Pregnancy-associated Plasma protein-A Levels Research Articles

Association of First-Trimester Low PAPP-A Levels (<0.2 MoM) with Maternal and Fetal Outcomes

Background and Aim: First-trimester screening is routinely performed globally to detect chromosomal abnormalities using non-invasive methods such as nuchal translucency (NT) measurements, pregnancy-associated plasma protein A (PAPP-A), and β-human chorionic gonadotropin (β-hCG). Recent studies have highlighted that low PAPP-A levels may be associated with adverse pregnancy outcomes, including pre-eclampsia, intrauterine growth restriction (IUGR), and pre-term delivery. Generally, low PAPP-A is defined as below 0.4 multiples of the median (MoM) or under the 5th percentile. However, extremely low PAPP-A, defined as levels below 0.2 MoM or under the 1st percentile, significantly increases the risk of adverse outcomes. This category has received less attention in research. Our study aims to investigate the correlation between PAPP-A levels below 0.2 MoM and adverse pregnancy outcomes. Materials and Methods: A retrospective cross-sectional study was conducted on 10,256 pregnant women who underwent first-trimester screening at Imam Khomeini Hospital in Ahvaz between January 2010 and April 2024. PAPP-A and β-hCG levels were measured, and factors such as maternal age, weight, parity, and abortion history were assessed. Data were obtained using the Fetal Medicine Foundation (FMF) software and medical records. Statistical analysis was performed using SPSS version 26. Results: Out of 10,256 pregnancies, 6,040 (6.4%) had PAPP-A levels below the 5th percentile, while 45 women had PAPP-A levels below 0.2 MoM. The average age of these women was 30.4 ± 4.812 years. Among those with PAPP-A < 0.2 MoM, 2.2% had trisomy 21, 6.7% had IUGR, 26.7% experienced gestational hypertension, and 15.6% developed pre-eclampsia. Trisomies 13 and 18 were not observed in the study population. Conclusions: Pregnant women with PAPP-A levels below 0.2 MoM showed increased incidences of trisomy 21, pre-eclampsia, gestational hypertension, and IUGR. Although low PAPP-A appears to contribute to both maternal and fetal complications, it cannot be used independently to predict adverse pregnancy outcomes. Further large-scale studies are required to better understand the implications of extremely low PAPP-A on pregnancy outcomes.

Can First Trimester Plasma Protein A Level Predict Gestational Diabetes Mellitus

Aim: Gestational diabetes mellitus (GDM), a condition with multifactorial etiology and adverse perinatal consequences, affects approximately 15% of pregnancies globally, with higher prevalence in certain populations, such as Türkiye. The role of pregnancy-associated plasma protein-A (PAPP-A) on GDM risk remains unclear. This prospective study aimed to assess whether first-trimester maternal PAPP-A levels are predictive of GDM. Material and Method: This study involved 573 singleton pregnancies in women aged 18 to 45 years, conducted at a tertiary maternity hospital. PAPP-A and free β-hCG were assessed, and GDM screening was carried out using a 75 g oral glucose tolerance test. Comprehensive statistical analyses were applied to evaluate the findings. Results: Of the participants, 28.09% were diagnosed with GDM. GDM group exhibited significantly lower PAPP-A MoM levels compared to controls (p=0.042). ROC analysis revealed limited predictive utility, with a PAPP-A threshold of 0.99 demonstrating 52.3% sensitivity and 51.7% specificity. Logistic regression identified low PAPP-A levels, advanced maternal age, and higher body mass index (BMI) as independent GDM risk factors. Conclusion: While the findings underscore a potential association between PAPP-A levels and GDM, the predictive capacity of PAPP-A alone is modest. Future research should explore integrated predictive models incorporating PAPP-A and other biomarkers for improved early GDM screening.

Comparison of Pregnancy Associated Plasma Protein A (PAPP-A) Levels in IVF-Induced Pregnancies and Physiological Pregnancies: A Case- Control Study

Introduction: Infertility is an important issue in reproductive health. In the field of reproductive medicine, In vitro Fertilization (IVF) stands out as a central approach to helping infertile couples. Pregnancy-associated Plasma Protein-A (PAPP-A) levels increase progressively throughout pregnancy until delivery. Therefore, the present study aimed to conduct a detailed examination and comparison of PAPP-A levels between women who have undergone IVF treatment due to infertility and those with natural pregnancies, all of whom have been referred to the Gynecology and Infertility Clinic of Besat Hospital in 2020. Methods: The present case-control study was conducted on women with IVF-induced pregnancies and those with physiological pregnancies who have been referred to the Gynecology and Infertility Clinic of Besat Hospital in 2020. Pregnant women who did not have a complete medical record and had a history of other diseases were excluded from the study. In this study, venous blood was collected from the pregnant women, and the serum level of the PAPP-A marker was checked. This information was recorded in their medical records and then subjected to statistical analysis. Results: For this purpose, 28 pregnant women by IVF and 34 physiological pregnant women were included in the study. There was a significant relationship between the type of pregnancy (IVF and physiological pregnancy) and the serum level of PAPP-A dispersion based on the KID test, and 70.59% of pregnancies were physiological at the level of 0.5-0.9. Based on the results of the ROC curve test, the cut-off point of the serum level of PAPP-A in pregnancy caused by IVF and physiological pregnancy was 0.63. This means that in 90.91% of people whose serum level of PAPP-A was less than 0.63, the method of pregnancy was IVF. Conclusion: The results of the present study have revealed the serum level of PAPP-A to be different depending on the type of pregnancy, and it has been found to be significantly higher in pregnant women with physiological pregnancy than in pregnancy due to IVF.

Early Prediction of Gestational Diabetes Mellitus and Insulin Therapy Requirement Using First-Trimester PAPP-A and Free β-hCG MoMs Levels: A Retrospective Case-Control Study.

Objectives: To evaluate the association between gestational diabetes mellitus (GDM), including insulin-dependent GDM with pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) and free beta human chorionic gonadotropin (free β-hCG) MoM levels, and to assess their potential as predictive risk factors. Methods: This retrospective study included 2588 women with singleton pregnancies who underwent combined first-trimester screening, along with the 50 g glucose challenge test (GCT) and a 100 g oral glucose tolerance test (OGTT) between 24 and 28 weeks of gestation. Patients were initially divided into four groups based on the glucose screening results, and PAPP-A and free β-hCG MoMs were compared between these groups. GDM cases managed by diet were then compared with those requiring insulin therapy. Results: Of the study population, 132 women (5.10%) were diagnosed with GDM, 112 (84.8%) managed their glycemia with dietary changes, while 20 (15.2%) required insulin therapy. PAPP-A levels were significantly lower in the GDM group compared to the control group (p < 0.001). In addition, the insulin-dependent GDM group had significantly lower PAPP-A levels than the diet-controlled group (p < 0.001). No significant differences were observed in the free β-hCG MoM levels between the groups (p = 0.292). Receiver operating characteristic analysis identified 0.815 as the optimal PAPP-A cut-off value for predicting GDM, with a sensitivity of 61.4%, specificity of 61.6%, and an area under the curve (AUC) of 0.649 (95% CI: 0.595-0.703). For insulin-dependent GDM, the same threshold yielded an AUC of 0.621 (95% CI: 0.563-0.679), with a sensitivity of 58.6% and a specificity of 59.7%. Conclusions: Low serum PAPP-A MoM levels are significantly associated with the development of GDM, including insulin-dependent cases. Although PAPP-A alone may not be a definitive predictive marker for GDM, low levels could support the recommendation for early screening as part of a broader diagnostic approach.

Low PAPPA and Its Association with Adverse Pregnancy Outcomes in Twin Pregnancies: A Systematic Review of the Literature and Meta-Analysis.

Background: It is well established in the literature that pregnancy-associated plasma protein-A (PAPP-A) is linked to several adverse pregnancy outcomes, including pre-eclampsia (PE), fetal growth restriction (FGR), and preterm birth (PTB) in singleton pregnancies. However, data regarding such an association in twin pregnancies are lacking. The primary goal of this systematic review and meta-analysis was to assess the potential value of low PAPP-A levels in the prediction of the subsequent development of hypertensive disorders of pregnancy (HDPs), PTB, and small for gestational age (SGA)/FGR fetuses in twin pregnancies and investigate its association with the development of gestational diabetes, intrauterine death (IUD) of at least one twin, and birth weight discordance (BWD) among the fetuses. Methods: Medline, Scopus, CENTRAL, Clinicaltrials.gov, and Google Scholar databases were systematically searched from inception until 31 July 2024. All observational studies reporting low PAPP-A levels after the performance of the first-trimester combined test as part of the screening for chromosomal abnormalities with reported adverse pregnancy outcomes were included. Results: The current systematic review encompassed a total of 11 studies (among which 6 were included in the current meta-analysis) that enrolled a total of 3741 patients. Low PAPP-A levels were not associated with HDPs (OR 1.25, 95% CI 0.78, 2.02, I-square test: 13%). Low PAPP-A levels were positively associated with both the development of preterm birth prior to 32 (OR 2.85, 95% CI 1.70, 4.77, I-square test: 0%) and 34 weeks of gestational age (OR 2.09, 95% CI 1.34, 3.28, I-square test: 0%). Furthermore, low PAPP-A levels were positively associated with SGA/FGR (OR 1.58, 95% CI 1.04, 2.41, I-square test: 0%). Prediction intervals indicated that the sample size that was used did not suffice to support these findings in future studies. Conclusions: Our study indicated that low PAPP-A levels are correlated with an increased incidence of adverse perinatal outcomes in twin pregnancies. Identifying women at elevated risk for such adversities in twin pregnancies may facilitate appropriate management and potential interventions, but additional studies are required to identify the underlying mechanism linking PAPP-A with those obstetrical complications.

Combined detection of serum adiponectin and pregnancy-associated plasma protein A for early prediction of gestational diabetes mellitus.

Early diagnosis of gestational diabetes mellitus (GDM) reduces the risk of adverse perinatal and maternal outcomes. At present, the value of serum adiponectin (ADP) and pregnancy-associated plasma protein A (PAPP-A) in clinical practice for the diagnosis of GDM in early pregnancy is unclear. To investigate the predictive value of serum ADP and PAPP-A in GDM. The electronic medical record data of all pregnant women from Zhongshan People's Hospital from 2018 to 2021 were retrospectively collected and divided into GDM group and control group according to whether GDM occurred. ADP and PAPP-A levels of the 2 groups were detected in early pregnancy, and the related factors of GDM were analyzed by binary logistic regression analysis. Receiver operating characteristic (ROC) curves of ADP and PAPP-A in predicting GDM in the early pregnancy were plotted and their clinical predictive value was analyzed. The significance level for all statistical tests is 0.05. Compared with the non-GDM group, the ADP of the GDM group was significantly lower than that of the non-GDM group [(8.19 ± 2.24) vs. (10.04 ± 2.73)]mg/L, the difference between groups was statistically significant (P < .05), and the multiple of median (MoM) of PAPP-A was significantly lower than that of the non-GDM group (1.13 ± 0.52) versus (1.45 ± 0.61) (P < .05). Binary logistic regression analysis showed that elevated serum ADP and PAPP-A levels were negatively correlated with the subsequent development of GDM [odds ratio (OR) 95% confidence interval (95% CI)] was 0.626 (0.536, 0.816), 0.934 (0.908, 0.961), respectively, P < .05.ROC curve analysis showed that the sensitivity and specificity of ADP and PAPP-A in predicting gestational diabetes were79.1% and 58.6%, respectively, 92.7% and 73.1%, and respectively. The area under curve (AUC) is 0.755 for ADP and 0.770 for PAPP-A. The AUC of the combined detection was 0.867, both of which were higher than that of single index diagnosis, and the sensitivity and specificity of the combined detection were 0.958 and 0.853, respectively. In summary, PAPP-A and ADP levels are independent related factors affecting the occurrence of GDM. The combined detection of PAPP-A and ADP should be utilized in diagnosing GDM to improve pregnancy outcomes for pregnant women.

Early prediction of gestational diabetes mellitus using first trimester maternal serum pregnancy-associated plasma protein-a: A cross-sectional study.

The oral glucose tolerance test with 75 g glucose is commonly regarded as the gold standard (GS) for the detection of gestational diabetes mellitus (GDM). However, one limitation of this test is its administration in the late second trimester of pregnancy in some countries (e.g., Iran). This study aimed to evaluate the accuracy of pregnancy-associated plasma protein-A (PAPP-A) for predicting GDM in the early first trimester of pregnancy using a novel statistical modeling technique. The study population consisted of 344 pregnant women who participated in the first trimester screening program for GDM. Maternal serum PAPP-A levels were measured between 11 and 13 gestational weeks for all participants. A Bayesian latent profile model (LPM) under the skew-t (ST) distribution was employed to estimate the diagnostic accuracy measures of PAPP-A in the absence of GS test outcomes. The mean (standard deviation) age of the participants was 28.87 ± 5.20 years. The median (interquartile range (IQR)) PAPP-A MoM was 0.91 (0.69-1.34). Utilizing the LPM under the ST distribution while adjusting for covariates, the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of PAPP-A were 92% (95% credible interval [CrI]: 0.89, 0.98), 81% (95% CrI: 0.76, 0.91), and 0.91 (95% CrI: 0.83, 0.97), respectively. Notably, the pregnant women with GDM had significantly lower PAPP-A values ( -0.52, 95% CrI [-0.61, -0.46]). Generally, our findings confirmed that PAPP-A could serve as a potential screening tool for the identification of GDM in the early stages of pregnancy.

Exploring free pregnancy associated plasma protein a (fPAPP-A) as a biomarker in early pregnancy

ObjectivesIn combined first trimester screening for Down syndrome, Pregnancy-Associated Plasma Protein A (PAPP-A) is pivotal. PAPP-A tests evaluate total PAPP-A, consisting of the biologically active free PAPP-A (fPAPP-A) and PAPP-A complexed with eosinophil major basic protein's proform (proMBP). While PAPP-A is well-researched, limited understanding persists regarding fPAPP-A's first trimester concentrations and diagnostic utility. Designand methods: PAPP-A and fPAPP-A levels were gauged in 602 serum samples at 2-week intervals (gestational weeks 4–14) from 159 women with delivery of a healthy neonate and 80 samples from 37 miscarriages. The final sample at the time of diagnosis from women who miscarried was included in analyses. ResultsDuring the first trimester, PAPP-A and fPAPP-A levels displayed significant and strong correlation (r = 0.94), with median values doubling weekly. Free PAPP-A constituted only 3.0 % of PAPP-A over gestational weeks. Low fPAPP-A linked to miscarriage (p < 0.001), maternal weight (p < 0.001), and smoking (p = 0.02). For miscarriage prediction fPAPP-A was equal to PAPP-A (area under the receiver operating characteristics curve 0.79 vs. 0.81, p = 0.44). ConclusionsInvestigating fPAPP-A presence and concentration directly in first trimester serum has not been done previously. This study report lower fPAPP-A values than anticipated from prior enzymatic studies of fPAPP-A. fPAPP-A was not superior to PAPP-A as a first trimester biomarker in this dataset.

First trimester maternal serum PAPP-A and free β-hCG levels and risk of SGA or LGA in women with and without GDM

BackgroundMaternal 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 (fβ-hCG) were associated with SGA and LGA in GDM pregnancies and controls.MethodsAltogether 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 fβ-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.ResultsIn 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 fβ-hCG MoM group, aORs for SGA was 2.3 (95% CI 1.8–3.1) in the control group. In fβ-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.ConclusionAssociation 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 fβ-hCG levels are associated with SGA only in non-GDM pregnancies.

Combined first-trimester screening and invasive diagnostics for atypical chromosomal aberrations: Danish nationwide study of prenatal profiles and detection compared with NIPT.

Our aim was to examine the prenatal profiles of pregnancies affected by an atypical chromosomal aberration, focusing on pathogenic copy-number variants (pCNVs). We also wanted to quantify the performance of combined first-trimester screening (cFTS) and a second-trimester anomaly scan in detecting these aberrations. Finally, we aimed to estimate the consequences of a policy of using non-invasive prenatal testing (NIPT) rather than invasive testing with chromosomal microarray analysis (CMA) to manage pregnancies identified as high risk by cFTS. This was a retrospective review of the Danish Fetal Medicine Database of all pregnant women who underwent cFTS and a risk assessment for trisomy 21 between 1 January 2008 and 31 December 2018. Chromosomal aberrations diagnosed prenatally, postnatally or from fetal tissue following pregnancy loss or termination of pregnancy were identified. Chromosomal aberrations were grouped into one of six categories: triploidy; common trisomy (13, 18 or 21); monosomy X; other sex-chromosome aberration (SCA); pCNV; and rare autosomal trisomy (RAT) or mosaicism. The prevalence of each aberration category was stratified by the individual cFTS markers and trisomy 21 risk estimate, and the size of each pCNV diagnosed by CMA was calculated. We retrieved data on 565 708 pregnancies, of which 3982 (0.70%) were diagnosed with a fetal chromosomal aberration. cFTS identified 87% of the common trisomies, but it also performed well in identifying triploidies (86%), monosomy X (92%), atypical SCAs (58%) and RATs or mosaicisms (70%). pCNVs comprised 27% (n = 1091) of the chromosomal aberrations diagnosed overall, and the prevalence increased during the study period, as prenatal CMA was increasingly being performed. In pregnancies with a maternal age < 30 years, nuchal translucency (NT) thickness ≤ 95th centile, pregnancy-associated plasma protein-A (PAPP-A) ≥ 1 multiple of the median, or trisomy 21 risk of ≤ 1 in 1000, the prevalence of pCNVs exceeded significantly the prevalence of trisomies 21, 18 and 13. Pregnancies affected by a pCNV had significantly increased NT and decreased levels of the maternal biomarkers PAPP-A and β-human chorionic gonadotropin compared with unaffected pregnancies. However, only 23% of these pregnancies screened positive on cFTS and 51% of pCNVs were not detected until after birth. Among high-risk pregnancies, pCNVs comprised 14% of diagnosed aberrations, and when other atypical aberrations were considered, conventional NIPT (screening for trisomies 21, 18 and 13 and monosomy X) would miss 27% of all pathogenic aberrations diagnosed from invasive testing following a high-risk cFTS result. Thus, 1 in 26 pregnancies at high risk following cFTS would be affected by a chromosomal aberration despite a normal result from conventional NIPT. In a contingent screening model using NIPT for the 'intermediate'-risk group (trisomy 21 risk of 1 in 100-299), 50% of the aberrations would be missed. In our cohort, 79% of the pCNVs diagnosed were < 5Mb and therefore not detectable using current forms of 'genome-wide' NIPT. As a by-product of screening for trisomies 21, 18 and 13, most triploidies and the majority of atypical SCAs, RATs and mosaicisms are detected before birth. However, only 23% of pCNVs are associated with a high-risk result according to cFTS and only half are diagnosed before birth. Replacing invasive testing with NIPT for high-risk pregnancies would substantially decrease the first-trimester detection of pathogenic chromosomal anomalies. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Evaluating the predictive efficacy of first trimester biochemical markers (PAPP-A, fβ-hCG) in forecasting preterm delivery incidences

In this investigation, we explored the correlation between first-trimester biochemical markers and the incidence of preterm birth (PTB), irrespective of the cause, spontaneous preterm birth (sPTB), and preterm premature rupture of membranes (pPROM) within a cohort comprising 1164 patients. It was discovered that diminished levels of Pregnancy-Associated Plasma Protein-A (PAPP-A) between 11 and 13 + 6 weeks of gestation significantly contributed to the risk of preterm deliveries both before 35 and 37 weeks, as well as to pPROM instances. Furthermore, women experiencing sPTB before the 37th week of gestation also exhibited lower concentrations of PAPP-A. Moreover, reduced first-trimester concentrations of free beta-human chorionic gonadotropin (fb-HCG) were identified as a risk factor for deliveries preceding 37 weeks, pPROM, and sPTB before 35 weeks of gestation. Despite these correlations, the area under the curve for these biochemical markers did not surpass 0.7, indicating their limited diagnostic potential. The most significant discriminatory capability was noted for PAPP-A levels, with a threshold of < 0.71 multiples of the median (MoM) predicting PTB before 37 weeks, yielding an odds ratio of 3.11 (95% Confidence Interval [CI] 1.97–4.92). For sPTB, the greatest discriminatory potential was observed for PAPP-A < 0.688, providing an OR of 2.66 (95% CI 1.51–4.66). The cut-off points corresponded to accuracies of 76.05% and 79.1%, respectively. In regression analyses, the combined predictive models exhibited low explanatory power with R2 values of 9.2% for PTB and 7.7% for sPTB below 35 weeks of gestation. In conclusion, while certain biochemical markers demonstrated associations with outcomes of preterm birth, their individual and collective predictive efficacies for foreseeing such events were found to be suboptimal.

Clinical value of prenatal screening markers in early pregnancy combined with perinatal characteristics to predict fetal growth restriction.

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 β-hCG)]. Herein, we performed a retrospective cohort study to investigate the correlation and diagnostic value of maternal markers such as PAPP-A, free β-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. 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. 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 β-hCG + NT for predicting FGR was 0.190, with a sensitivity of 0.547 and a specificity of 0.778. 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.

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.

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 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.

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.

The early predictive value of maternal serum PAPP-A concentration at 11-14 weeks of pregnancy for preeclampsia.

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. 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. 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. 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.

Decoding 22q11.2: prenatal profiling and first-trimester risk assessment in Danish nationwide cohort.

To examine the distribution of nuchal translucency thickness (NT), free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in pregnancies with a fetal 22q11.2 aberration. Furthermore, the performance of combined first-trimester screening (cFTS) and a new risk algorithm targeting 22q11.2 deletions in detecting affected pregnancies was evaluated. Finally, prenatal malformations and pregnancy outcome were assessed. This was a nationwide registry-based cohort study of all pregnancies that underwent prenatal screening with a due date between January 2008 and December 2018 in Denmark. All cases with a fetal 22q11.2 deletion or duplication (hg19 chr22:18.9mio-25.0mio) diagnosed pre- or postnatally or following pregnancy loss or termination of pregnancy were retrieved from the Danish Cytogenetic Central Register and linked with pregnancy data from the Danish Fetal Medicine Database. Fetal and maternal characteristics, including cFTS results and pregnancy outcome, of pregnancies with any 22q11.2 deletion or duplication (LCR22-A to -H) and pregnancies with a classic deletion or duplication (LCR22-A to -D) diagnosed by chromosomal microarray were compared with those of a chromosomally normal reference group. A risk algorithm was developed for assessing patient-specific risks for classic 22q11.2 deletions based on NT, PAPP-A and β-hCG. Detection rates and false-positive rates at different risk cut-offs were calculated. We included data on 143 pregnancies with a fetal 22q11.2 aberration, of which 97 were deletions (54 classic) and 46 were duplications (32 classic). NT was significantly increased in fetuses with a classic deletion (mean, 1.89 mm), those with any deletion (mean, 1.78 mm) and those with any duplication (mean, 1.86 mm) compared to the reference group (mean, 1.65 mm). β-hCG multiples of the median (MoM) was decreased in all 22q11.2 subgroups compared with the reference group (mean, 1.02) and reached significance in pregnancies with a classic deletion and those with any deletion (mean, 0.77 and 0.71, respectively). PAPP-A MoM was significantly decreased in pregnancies with a classic duplication and those with any duplication (mean, 0.57 and 0.63, respectively), and was significantly increased in pregnancies with a classic deletion and those with any deletion (mean, 1.34 and 1.16, respectively), compared to reference pregnancies (mean, 1.01). The screen-positive rate by cFTS was significantly increased in pregnancies with a classic deletion (13.7%), any deletion (12.5%), a classic duplication (46.9%) or any duplication (37.8%) compared to the reference group (4.5%). A risk algorithm targeting classic 22q11.2 deletions more than doubled the prenatal detection rate of classic 22q11.2 deletions, but with a substantial increase in the false-positive rate. Structural malformations were detected in 41%, 35%, 17% and 25% of the pregnancies with a classic deletion, any deletion, classic duplication or any duplication, respectively. Pregnancy loss occurred in 40% of pregnancies with a classic deletion and 5% of those with a classic duplication diagnosed prenatally or following pregnancy loss. The distribution of cFTS markers in pregnancies with a classic 22q11.2 duplication resembles that of the common trisomies, with decreased levels of PAPP-A. However, classic 22q11.2 deletions are associated with increased levels of PAPP-A, which likely limits early prenatal detection using the current cFTS risk algorithm. The scope for improving early detection of classic 22q11.2 deletions using targeted risk algorithms based on NT, PAPP-A and β-hCG is limited. This demonstrates the capability, but also the limitations, of cFTS markers in detecting atypical chromosomal anomalies, which is important knowledge when designing new prenatal screening programs. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Relationship between first trimester maternal PAPP-A (pregnancy associated plasma protein-A) and free β-hCG (human chorionic gonadotropin) levels with fetal birth weight

Relationship between first trimester maternal PAPP-A (pregnancy associated plasma protein-A) and free β-hCG (human chorionic gonadotropin) levels with fetal birth weight