Pregnancy-associated Plasma protein-A Research Articles

Atypicality index as an add-on to combined first-trimester screening for chromosomal aberrations.

To compute a set of atypicality indices based on combined first-trimester screening (cFTS) markers and second-trimester estimated fetal weight (EFW), and to demonstrate their potential in identifying pregnancies at reduced or increased risk of chromosomal aberrations following a low-risk cFTS result. The atypicality index quantifies the unusualness of an individual set of measurements relative to a reference distribution and can be computed from any variables or measurements available. A score of 0% on the atypicality index represents the most typical profiles, while a score of 100% indicates the highest level of atypicality. From the Danish Fetal Medicine Database, we retrieved data on all pregnant women seen for cFTS in the Central Denmark Region between January 2008 and December 2018. All pregnancies with a cytogenetic or molecular analysis obtained prenatally, postnatally or following pregnancy loss or termination were identified. A first-trimester atypicality index (AcFTS) was computed based on nuchal translucency (NT) thickness, maternal serum free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Furthermore, a second-trimester index (AcFTS + EFW) was computed from cFTS markers and EFW from a routine second-trimester anomaly scan. All pregnancies were stratified into subgroups based on their atypicality levels and their cFTS risk estimates. The risk of chromosomal aberrations in each subgroup was then compared with the overall prevalence, and a graphical presentation of the multivariate measurement profiles was developed. We retrieved data on 145 955 singleton pregnancies, of which 9824 (6.7%) were genetically examined. Overall, 1 in 122 (0.82% (95% CI, 0.77-0.87%)) of all pregnancies seen for cFTS were affected by a fetal chromosomal aberration, and in screen-negative pregnancies (cFTS trisomy 21 risk < 1 in 100 and/or trisomy 18/13 risk < 1 in 50), 0.41% (95% CI, 0.38-0.44%) were affected. In screen-negative pregnancies with a typical first-trimester profile (AcFTS < 80%), the risk of chromosomal aberrations was significantly reduced (0.28%) compared with the overall risk. The risk of chromosomal aberrations increased with higher atypicality index to 0.49% (AcFTS [80-90%)), 1.52% (AcFTS [90-99%)) and 4.44% (AcFTS ≥ 99%) and was significantly increased in the two most atypical subgroups. The same applied for the second-trimester atypicality index, with risks of chromosomal aberrations of 0.76% and 4.16% in the two most atypical subgroups (AcFTS + EFW [90-99%) and AcFTS + EFW ≥ 99%, respectively). As an add-on to cFTS, the atypicality index identifies women with typical measurement profiles, which may provide reassurance, whereas atypical profiles may warrant specialist referral and further investigation. In pregnancies identified as low risk on cFTS but with a highly atypical distribution of NT, PAPP-A and β-hCG, the risk of a chromosomal aberration is substantially increased. The atypicality index optimizes the interpretation of pre-existing prenatal screening profiles and is not limited to cFTS markers or EFW. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of hypertensive disorders in pregnant women in the «gray» risk zone following combined first-trimester screening

Introduction. In obstetrics, hypertensive disorders of pregnancy (HDP) including preeclampsia (РЕ) are one of the primary causes resulting in critical cases and maternal mortality. HDP prediction is a milestone that allows preventing complications as well as reducing the number of most common relevant complications of pregnancy. Existing algorithms that predict PE risk distribute the risks in such a way that a considerable number of patients fall into the category of false negative results, and, consequently, receive no timely prevention and proper follow-up. In particular, this cohort usually consists of patients with borderline high risks, who may be designated as a medium risk group or located in a “gray” zone. Aim: to develop a prognostic model for risk stratification in female patients with borderline to high developing PE risk based on combined first-trimester screening. Materials and Methods. A prospective comparative study included 1089 female patients who underwent a combined screening at 11–14 weeks of gestation. Group 1 consisted of female patients at high РЕ risk (1:100 and greater), while female patients at moderate risk (1:101–1:250) and low risk (below 1:250) were included into Group 2 and Group 3, respectively. All pregnant women underwent examination including assessed anamnestic, general clinical and laboratory data, mean blood pressure (BP), uterine artery pulsatility index, serum level of human chorionic gonadotropin beta-subunits (β-hCG), placental growth factor (PlGF), pregnancy-associated plasma protein-A (PAPP-A). Results. An impact of various factors on risk of developing hypertensive disorders in pregnancy was assessed by binary logistic regression by identifying most significant among them and generating a statistical prediction model – the prognostic index of hypertensive disorders in pregnancy. The latter included: obstetric history, body mass index, PlGF, mean ВР, and alanine aminotransferase level. The sensitivity and specificity comprised 91.2 and 53.6 %, respectively, and the method effectivenesswas 81.8 %. Conclusion. The method proposed for HDP prediction is a second-line approach that may be used in clinical practice to stratify patients with borderline high risk of developing PE.

First-trimester serum biomarkers in twin pregnancies and adverse obstetric outcomes–a single center cohort study

PurposeThis study aimed to determine the association of first-trimester maternal serum biomarkers with preterm birth (PTB), fetal growth restriction (FGR) and hypertensive disorders of pregnancy (HDP) in twin pregnancies.MethodsThis is a retrospective cohort study of twin pregnancies followed at Maternidade Dr. Alfredo da Costa, Lisbon, Portugal, between January 2010 and December 2022. We included women who completed first-trimester screening in our unit and had ongoing pregnancies with two live fetuses, and delivered after 24 weeks. Maternal characteristics, pregnancy-associated plasma protein-A (PAPP-A) and β-human chorionic gonadotropin (β-hCG) levels were analyzed for different outcomes: small for gestational age (SGA), gestational hypertension (GH), early and late-onset pre-eclampsia (PE), as well as the composite outcome of PTB associated with FGR and/or HDP. Univariable, multivariable logistic regression analyses and receiver-operating characteristic curve were used.Results466 twin pregnancies met the inclusion criteria. Overall, 185 (39.7%) pregnancies were affected by SGA < 5th percentile and/or HDP. PAPP-A demonstrated a linear association with gestational age at birth and mean birth weight. PAPP-A proved to be an independent risk factor for SGA and PTB (< 34 and < 36 weeks) related to FGR and/or HDP. None of the women with PAPP-A MoM > 90th percentile developed early-onset PE or PTB < 34 weeks.ConclusionA high serum PAPP-A (> 90th percentile) ruled out early-onset PE and PTB < 34 weeks. Unless other major risk factors for hypertensive disorders are present, these women should not be considered candidates for aspirin prophylaxis. Nevertheless, close monitoring of all TwP for adverse obstetric outcomes is still recommended.

Prospective Validation of First-Trimester Screening for Preterm Preeclampsia in Nulliparous Women (PREDICTION Study).

Fetal Medicine Foundation (FMF) studies suggest that preterm preeclampsia can be predicted in the first trimester by combining biophysical, biochemical, and ultrasound markers and prevented using aspirin. We aimed to evaluate the FMF preterm preeclampsia screening test in nulliparous women. We conducted a prospective multicenter cohort study of nulliparous women recruited at 11 to 14 weeks. Maternal characteristics, mean arterial blood pressure, PAPP-A (pregnancy-associated plasma protein A), PlGF (placental growth factor) in maternal blood, and uterine artery pulsatility index were collected at recruitment. The risk of preterm preeclampsia was calculated by a third party blinded to pregnancy outcomes. Receiver operating characteristic curves were used to estimate the detection rate (sensitivity) and the false-positive rate (1-specificity) for preterm (<37 weeks) and for early-onset (<34 weeks) preeclampsia according to the FMF screening test and according to the American College of Obstetricians and Gynecologists criteria. We recruited 7554 participants including 7325 (97%) who remained eligible after 20 weeks of which 65 (0.9%) developed preterm preeclampsia, and 22 (0.3%) developed early-onset preeclampsia. Using the FMF algorithm (cutoff of ≥1 in 110 for preterm preeclampsia), the detection rate was 63.1% for preterm preeclampsia and 77.3% for early-onset preeclampsia at a false-positive rate of 15.8%. Using the American College of Obstetricians and Gynecologists criteria, the equivalent detection rates would have been 61.5% and 59.1%, respectively, for a false-positive rate of 34.3%. The first-trimester FMF preeclampsia screening test predicts two-thirds of preterm preeclampsia and three-quarters of early-onset preeclampsia in nulliparous women, with a false-positive rate of ≈16%. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02189148.

Externally validated prediction models for pre-eclampsia: systematic review and meta-analysis.

This systematic review and meta-analysis aimed to evaluate the performance of existing externally validated prediction models for pre-eclampsia (PE) (specifically, any-onset, early-onset, late-onset and pretermPE). A systematic search was conducted in five databases (MEDLINE, EMBASE, Emcare, CINAHL and Maternity & Infant Care Database) and using Google Scholar/reference search to identify studies based on the Population, Index prediction model, Comparator, Outcome, Timing and Setting (PICOTS) approach until 20 May 2023. We extracted data using the CHARMS checklist and appraised the risk of bias using the PROBAST tool. A meta-analysis of discrimination and calibration performance was conducted when appropriate. Twenty-three studies reported 52 externally validated prediction models for PE (one preterm, 20 any-onset, 17 early-onset and 14 late-onset PE models). No model had the same set of predictors. Fifteen any-onset PE models were validated externally once, two were validated twice and three were validated three times, while the Fetal Medicine Foundation (FMF) competing-risks model for preterm PE prediction was validated widely in 16 different settings. The most common predictors were maternal characteristics (prepregnancy body mass index, prior PE, family history of PE, chronic medical conditions and ethnicity) and biomarkers (uterine artery pulsatility index and pregnancy-associated plasma protein-A). The FMF model for preterm PE (triple test plus maternal factors) had the best performance, with a pooled area under the receiver-operating-characteristics curve (AUC) of 0.90 (95% prediction interval (PI), 0.76-0.96), and was well calibrated. The other models generally had poor-to-good discrimination performance (median AUC, 0.66 (range, 0.53-0.77)) and were overfitted on external validation. Apart from the FMF model, only two models that were validated multiple times for any-onset PE prediction, which were based on maternal characteristics only, produced reasonable pooled AUCs of 0.71 (95% PI, 0.66-0.76) and 0.73 (95% PI, 0.55-0.86). Existing externally validated prediction models for any-, early- and late-onset PE have limited discrimination and calibration performance, and include inconsistent input variables. The triple-test FMF model had outstanding discrimination performance in predicting preterm PE in numerous settings, but the inclusion of specialized biomarkers may limit feasibility and implementation outside of high-resource settings. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Sex-based differences in growth-related IGF1 signaling in response to PAPP-A2 deficiency: comparative effects of rhGH, rhIGF1 and rhPAPP-A2 treatments

BackgroundChildren with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations resulting in low levels of bioactive insulin-like growth factor-1 (IGF1) and progressive postnatal growth retardation have improved growth velocity and height following recombinant human (rh)IGF1 treatment. The present study aimed to evaluate whether Pappa2 deficiency and pharmacological manipulation of GH/IGF1 system are associated with sex-specific differences in growth-related signaling pathways.MethodsPlasma, hypothalamus, pituitary gland and liver of Pappa2ko/ko mice of both sexes, showing reduced skeletal growth, and liver of these mice treated with rhGH, rhIGF1 and rhPAPP-A2 from postnatal day (PND) 5 to PND35 were analyzed.ResultsReduced body and femur length of Pappa2ko/ko mice was associated with increases in: (1) components of IGF1 ternary complexes (IGF1, IGFBP5/Igfbp5, Igfbp3, Igfals) in plasma, hypothalamus and/or liver; and (2) key signaling regulators (phosphorylated PI3K, AKT, mTOR, GSK3β, ERK1/2 and AMPKα) in hypothalamus, pituitary gland and/or liver, with Pappa2ko/ko females having a more prominent effect. Compared to rhGH and rhIGF1, rhPAPP-A2 specifically induced: (1) increased body and femur length, and reduced plasma total IGF1 and IGFBP5 concentrations in Pappa2ko/ko females; and (2) increased Igf1 and Igf1r levels and decreased Ghr, Igfbp3 and Igfals levels in the liver of Pappa2ko/ko females. These changes were accompanied by lower phospho-STAT5, phospho-AKT and phospho-ERK2 levels and higher phospho-AMPK levels in the liver of Pappa2ko/ko females.ConclusionsSex-specific differences in IGF1 system and signaling pathways are associated with Pappa2 deficiency, pointing to rhPAPP-A2 as a promising drug to alleviate postnatal growth retardation underlying low IGF1 bioavailability in a female-specific manner.

Navigating Uncertain Waters: First-Trimester Screening's Role in Identifying Neonatal Complications.

Background: Contemporary diagnostic methods aimed at assessing neonatal outcomes predominantly rely on the medical history of pregnant women. Ideally, universal biomarkers indicating an increased risk of delivering infants in poor clinical condition, with a heightened likelihood of requiring hospitalization in a Neonatal Intensive Care Unit (NICU), would be beneficial for appropriately stratifying pregnant women into a high-risk category. Our study evaluated whether biochemical and ultrasonographical markers universally used in first-trimester screenings for non-heritable chromosomal aberrations could serve this purpose. Methods: This study encompassed 1164 patients who underwent first-trimester screening, including patient history, ultrasound examinations, and biochemical tests for pregnancy-associated plasma protein-A (PAPP-A) and the free beta-HCG subunit (fbHCG), from January 2019 to December 2021. The research concentrated on the correlation between these prenatal test results and neonatal outcomes, particularly Apgar scores, umbilical blood pH levels, and the necessity for NICU admission. Results: In our cohort, neonates scoring lower than 8 on the Apgar scale at birth exhibited lower concentrations of PAPP-A in the first trimester, both in raw and normalized values (PAPP-A MoM 0.93 vs. 1.027, p = 0.032). We also observed a higher pulsatility index in the venous duct in the first trimester in full-term neonates born with <8 points on the Apgar scale. Additionally, newborns born with an umbilical blood pH < 7.2 had lower normalized first-trimester PAPP-A concentrations (0.69 vs. 1.01 MoM, p = 0.04). We also noted that neonates requiring NICU hospitalization post-delivery had lower first-trimester bHCG concentrations (0.93 MoM vs. 1.11 MoM, p = 0.03). However, none of the correlations in our study translated into a robust prognostic ability for predicting dichotomous outcomes. All areas under the curve achieved a value < 0.7. Conclusions: Low concentrations of PAPP-A and free bHCG subunit in the first trimester may be associated with poorer clinical and biochemical conditions in neonates post-delivery. However, the relationship is weak and has limited predictive capability. Further research evaluating these relationships is necessary for the appropriate stratification of pregnant women into high-risk categories for neonatological complications.

Pregnancy Associated Plasma Protein-A (PAPP-A) as a Marker to Distinguish Normotensive with Early 2nd Trimester and Late 3rd Trimester Onset of Preeclampsia

Introduction: Preeclampsia is a hypertensive condition that occurs after 20 weeks of gestation accompanied by target organ damage. Complications of preeclampsia can cause intrauterine fetal growth retardation, and placental hypoperfusion, even in the most serious situations, namely termination of pregnancy and death of the fetus and/or mother. Pregnancy-associated plasma protein-A (PAPP-A) is a high molecular weight glycoprotein that is produced in the placenta and secreted into the maternal bloodstream. However, based on several studies that have been conducted, there is uncertainty in the results of assessing PAPP-A levels obtained in pregnant women in the second and third trimesters. Aim: Proving differences in PAPP-A levels in the second and third trimesters in the incidence of early-onset preeclampsia and normotensive pregnancy. Methods: An analytic observational study with a cross-sectional approach was carried out in the delivery room of RSUP Dr. Kariadi Semarang, Halmahera Health Center, Ngesrep Health Center, Bulu Health Center, and private midwife practice in Semarang City. The subjects of the study were six 2nd-trimester preeclampsia patients, fourteen 3rd-trimester preeclampsia patients, and twenty normotensive pregnancy patients who met the inclusion and exclusion criteria. Data were analyzed using Mann Whitney with a significance of p&lt;0.05 Results: There was a significant difference in PAPP-A levels (p&lt;0.001) between the preeclampsia and normotensive pregnancy groups, whereas PAPP-A levels were higher in the preeclampsia group. There were significant differences in PAPP-A levels (p&lt;0.001) between the 2nd-trimester preeclampsia, 3rd-trimester preeclampsia, and normotensive pregnancies, where the highest PAPP-A levels were found in the 2nd-trimester preeclampsia group. Conclusion: There was a significant difference in PAPP-A levels between the second and third trimesters of early-onset preeclampsia compared to normotensive pregnancies, where PAPP-A levels were higher in the second and third trimesters of early-onset preeclampsia. Elevated PAPP-A levels in the second and third trimesters are associated with an increased risk of early-onset preeclampsia.

Abstract P357: Health Behaviors in Early Pregnancy Are Associated With Mid-Pregnancy Biomarkers of Placental Health and Function

Introduction: Placental blood biomarkers are dysregulated in adverse pregnancy outcomes (APO). While health behaviors are associated with APO risk, it is not well-characterized whether health behaviors impact placental blood biomarkers. Thus, we examined the associations between health behaviors and placental biomarkers of angiogenesis in mid-pregnancy. Hypothesis: Pregnant people engaging in healthier behaviors in the 1 st trimester would demonstrate more favorable 2 nd trimester concentrations of placental biomarkers. Methods: Data from 2,078 participants with available analytes from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be were included, representing an enriched sample of APO (preterm birth, preeclampsia/eclampsia, small-for-gestational age, or stillbirth; n=1,284) and 12% of those without these diagnoses (n=794). Health behaviors of physical activity, sleep, smoking, and diet assessed in the 1 st trimester were scored from 0-100 according to the Life’s Essential 8 algorithm; a higher score is more favorable. Biomarkers assayed included total endoglin, pregnancy-associated plasma protein A (PAPP-A), vascular endothelial growth factor, placental growth factor, and soluble FMS-like tyrosine 1. The association between health behaviors and each biomarker was examined using linear (continuous) or logistic (odds of concentration below multiple of the median [MoM] cut point) regression adjusted for demographics, BMI, resilience (Connor-Davidson Scale), and perceived discrimination (Krieger Racism Scale) using a backwards stepwise approach; analyses were repeated stratified by APO status. Bonferroni-corrected significance was p&lt;0.001. Results: The overall APO rate in this enriched sample was 62%; this was significantly lower in those with ≥150 min/week compared with no physical activity (58% vs 66%, p=0.04). Lower (worse) smoking score was associated with lower (adverse) PAPP-A concentration in those who developed APO (p&lt;0.001). Higher physical activity score (healthier) was associated with lower PAPP-A concentration (adverse) regardless of APO occurrence; for every 10-point higher physical activity score, odds of PAPP-A &lt; 0.3 MoM increased 10% (OR 1.10; 95% CI 1.05, 1.16). No associations were observed between the other health behaviors and biomarkers. Conclusions: Higher levels of physical activity were associated with lower APO occurrence. In contrast, PAPP-A concentrations were lower in those with higher physical activity regardless of pregnancy outcome. Lower 2 nd trimester PAPP-A was observed in those with higher smoking exposure who developed APO. Our findings support prior work demonstrating lower risk of APO with more physical activity in pregnancy, but also indicate that PAPP-A concentrations may be sensitive to physical activity and smoking. Further work to elucidate the mechanisms of these associations is warranted.

Unveiling the Role of Pregnancy-Associated Plasma Protein A (PAPP-A) in Pregnancy-Associated Breast Cancer: A Comprehensive Review.

Pregnancy-associated breast cancer (PABC) presents unique challenges due to its occurrence during or shortly after pregnancy. Pregnancy-associated plasma protein A (PAPP-A) has emerged as a potential biomarker and regulator in PABC. This comprehensive review examines the role of PAPP-A in PABC, highlighting its involvement in tissue remodeling and cancer progression. Molecular mechanisms linking PAPP-A to breast cancer, including signaling pathways and interactions with other molecules, are explored. The review also discusses the diagnostic and therapeutic implications of PAPP-A dysregulation in PABC, emphasizing the need for further research to elucidate underlying mechanisms and develop targeted therapies. Collaborative efforts among researchers, clinicians, and industry stakeholders are essential for translating findings into clinically relevant interventions to improve outcomes for PABC patients.

Primary osteoarthritis chondrocyte map of chromatin conformation reveals novel candidate effector genes

ObjectivesOsteoarthritis is a complex disease with a huge public health burden. Genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated sequence variants, but the effector genes underpinning these signals remain...

Cell‑free fetal DNA at11‑13weeks of gestation is not altered in complicated pregnancies.

Non-invasive maternal cell-free fetal DNA (cffDNA) is a promising biomarker for screening common genetic syndromes. Alterations in the expression levels of cffDNA in the maternal circulation have been demonstrated in abnormal pregnancies. However, the results are conflicting. The present study aimed to investigate whether cffDNA levels are associated with pregnancy complications. The study group comprised pregnant women who presented with pregnancy complications, such as preterm birth, gestational hypertension, intrauterine growth retardation, gestational diabetes, polyhydramnios, oligohydramnios, vaginal bleeding and placental abruption. The control group comprised women who had a normal pregnancy course. Blood samples were obtained from 500 pregnant women between 11-13 weeks of gestation. cffDNA was amplified, sequenced and analyzed using the next-generation aneuploidy test of a Panorama-Natera kit. Nuchal translucency (NT) thickness as well as pregnancy associated plasma protein-A (PAPP-A) and β-human chorionic gonadotropin (β-hCG) levels were also assessed. Statistical analysis was performed in 494 out of the 500 samples collected with SPSS v.26 using non-parametric methods. The parameters were normalized by the multiples of median (MoM) method. The expression levels of PAPP-A, β-hCG, and the NT mean MoM values were significantly different between the study and control groups (P=0.005, P<0.001 and P=0.007, respectively). However, the expression levels of cffDNA and the mean MoM values were not significantly different between these two groups (P=0.687). The findings of the present study support the conclusion that cffDNA expression is not altered in a series of pregnancy complications. The prognostic value of cffDNA in predicting adverse pregnancy outcomes requires further investigation.

The predictive value of first trimester maternal serum pregnancy-associated plasma protein-a (papp-a) level in predicting gestational diabetes mellitus

Aims: The aim of this study is to evaluate the predictive value of first trimester biochemical markers in the subsequent development of gestational diabetes mellitus. Methods: Data were retrospectively collected from the file records of 361 pregnant patients, who were admitted to the 1st Obstetrics and Gynecology Clinic at Sisli Etfal Education and Training Hospital for first trimester prenatal screening test between 11-14 weeks of their gestation and who later had undergone 50 gram glucose challenge test at 24-28 weeks of their gestation, between November 2007 and February 2011. Age, patient weight, Crown rump length (CRL), gestational week, Pregnancy-Associated Plasma Protein-A (PAPP-A) concentration, PAPP-A multiple of median (MoM) value, Beta-human koryonik gonadotropin (B-HCG) concentration, B-HCG MoM value, 50 and 100 g oral glucose challange test result were recorded from the files. Gestational diabetes was diagnosed according to National Diabates Data Grup cutt-off values and criteria. The association between first trimester biochemical markers and subsequent development of gestational diabetes was evaluated. Results: In this study low PAPP-A and/or HCG MoM values and increased Nuchal translucency (NT) MoM values were found to be statistically significant for subsequent development of gestational diabetes. Conclusion: GDM is an important health problem that carries many risks of complications for both mother and fetus. Pregnant women with GDM may have high blood sugar levels before diagnosis at 24 weeks of gestation, so fetal growth may be negatively affected by maternal hyperglycemia. Use of first trimester screening maternal serum biomarkers may lead to early diagnosis of GDM and interventions to improve maternal and fetal outcomes.

The role of second trimester uterine artery Doppler in predicting obstetric and neonatal outcomes in abnormal first trimester maternal serum pregnancy-associated plasma protein-A and free β-human chorionic gonadotropin values.

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 β-human chorionic gonadotropin (β-Hcg) levels predicts adverse obstetric and neonatal outcomes. This study of 289 pregnant women included 196 with normal PAPP-A and free β-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. 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. Adding UtA Doppler in the second trimester to pregnancies with abnormal PAPP-A and/or free β-Hcg values in the first trimester may be a useful screening method for adverse outcomes.

The IGF-PAPP-A-Stanniocalcin Axis in Serum and Ascites Associates with Prognosis in Patients with Ovarian Cancer.

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.

Decreased Expression of Placental Proteins in Recurrent Pregnancy Loss: Functional Relevance and Diagnostic Value.

Miscarriages affect 50-70% of all conceptions and 15-20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL, ≥2 miscarriages) affects 1-5% of recognized pregnancies. Nevertheless, our knowledge about the etiologies and pathophysiology of RPL is incomplete, and thus, reliable diagnostic/preventive tools are not yet available. Here, we aimed to define the diagnostic value of three placental proteins for RPL: human chorionic gonadotropin free beta-subunit (free-β-hCG), pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF). Blood samples were collected from women with RPL (n = 14) and controls undergoing elective termination of pregnancy (n = 30) at the time of surgery. Maternal serum protein concentrations were measured by BRAHMS KRYPTOR Analyzer. Daily multiple of median (dMoM) values were calculated for gestational age-specific normalization. To obtain classifiers, logistic regression analysis was performed, and ROC curves were calculated. There were differences in changes of maternal serum protein concentrations with advancing healthy gestation. Between 6 and 13 weeks, women with RPL had lower concentrations and dMoMs of free β-hCG, PAPP-A, and PlGF than controls. PAPP-A dMoM had the best discriminative properties (AUC = 0.880). Between 9 and 13 weeks, discriminative properties of all protein dMoMs were excellent (free β-hCG: AUC = 0.975; PAPP-A: AUC = 0.998; PlGF: AUC = 0.924). In conclusion, free-β-hCG and PAPP-A are valuable biomarkers for RPL, especially between 9 and 13 weeks. Their decreased concentrations indicate the deterioration of placental functions, while lower PlGF levels indicate problems with placental angiogenesis after 9 weeks.

PAPP-A Levels and IGF-1 Levels in Early-Onset Preeclampsia and Late-Onset Preeclampsia

Introduction: The pathophysiology of preeclampsy is not yet fully understood, but failure of tropoblastinvasion and placentation, which is influenced by factors such as pregnancy-associated plasma proteinA (PAPP-A) and insulin-like growth factor 1 (IGF-1), is thought to play a role.Aims: This study aimed to explore the difference in PAPP-A and IGF-1 levels between Early OnsetPreeclampsia (PEAD) and Late Onset Preeclampsia (PEAL) assuming that the role of PAPP-A andIGF-1 is more significant in the pathogenesis of PEAD than PEAL.Methods: This is an analytical observational study with a cross-partition comparative study design.Clinical data were obtained at Dr. M. Djamil Padang Hospital, while PAPP-A and IGF-1 levels weremeasured at the Biomedical Laboratory of the Faculty of Medicine, Andalas University. Samples aretested according to reagent procedures and analyzed by experts.Results: Average PAPP-A levels were 2.45+0.35 pg/mL in the early onset preeclampsy group and2.85+0.50 pg/mL in the late onset preeclampsy group. These two levels differed statisticallysignificantly (p=0.006). That means that low levels of PAPP-A are associated with and play a role inthe pathogenesis of early onset preeclampsy. Average IGF-1 levels were 4.66+0.91 pg/mL in the earlyonset preeclampsy group and 5.39+0.74 pg/mL in the late-onset preeclampsy group. These two levelsdiffered statistically significantly (p=0.010). That means that low levels of IGF-1 are associated withand play a role in the pathogenesis of early onset preeclampsy. PAPP-A levels were significantlypositively correlated with IGF-1 levels (p=0.000).Conclusion: PAPP-A levels are lower in PEAD than PEAL, as are IGF-1 levels. These findings confirmthe role of PAPP-A and IGF-1 in preeclampsia. Both of these hormones have potential as indicatorsand markers for the prediction and management of preeclampsy in early and late onset periods.

Pregnancy associated plasma protein-A2 (PAPP-A2) and stanniocalcin-2 (STC2) but not PAPP-A are associated with circulating total IGF-1 in a human adult population

The pappalysins pregnancy associated plasma protein-A (PAPP-A) and -A2 (PAPP-A2) act as proteinases of insulin-like growth factor-1 (IGF-1) binding proteins, while stanniocalcin-2 (STC2) was identified as a pappalysin inhibitor. While there is some evidence from studies in children and adolescents, it is unclear whether these molecules are related to concentrations of IGF-1 and its binding proteins in adults. We investigated cross-sectionally the association of circulating PAPP-A, PAPP-A2 and STC2 with IGF-1 and its binding proteins (IGFBPs) in 394 adult pretest participants (20–69 years) of the German National Cohort Berlin North study center. Plasma PAPP-A, PAPP-A2, total and free IGF-1, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-5 and STC2 were measured by ELISAs. The associations of PAPP-A, PAPP-A2 and STC2 with IGF-1 or IGFBPs were investigated using multivariable linear regression analyses adjusting for age, sex, body mass index and pretest phase. We observed significant inverse associations of PAPP-A2 (difference in concentrations per 0.5 ng/mL higher PAPP-A2 levels) with total IGF-1 (− 4.3 ng/mL; 95% CI − 7.0; − 1.6), the IGF-1:IGFBP-3 molar ratio (− 0.34%; 95%-CI − 0.59; − 0.09), but not free IGF-1 and a positive association with IGFBP-2 (11.9 ng/mL; 95% CI 5.0; 18.8). PAPP-A was not related to total or free IGF-1, but positively associated with IGFBP-5. STC2 was inversely related to total IGF-1, IGFBP-2 and IGFBP-3 and positively to IGFBP-1. This first investigation of these associations in a general adult population supports the hypothesis that PAPP-A2 as well as STC2 play a role for IGF-1 and its binding proteins, especially for total IGF-1. The role of PAPP-A2 and STC2 for health and disease in adults warrants further investigation.

Can we improve the outcome of pregnancies with low serum PAPP-A in the first trimester?

Low birth weight is associated with various complications, and recent findings rely on the fact that micronized progesterone supplementation leads to improved birth weight, which is crucial for addressing concerns related to fetal growth. Objective This study aimed to assess the impact of micronized progesterone (VMP4) supplementation on pregnancies with low serum pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) values during first-trimester screening. Methods Out of 8933 patients evaluated, 116 pregnant women with low PAPP-A concentrations in their blood and no fetal chromosomal anomalies (CAs) were included. Three groups were formed: group 1 received VMP4 from 11 to 16 weeks (29 women, 25%), group 2 received VMP4 from 11 to 36 weeks (25 women, 21.5%), and group 3 (62 women, 53.5%) served as controls without receiving progesterone. Results Results indicated that group 3 had higher rates of complications, including miscarriages (16.37%), preterm delivery (17.8%), and fetal developmental abnormalities (19.4%). Birthweight variations were elevated in pregnancies without progesterone, contrasting with lower variations in VMP4 groups. Group 2, receiving VMP4 until 36 weeks, reported the lowest incidence of abortion and preterm birth (PB), along with the highest mean birth weight. Conclusions The conclusion suggests that 200 mg per day of VMP4 up to 36 weeks of supplementation led to fewer placental-related complications in women with very low PAPP-A at first-trimester screening (0.399 MoM). By reporting lower rates of miscarriages, PBs, and fetal developmental abnormalities in the micronized progesterone-treated groups, the study suggests a potential reduction in complications.

A statistical investigation of parameters associated with low cell-free fetal DNA fraction in maternal plasma for noninvasive prenatal testing

Background Noninvasive prenatal testing (NIPT) is the most common method for prenatal aneuploidy screening. Low fetal fraction (LFF) is the primary reason for NIPT failure. Consequently, factors associated with LFF should be elucidated for optimal clinical implementation of NIPT. Methods In this study, NIPT data from January 2019 to December 2022 from the laboratory records and obstetrical and neonatal data from the electronic medical records were collected and analyzed. Subjects with FF >3.50% were assigned to the control group, subjects with FF <3.50% once were assigned to the LFF group, and subjects with FF <3.50% twice were assigned to the repetitive low fetal fraction (RLFF) group. Factors, including body mass index (BMI), gestational age, maternal age, twin pregnancy, and in vitro fertilization (IVF) known to be associated with LFF were assessed by Kruskal–Wallis H test and logistic regression. Clinical data on first trimester pregnancy-associated plasma protein-A (PAPP-A), beta-human chorionic gonadotropin (β-hCG), gestational age at delivery, birth weight at delivery, and maternal diseases were obtained from the hospital’s prenatal and neonatal screening systems (twin pregnancy was not included in the data on gestational age at delivery and the control group did not include data on maternal diseases.), and were analyzed using Kruskal–Wallis H test and Chi-square test. Results Among the total of 63,883 subjects, 63,605 subjects were assigned to the control group, 197 subjects were assigned to the LFF group, and 81 subjects were assigned to the RLFF group. The median of BMI in the three groups was 22.43 kg/m2 (control), 25.71 kg/m2 (LFF), and 24.54 kg/m2 (RLFF). The median gestational age in the three groups was 130 days (control), 126 days (LFF), and 122/133 days (RLFF). The median maternal age in the three groups was 29 (control), 29 (LFF), and 33-years-old (RLFF). The proportion of twin pregnancies in the three groups was 3.3% (control), 10.7% (LFF), and 11.7% (RLFF). The proportion of IVF in the three groups was 4.7% (control), 11.7% (LFF), and 21.3% (RLFF). The factors significantly associated with LFF included BMI [2.18, (1.94, 2.45), p < 0.0001], gestational age [0.76, (0.67, 0.87), p < 0.0001], twin pregnancy [1.62, (1.02, 2.52), p = 0.0353], and IVF [2.68, (1.82, 3.86), p < 0.0001]. The factors associated with RLFF included maternal age [1.54, (1.17, 2.05), p = 0.0023] and IVF [2.55, (1.19, 5.54), p = 0.016]. Multiples of the median (MOM) value of β-hCG and pregnant persons’ gestational age at delivery were significantly decreased in the LFF and RLFF groups compared to the control group. Conclusion According to our findings based on the OR value, factors associated strongly with LFF include a high BMI and the use of IVF. Factors associated less strongly with LFF include early gestational age and twin pregnancy, while advanced maternal age and IVF were independent risk factors for a second LFF result.