment in the main study will begin as of October 2023.
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This review provides a comprehensive exploration of the roles of placenta growth factor (PlGF) and pregnancy-associated plasma protein A (PAPP-A) in the context of pre-eclampsia, a pregnancy-related hypertensive disorder with significant implications for maternal and fetal health. The background elucidates the clinical significance of pre-eclampsia, highlighting its prevalence and impact. The review delves into the biological importance of PlGF and PAPP-A, emphasizing their critical roles in normal placental development and their dysregulation in pre-eclampsia. Notably, altered levels of these biomarkers emerge as potential diagnostic indicators, offering insights into the pathophysiology of the disorder. The exploration of pathophysiological mechanisms, including angiogenic imbalance and placental dysfunction, provides a nuanced understanding of pre-eclampsia's molecular landscape. The therapeutic implications of targeting PlGF and PAPP-A open avenues for future research, aiming at effective intervention strategies. The conclusion summarizes key findings, outlines implications for future research, and underscores the crucial role of PlGF and PAPP-A in understanding and managing pre-eclampsia, with the ultimate goal of improving outcomes for both mothers and infants.
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AIM: This study aims to determine whether second-trimester uterine artery (UtA) Doppler combined with first-trimester abnormal pregnancy-associated plasma protein-A (PAPP-A) and ß-human chorionic gonadotropin (ß-Hcg) levels predicts adverse obstetric and neonatal outcomes. MATERIALS AND METHODS: This study of 289 pregnant women included 196 with normal PAPP-A and free ß-HCG values (control group) and 93 with abnormal values (study group) in the first-trimester screening test. Second-trimester UtA Doppler sonography was done in these pregnancies. The perinatal prediction and screening potential of UtA Doppler pulsatility index (PI) parameters were examined in the study group. RESULTS: UtA PI >95 percentile increased birth before the 37th week by 4.46 times, birth before the 34th week by 7.44 times, preeclampsia risk by 3.25 times, fetal growth restriction (FGR) risk by 4.89 times, and neonatal intensive care unit (NICU) admission rates by 3.66 times in the study group (p < 0.05 for all). UtA PI >95 percentile had 49.2% sensitivity and 82.1% specificity for birth before 37 weeks. For birth before 34 weeks, sensitivity was 80.0% and specificity 65.0%. FGR has 70.5% sensitivity and 67.1% specificity. Screening for preeclampsia has 66.6% sensitivity and 61.9% specificity. CONCLUSION: Adding UtA Doppler in the second trimester to pregnancies with abnormal PAPP-A and/or free ß-Hcg values in the first trimester may be a useful screening method for adverse outcomes.
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Gonadotropina Coriónica Humana de Subunidad beta , Valor Predictivo de las Pruebas , Resultado del Embarazo , Primer Trimestre del Embarazo , Segundo Trimestre del Embarazo , Proteína Plasmática A Asociada al Embarazo , Ultrasonografía Doppler , Ultrasonografía Prenatal , Arteria Uterina , Humanos , Femenino , Embarazo , Arteria Uterina/diagnóstico por imagen , Proteína Plasmática A Asociada al Embarazo/análisis , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Adulto , Ultrasonografía Prenatal/métodos , Segundo Trimestre del Embarazo/sangre , Ultrasonografía Doppler/métodos , Primer Trimestre del Embarazo/sangre , Recién Nacido , Biomarcadores/sangre , Flujo PulsátilRESUMEN
Pregnancy associated plasma protein-A (PAPP-A) plays an integral role in breast cancer (BC), especially triple negative breast cancer (TNBC). This subtype accounts for the most aggressive BC, possesses high tumor heterogeneity, is least responsive to standard treatments and has the poorest clinical outcomes. There is a critical need to address the lack of effective targeted therapeutic options available. PAPP-A is a protein that is highly elevated during pregnancy. Frequently, higher PAPP-A expression is detected in tumors than in healthy tissues. The increase in expression coincides with increased rates of aggressive cancers. In BC, PAPP-A has been demonstrated to play a role in tumor initiation, progression, metastasis including epithelial-mesenchymal transition (EMT), as well as acting as a biomarker for predicting patient outcomes. In this review, we present the role of PAPP-A, with specific focus on TNBC. The structure and function of PAPP-A, belonging to the pappalysin subfamily, and its proteolytic activity are assessed. We highlight the link of BC and PAPP-A with respect to the IGFBP/IGF axis, EMT, the window of susceptibility and the impact of pregnancy. Importantly, the relevance of PAPP-A as a TNBC clinical marker is reviewed and its influence on immune-related pathways are explored. The relationship and mechanisms involving PAPP-A reveal the potential for more treatment options that can lead to successful immunotherapeutic targets and the ability to assist with better predicting clinical outcomes in TNBC.
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Neoplasias de la Mama Triple Negativas , Femenino , Embarazo , Humanos , Neoplasias de la Mama Triple Negativas/terapia , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Proteína Plasmática A Asociada al Embarazo/metabolismo , Transformación Celular Neoplásica , Transición Epitelial-MesenquimalRESUMEN
Pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2 modulate insulin-like growth factor (IGF) action and are inhibited by the stanniocalcins (STC1 and STC2). We previously demonstrated increased PAPP-A and IGF activity in ascites from women with ovarian carcinomas. In this prospective, longitudinal study of 107 women with ovarian cancer and ascites accumulation, we determined corresponding serum and ascites levels of IGF-1, IGF-2, PAPP-A, PAPP-A2, STC1, and STC2 and assessed their relationship with mortality. As compared to serum, we found highly increased ascites levels of PAPP-A (51-fold) and PAPP-A2 (4-fold). Elevated levels were also observed for IGF-1 (12%), STC1 (90%) and STC2 (68%). In contrast, IGF-2 was reduced by 29% in ascites. Patients were followed for a median of 38.4 months (range: 45 days to 8.9 years), during which 73 patients (68.2%) died. Overall survival was longer for patients with high serum IGF-1 (hazard ratio (HR) per doubling in protein concentration: 0.60, 95% CI: 0.40-0.90). However, patients with high ascites levels of IGF-1 showed a poorer prognosis (HR: 2.00 (1.26-3.27)). High serum and ascites IGF-2 levels were associated with increased risk of mortality (HR: 2.01 (1.22-3.30) and HR: 1.78 (1.24-2.54), respectively). Similarly, serum PAPP-A2 was associated with mortality (HR: 1.26 (1.08-1.48)). Our findings demonstrate the presence and activity of the IGF system in the local tumor ecosystem, which is likely a characteristic feature of malignant disease and plays a role in its peritoneal dissemination. The potential clinical implications are supported by our finding that serum levels of the proteins are associated with patient prognosis.
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Glicoproteínas , Factor I del Crecimiento Similar a la Insulina , Neoplasias Ováricas , Humanos , Femenino , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor II del Crecimiento Similar a la Insulina , Proteína Plasmática A Asociada al Embarazo/metabolismo , Ascitis , Estudios Prospectivos , Ecosistema , Estudios Longitudinales , Neoplasias Ováricas/complicacionesRESUMEN
OBJECTIVE: Effective first-trimester screening for pre-eclampsia (PE) can be achieved using a competing-risks model that combines risk factors from the maternal history with multiples of the median (MoM) values of biomarkers. A new model using artificial intelligence through machine-learning methods has been shown to achieve similar screening performance without the need for conversion of raw data of biomarkers into MoM. This study aimed to investigate whether this model can be used across populations without specific adaptations. METHODS: Previously, a machine-learning model derived with the use of a fully connected neural network for first-trimester prediction of early (< 34 weeks), preterm (< 37 weeks) and all PE was developed and tested in a cohort of pregnant women in the UK. The model was based on maternal risk factors and mean arterial blood pressure (MAP), uterine artery pulsatility index (UtA-PI), placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A). In this study, the model was applied to a dataset of 10 110 singleton pregnancies examined in Spain who participated in the first-trimester PE validation (PREVAL) study, in which first-trimester screening for PE was carried out using the Fetal Medicine Foundation (FMF) competing-risks model. The performance of screening was assessed by examining the area under the receiver-operating-characteristics curve (AUC) and detection rate (DR) at a 10% screen-positive rate (SPR). These indices were compared with those derived from the application of the FMF competing-risks model. The performance of screening was poor if no adjustment was made for the analyzer used to measure PlGF, which was different in the UK and Spain. Therefore, adjustment for the analyzer used was performed using simple linear regression. RESULTS: The DRs at 10% SPR for early, preterm and all PE with the machine-learning model were 84.4% (95% CI, 67.2-94.7%), 77.8% (95% CI, 66.4-86.7%) and 55.7% (95% CI, 49.0-62.2%), respectively, with the corresponding AUCs of 0.920 (95% CI, 0.864-0.975), 0.913 (95% CI, 0.882-0.944) and 0.846 (95% CI, 0.820-0.872). This performance was achieved with the use of three of the biomarkers (MAP, UtA-PI and PlGF); inclusion of PAPP-A did not provide significant improvement in DR. The machine-learning model had similar performance to that achieved by the FMF competing-risks model (DR at 10% SPR, 82.7% (95% CI, 69.6-95.8%) for early PE, 72.7% (95% CI, 62.9-82.6%) for preterm PE and 55.1% (95% CI, 48.8-61.4%) for all PE) without requiring specific adaptations to the population. CONCLUSIONS: A machine-learning model for first-trimester prediction of PE based on a neural network provides effective screening for PE that can be applied in different populations. However, before doing so, it is essential to make adjustments for the analyzer used for biochemical testing. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
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Preeclampsia , Recién Nacido , Embarazo , Femenino , Humanos , Primer Trimestre del Embarazo , Preeclampsia/epidemiología , Diagnóstico Prenatal/métodos , Proteína Plasmática A Asociada al Embarazo , Inteligencia Artificial , Presión Arterial/fisiología , Factor de Crecimiento Placentario , Flujo Pulsátil/fisiología , Arteria Uterina , Biomarcadores , Aprendizaje AutomáticoRESUMEN
OBJECTIVES: This study aims to evaluate if low levels of serum maternal pregnancy associated plasma protein-A (PAPP-A) during the first trimester are related to increased umbilical artery pulsatility index (UA PI) later in pregnancy, in cases of estimated fetal weight between the 3rd and 10th percentiles, in order to establish PAPP-A as a predictor of this particular cases of fetal growth restriction (FGR). METHODS: An observational, retrospective cohort study, conducted at a tertiary University Hospital located in Oporto, Portugal. Pregnant women who did the first trimester combined screening, between May 2013 and June 2020 and gave birth in the same hospital, with an estimated fetal weight (EFW) between the 3rd and 10th percentiles were included. The primary outcome is the difference in increased UA PI prevalence between two groups: PAPP-A<0.45 MoM and PAPP-A≥0.45 MoM. As secondary outcomes were evaluated differences in neonatal weight, gestational age at delivery, cesarean delivery, neonatal intensive care unit hospitalization, 5-min Apgar score below 7 and live birth rate between the same two groups. RESULTS: We included 664 pregnancies: 110 cases of PAPP-A<0.45 MoM and 554 cases with PAPP-A≥0.45 MoM. Increased UA PI prevalence, which was the primary outcome of this study, was significantly different between the two groups (p=0.005), as the PAPP-A<0.45 MoM group presents a higher prevalence (12.7â¯%) when compared to the PAPP-A≥0.45 MoM group (5.4â¯%). The secondary outcome cesarean delivery rate was significantly different between the groups (p=0.014), as the PAPP-A<0.45 MoM group presents a higher prevalence (42.7â¯%) than the PAPP-A≥0.45 MoM group (30.1â¯%). No other secondary outcomes showed differences between the two groups. CONCLUSIONS: There is an association of low serum maternal PAPP-A (<0.45 MoM) during the first trimester and increased UA PI (>95th percentile) later in pregnancy, in cases of EFW between the 3rd and 10th percentiles. However, this association is not strong enough alone for low PAPP-A to be a reliable predictor of increased UA PI in this population.
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Peso Fetal , Proteína Plasmática A Asociada al Embarazo , Recién Nacido , Embarazo , Humanos , Femenino , Arterias Umbilicales/diagnóstico por imagen , Estudios Retrospectivos , Ultrasonografía Prenatal , Retardo del Crecimiento Fetal/diagnóstico , Edad GestacionalRESUMEN
Objective:To investigate the predictive value of pregnancy-associated plasma protein A(PAPP-A),fasting blood glucose(FPG),body mass index(BMI)and age in gestational diabetes mellitus(GDM)during the first trimester.Methods:A retrospective analysis was performed on 792 pregnant women who underwent pre-natal examination and delivered in Sichuan Provincial Maternal and Child Health Care Hospital from December 2021 to June 2022.They were divided into GDM group(232 cases)and control group(560 cases)according to whether they had GDM.The clinical data,serum PAPP-A median multiple(PAPP-A MoM)in early pregnancy and FPG levels were compared between the two groups.The indicators with statistical significance in univariate analy-sis were included in multivariate Logistic regression analysis to analyze the related factors affecting the occurrence of GDM.The receiver operating curve(ROC)and area under the curve(AUC)of different indexes were plotted to compare the efficacy of GDM prediction.Results:①The age,pre pregnancy BMI,early pregnancy FPG and the proportion of assisted reproductive technology in GDM group were higher than those in control group,and the differences were statistically significant(P＜0.05).The early pregnancy PAPP-A MoM level in GDM group was lower than that in control group,and the difference was statistically significant(P＜0.05).②Multivariate Logistic regression analysis showed that older age,lager pre-pregnancy BMI and lager FPG in the first trimester were in-dependent risk factors for GDM occurrence(OR＞1,P＜0.05),while an increase of PAPP-A MoM in the first tri-mester was a protective factor(OR＜1,P＜0.05).③ROC showed that the combination of PAPP-A MoM in early pregnancy,FPG in early pregnancy,BMI in pre-pregnancy and age had the highest AUC(0.752)when predicting GDM,with a sensitivity of 55.6％and a specificity of 84.3％.Conclusions:The combined screening of serologi-cal(PAPP-A +FPG)and clinical data(pre-pregnancy BMI +age)in early pregnancy has a high clinical application prospect and can be popularized.
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BACKGROUND: Metabolic syndrome leading to type 2 diabetes mellitus and cardiovascular diseases is a chronic multifactorial syndrome, associated with low-grade inflammation status. In our study, we aimed at assessing the serum levels of follistatin (FST), pregnancy-associated plasma protein-A (PAPP-A), and platelet/endothelial cell adhesion molecule-1 (PECAM-1) in adolescent patients with metabolic syndrome. METHODS: This study was performed in 43 (19 males, 24 females) metabolic syndrome adolescents and 37 lean controls matched for age and sex. The serum levels of FST, PECAM-1, and PAPP-A were measured by using ELISA method. RESULTS: Serum FST and PAPP-A levels in metabolic syndrome were significantly higher than those of controls (p < 0.005 and p < 0.05). However, there was no difference in serum PECAM-1 levels between metabolic syndrome and control groups (p = 0.927). There was a significant positive correlation between serum FST and triglyceride (r = 0.252; p < 0.05), and PAPP-A and weight, (r = 0.252; p < 0.05) in metabolic syndrome groups. Follistatin was determined statistically significant in both univariate (p = 0,008) and multivariate (p = 0,011) logistic regression analysis. CONCLUSIONS: Our findings indicated a significant relationship between FST and PAPP-A levels and metabolic syndrome. These findings offer the possibility of using these markers in diagnosis of metabolic syndrome in adolescents as the prevention of the future complications.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Síndrome Metabólico , Masculino , Femenino , Humanos , Adolescente , Síndrome Metabólico/complicaciones , Enfermedades Cardiovasculares/etiología , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Folistatina , Diabetes Mellitus Tipo 2/complicaciones , Biomarcadores , Factores de Riesgo , Proteína Plasmática A Asociada al Embarazo/análisis , Proteína Plasmática A Asociada al Embarazo/metabolismo , Factores de Riesgo de Enfermedad CardiacaRESUMEN
BACKGROUND: The exact mechanism by which aspirin prevents preeclampsia remains unclear. Its effects on serum placental biomarkers throughout pregnancy are also unknown. OBJECTIVE: To investigate the effects of aspirin on serum pregnancy-associated plasma protein A and placental growth factor trajectories using repeated measures from women at increased risk of preterm preeclampsia. STUDY DESIGN: This was a longitudinal secondary analysis of the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-based Preeclampsia Prevention trial using repeated measures of pregnancy-associated plasma protein A and placental growth factor. In the trial, 1620 women at increased risk of preterm preeclampsia were identified using the Fetal Medicine Foundation algorithm at 11 to 13+6 weeks of gestation, of whom 798 were randomly assigned to receive aspirin 150 mg and 822 to receive placebo daily from before 14 weeks to 36 weeks of gestation. Serum biomarkers were measured at baseline and follow-up visits at 19 to 24, 32 to 34, and 36 weeks of gestation. Generalized additive mixed models with treatment by gestational age interaction terms were used to investigate the effect of aspirin on biomarker trajectories over time. RESULTS: Overall, there were 5507 pregnancy-associated plasma protein A and 5523 placental growth factor measurements. Raw pregnancy-associated plasma protein A values increased over time, and raw placental growth factor increased until 32 weeks of gestation followed by a decline. The multiple of the median mean values of the same biomarkers were consistently below 1.0 multiple of the median, reflecting the high-risk profile of the study population. Trajectories of mean pregnancy-associated plasma protein A and placental growth factor multiple of the median values did not differ significantly between the aspirin and placebo groups (aspirin treatment by gestational age interaction P values: .259 and .335, respectively). CONCLUSION: In women at increased risk of preterm preeclampsia, aspirin 150 mg daily had no significant effects on pregnancy-associated plasma protein A or placental growth factor trajectories when compared to placebo.
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Aspirina , Biomarcadores , Factor de Crecimiento Placentario , Preeclampsia , Proteína Plasmática A Asociada al Embarazo , Humanos , Femenino , Aspirina/uso terapéutico , Embarazo , Factor de Crecimiento Placentario/sangre , Proteína Plasmática A Asociada al Embarazo/metabolismo , Proteína Plasmática A Asociada al Embarazo/análisis , Preeclampsia/prevención & control , Preeclampsia/sangre , Adulto , Biomarcadores/sangre , Estudios Longitudinales , Edad GestacionalRESUMEN
OBJECTIVE: Investigate cost-effectiveness of first trimester pre-eclampsia screening using the Fetal Medicine Foundation (FMF) algorithm and targeted aspirin prophylaxis in comparison with standard care. DESIGN: Retrospective observational study. SETTING: London tertiary hospital. POPULATION: 5957 pregnancies screened for pre-eclampsia using the National Institute for Health and Care Excellence (NICE) method. METHODS: Differences in pregnancy outcomes between those who developed pre-eclampsia, term pre-eclampsia and preterm pre-eclampsia were compared by the Kruskal-Wallis and Chi-square tests. The FMF algorithm was applied retrospectively to the cohort. A decision analytic model was used to estimate costs and outcomes for pregnancies screened using NICE and those screened using the FMF algorithm. The decision point probabilities were calculated using the included cohort. MAIN OUTCOME MEASURES: Incremental healthcare costs and QALY gained per pregnancy screened. RESULTS: Of 5957 pregnancies, 12.8% and 15.9% were screen-positive for development of pre-eclampsia using the NICE and FMF methods, respectively. Of those who were screen-positive by NICE recommendations, aspirin was not prescribed in 25%. Across the three groups, namely, pregnancies without pre-eclampsia, term pre-eclampsia and preterm pre-eclampsia there was a statistically significant trend in rates of emergency caesarean (respectively 21%, 43% and 71.4%; P < 0.001), admission to neonatal intensive care unit (NICU) (5.9%, 9.4%, 41%; P < 0.001) and length of stay in NICU. The FMF algorithm was associated with seven fewer cases of preterm pre-eclampsia, cost saving of £9.06 and QALY gain of 0.00006/pregnancy screened. CONCLUSIONS: Using a conservative approach, application of the FMF algorithm achieved clinical benefit and an economic cost saving.
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Aspirina , Preeclampsia , Embarazo , Femenino , Recién Nacido , Humanos , Aspirina/uso terapéutico , Primer Trimestre del Embarazo , Preeclampsia/diagnóstico , Preeclampsia/prevención & control , Preeclampsia/tratamiento farmacológico , Estudios de Cohortes , Estudios Retrospectivos , Análisis Costo-BeneficioRESUMEN
Abstract Objective This study aimed to investigate the effects of the presence of subchorionic hematoma (SH) in early pregnancies with threatened miscarriage (TM) on levels of first-trimester maternal serum markers, pregnancy-associated plasma protein-A (PAPP-A), and free β-human chorionic gonadotropin (β-hCG) levels. Methods The data of TM cases with SH in the first trimester between 2015 and 2021 were evaluated retrospectively. The data of age and gestational age-matched TM cases without SH were also assessed to constitute a control group. Demographic characteristics, obstetric histories, ultrasonographic findings, and free β-hCG and PAPP-A levels of the groups were compared. Results There were 119 cases in the study group and 153 cases in the control group. The median vertical and longitudinal lengths of the SH were 31 mm and 16 mm. The median age of both groups was similar (p=0.422). The MoM value of PAPP-A was 0.088 (.93) in the study group and 0.9 (0.63) in the control group (p=0.519). Similarly, the MoM value of free β-hCG was 1.04 (0.78) in the study group and 0.99 (0.86) in the control group (p=0.66). No significant relationship was found in the multivariate analysis between free β-hCG MoM, PAPP-A MoM, age, gravida, and vertical and longitudinal lengths of the hematoma (p>0.05). Conclusion The level of PAPP-A and free β-hCG were not affected by the SH. Therefore, these markers can be used reliably in TM cases with SH for the first-trimester fetal aneuploidy screening test.
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OBJECTIVE: This study aimed to investigate the association between first-trimester Pregnancy-associated plasma protein A (PAPP-A) levels and subsequent gestational diabetes mellitus (GDM) development. METHOD: The study was conducted on 5854 pregnant women who attended routine prenatal care. Maternal biomarkers, including PAPP-A and free beta hCG, were measured for all women in a referral laboratory and converted to MoM values. Pregnant women were divided into two groups, based on the serum concentration of PAPP-A, (PAPP-A > 0.4 (normal) and PAPP-A < 0.4 (low)). Data on the screening test for GDM and pregnancy outcomes were collected and analyzed with appropriate tests. RESULT: Of the 5854 pregnant women, 889 (15.19%) developed GDM. The maternal PAPP-A MoM concentrations were significantly lower in GDM cases compared to controls. Indeed, gestational age at delivery and birth weight were significantly lower (p < 0.001) in PAPP-A MoM < 0.4, and the rate of intrauterine growth restriction (IUGR) was significantly higher (p < 0.001). ROC analysis revealed that the sensitivity and specificity of MoM concentration for predicting GDM were 53.3% and 51.9%, respectively. CONCLUSION: Lower maternal PAPP-A in early pregnancy can lead to glucose intolerance and increase the risk of subsequent GDM development. In addition, decreased serum concentration of PAPP-A is significantly correlated to lower birth weight and IUGR.