Pregnancy-associated Plasma protein-A Research Articles

Second-trimester cardiovascular biometry in growth-restricted fetuses; a multicenter cohort study

Intrauterine growth restriction is associated with an increased risk of cardiovascular changes neonatally. However, the underlying pathways are poorly understood, and it is not clear whether the dysfunction is already present in the fetus. This study aimed to investigate fetal cardiac dimensions assessed from images at the second trimester anatomy scan from fetuses classified postnatally as small for gestational age and intrauterine growth restricted and compare them with appropriate for gestational age fetuses. This was a substudy from The Copenhagen Baby Heart Study, a prospective, multicenter cohort study including fetuses from the second trimester of pregnancy in Copenhagen from April 2016 to October 2018. The mothers were recruited at the second trimester anatomy scan that included extended cardiovascular image documentation followed by consecutively measured heart biometry by 2 investigators blinded for the pregnancy outcome. The fetuses were classified postnatally as small for gestational age and intrauterine growth restricted according to the International Society of Ultrasound in Obstetrics and Gynecology 2020 guidelines using birthweight and with a retrospective assessment of Doppler flow. The mean differences in the cardiovascular biometry were adjusted for gestational age at the time of the second trimester scan and the abdominal circumference. The z-scores were calculated, and the comparisons were Bonferroni corrected (significance level of P<.005). Receiver operating characteristic curves were computed after performing backward regression on several maternal characteristics and biomarkers. We included 8278 fetuses, with 625 (7.6%) of them being small for gestational age and 289 (3.5%) being intrauterine growth restricted. Both small for gestational age and intrauterine growth restricted fetuses had smaller heart biometry, including the diameter at the location of the aortic valve (P<.005), the ascending aorta in the 3-vessel view (P<.005), and at the location of the pulmonary valve (P<.005). The intrauterine growth restricted group had significantly smaller hearts with respect to length and width (P<.005) and smaller right and left ventricles (P<.005). After adjusting for the abdominal circumference, the differences in the aortic valve and the pulmonary valve remained significant in the intrauterine growth restricted group. Achievement of an optimal receiver operating characteristic curve included the following parameters: head circumference, abdominal circumference, femur length, gestational age, pregnancy associated plasma protein-A multiples of median, nullipara, spontaneous conception, smoking, body mass index <18.5, heart width, and pulmonary valve with an area under the curve of 0.91 (0.88-0.93) for intrauterine growth restricted cases. Intrauterine growth restricted fetuses had smaller prenatal cardiovascular biometry, even when adjusting for abdominal circumference. Our findings support that growth restriction is already associated with altered cardiac growth at an early stage of pregnancy. The heart biometry alone did perform well as a screening test, but combined with other factors, it increased the sensitivity and specificity for intrauterine growth restriction.

Circulating Insulin-Like Growth Factor 1-Related Biomarkers and Risk of Lethal Prostate Cancer.

BackgroundExperimental and epidemiologic evidence supports the role of circulating insulin-like growth factor-1 (IGF-1) levels with the risk of prostate cancer. Most circulating IGF-1 is bound to specific binding proteins, and only about 5% circulates in a free form. We explored the relation of free IGF-1 and other components of the IGF system with lethal prostate cancer.MethodsUsing prospectively collected samples, we undertook a nested case-only analysis among 434 men with lethal prostate cancer and 524 men with indolent, nonlethal prostate cancer in the Physicians’ Health Study and the Health Professionals Follow-up Study. Prediagnostic plasma samples were assayed for free IGF-1 and total IGF-1, acid labile subunit, pregnancy-associated plasma protein A (PAPP-A), and intact and total IGF binding protein 4. We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the associations between IGF-1–related biomarkers and lethal prostate cancer using unconditional logistic regression models adjusted for age, height, and body mass index.ResultsMen in the highest quartile of PAPP-A levels had 42% higher odds of lethal prostate cancer (pooled adjusted OR = 1.42, 95% CI = 1.04 to 1.92) compared with men in the lowest 3 quartiles. There were no statistically significant differences in the other plasma analytes. The positive association between PAPP-A and lethal prostate cancer was present among men with intact PTEN but not among those with tumor PTEN loss (2-sided Pinteraction = .001).ConclusionsOur study provides suggestive evidence that among men who later develop prostate cancer, higher plasma PAPP-A levels measured prior to diagnosis are associated with increased risk of lethal compared with indolent disease.

The relationship between first and second trimester biochemical parameters used to screen down syndrome and intrahepatic cholestasis of pregnancy

Objective: To assess the role of first and second-trimester screening biomarkers pregnancy-associated plasma protein-A(PAPP-A), free beta-human chorionic gonadotropin(free ß-hCG), estriol, alpha-fetoprotein and total β-hCG in the early diagnosis of intrahepatic cholestasis of pregnancy (ICP). Materials and Methods: Patients with ICP admitted to Mersin University Hospital for delivery between 2015 and 2019 and had first and second-trimester aneuploidy screening tests performed in the same facility were retrospectively assessed. Randomly 60 pregnant women without comorbid conditions during the same period were included as controls. Data regarding demographic characteristics, laboratory values including free ß-hCG and PAPP-A in first-trimester screening and total ß-hCG, estriol and alpha- fetoprotein in second-trimester screening were compared. Results: There were 46 eligible patients with ICP. In first trimester screening, it was found that PAPP-A MoM was significantly lower (0.89±0.55 vs. 1.94±0.73; p=0.035) while free ß-hCG MoM was significantly higher in ICP group when compared to controls (1.84±0.59 vs. 0.99±0.47; p=0.018). In second trimester screening, no significant difference was detected in aneuploidy markers between groups. For prediction of ICP development, first trimester free β-hCG &gt;1.44 MoM was found to have a sensitivity of 50%, a specificity of 80% and positive and negative predictive values of 33% and 88.9% respectively. Similarly first trimester PAPP-A values &lt;1.075 MoM was found to have 80% and 75% sensitivity and specificity with positive and negative predictive values of 75% and 44% respectively. Conclusion: Low PAPP-A MoM value and elevated free ß-hCG in first trimester seem to be associated with ICP development.

Performance of Fetal Medicine Foundation algorithm for first trimester preeclampsia screening in an indigenous south Asian population

BackgroundTo evaluate the performance of the Fetal Medicine Foundation (FMF) preterm preeclampsia (PE) screening algorithm in an indigenous South Asian population.MethodsThis was a prospective observational cohort study conducted in a tertiary maternal fetal unit in Delhi, India over 2 years. The study population comprised of 1863 women carrying a singleton pregnancy and of South Asian ethnicity who were screened for preterm pre-eclampsia (PE) between 11 and 14 weeks of gestation using Mean Arterial Pressure (MAP), transvaginal Mean Uterine Artery Pulsatility Index (UtAPI) and biochemical markers - Pregnancy Associated Plasma Protein-A (PAPP-A) and Placental Growth Factor.. Absolutemeasurements of noted biomarkers were converted to multiples of the expected gestational median (MoMS) which were then used to estimate risk for preterm PE < 37 weeks using Astraia software. Women with preterm PE risk of ≥1:100 was classified as as high risk. Detection rates (DR) at 10% false positive rate were calculated after adjusting for prophylactic aspirin use (either 75 or 150 mg).ResultsThe incidence of PE and preterm PE were 3.17% (59/1863) and 1.34% (25/1863) respectively. PAPP-A and PlGF MoM distribution medians were 0.86 and 0.87 MoM and significantly deviated from 1 MoM. 431 (23.1%) women had a risk of ≥1:100, 75 (17.8%) of who received aspirin. Unadjusted DR using ≥1:100 threshold was 76%.Estimated DRs for a fixed 10% FPR ranged from 52.5 to 80% depending on biomarker combination after recentering MoMs and adjusting for aspirin use.ConclusionThe FMF algorithm whilst performing satisfactorily could still be further improved to ensure that biophysical and biochemical markers are correctly adjusted for indigenous South Asian women.

Increase in Ischemia-Modified Albumin and Pregnancy-Associated Plasma Protein-A in COVID-19 Patients.

This study was undertaken due to the urgent need to explore reliable biomarkers for early SARS-CoV-2 infection. We performed a retrospective study analyzing the serum levels of the cardiovascular biomarkers IL-6, TNF-α, N-terminal pro-B natriuretic peptide, cardiac troponin T (cTnT), ischemia-modified albumin (IMA) and pregnancy-associated plasma protein-A (PAPP-A) in 84 patients with COVID-19.Patients were divided into three groups according to their RT-qPCR and IgG values: acute infection (n = 35), early infection (n = 25) or control subjects (n = 24). Levels of biomarkers were analyzed in patient serum samples using commercially available ELISA kits. Results showed a significant increase in IMA and PAPP-A levels in the early infected patients. Moreover, multivariate analysis and receiver operating characteristic (ROC) curve showed that IMA and PAPP-A had excellent discrimination value for the early stage of COVID-19. For IMA, the area under the ROC curve (AUC) had a value of 0.94 (95% confidence interval (CI): 0.881–0.999). Likewise, the serum level of PAPP-A was significantly higher in patients with early infection than in the control subjects (AUC = 0.801 (95% CI: 0.673–0.929)). The combined use of IMA and PAPP-A enhanced the sensitivity for total SARS-CoV-2-infected patients to 93%. These results suggest that the increased levels of PAPP-A and IMA shed light on underlying mechanisms of COVID-19 physiopathology and might be used as efficient biomarkers with high sensitivity and specificity for the early stage of COVID-19. Importantly, when monitoring pregnancy and cardiovascular diseases using PAPP-A or IMA levels, a SARS-CoV-2 infection should be discarded for proper interpretation of the results.

Prenatal cardiac biometry and flow assessment in fetuses with bicuspid aortic valve at 20 weeks' gestation: multicenter cohort study.

To investigate prenatal changes in cardiac biometric and flow parameters in fetuses with bicuspid aortic valve (BAV) diagnosed neonatally compared with controls with normal cardiac anatomy. This analysis was conducted as part of the Copenhagen Baby Heart Study, a multicenter cohort study of 25 556 neonates that underwent second-trimester anomaly scan at 18 + 0 to 22 + 6 weeks' gestation and neonatal echocardiography within 4 weeks after birth, in Copenhagen University Hospital Herlev, Hvidovre Hospital and Rigshospitalet in greater Copenhagen, between April 2016 and October 2018. From February 2017 (Rigshospitalet) and September 2017 (Herlev and Hvidovre hospitals), the protocol for second-trimester screening of the heart was extended to include evaluation of the four-chamber view, with assessment of flow across the atrioventricular valves, sagittal view of the aortic arch and midumbilical artery and ductus venosus pulsatility indices. All images were evaluated by two investigators, and cardiac biometric and flow parameters were measured and compared between cases with BAV and controls. All cases with neonatal BAV were assessed by a specialist. Maternal characteristics and first- and second-trimester biomarkers were also compared between the two groups. Fifty-five infants with BAV and 8316 controls with normal cardiac anatomy were identified during the study period and assessed using the extended prenatal cardiac imaging protocol. There were three times as many mothers who smoked before pregnancy in the group with BAV as in the control group (9.1% vs 2.7%; P = 0.003). All other baseline characteristics were similar between the two groups. Fetuses with BAV, compared with controls, had a significantly larger diameter of the aorta at the level of the aortic valve (3.1 mm vs 3.0 mm (mean difference, 0.12 mm (95% CI, 0.03-0.21 mm))) and the pulmonary artery at the level of the pulmonary valve (4.1 mm vs 3.9 mm (mean difference, 0.15 mm (95% CI, 0.03-0.28 mm))). Following conversion of the diameter measurements of the aorta and pulmonary artery to Z-scores and Bonferroni correction, the differences between the two groups were no longer statistically significant. Pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) was significantly lower in the BAV group than in the control group (0.85 vs 1.03; P = 0.04). Our findings suggest that fetuses with BAV may have a larger aortic diameter at the level of the aortic valve, measured in the left-ventricular-outflow-tract view, and a larger pulmonary artery diameter at the level of the pulmonary valve, measured in the three-vessel view, at 20 weeks' gestation. Moreover, we found an association of maternal smoking and low PAPP-A MoM with BAV. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

A Risk Model for Predicting Fetuses with Trisomy 21 Using Alpha-Fetoprotein Variants L2 Combined with Maternal Serum Biomarkers in Early Pregnancy

To establish a risk prediction model and the clinical value of trisomy 21 using alpha-fetoprotein variants L2 (AFP-L2) combined with maternal serum biomarkers and nuchal translucency (NT) thickness in early pregnancy. A retrospective case–control study was conducted. The subjects were divided into the case group (n = 40) or the control group (n = 40). An enzyme-linked immunosorbent assay was used to measure the maternal serum AFP-L2 level in both groups. The AFP-L2 single-index or multi-index combined risk model was used to predict the efficiency of trisomy 21. The best cut-off value and area under the curve (AUC) were determined to evaluate the predictive efficacy of different risk models constructed by AFP-L2. The maternal serum AFP-L2 level in the case group was 1.59 (0.61–3.61) Multiple of medium (MoM), which was higher than 1.00 (0.39–2.12) MoM in the control group (P < 0.001). The free beta-human chorionic gonadotropin (free β-hCG) level and NT in the case group were significantly higher than those in the control group (P < 0.001). The pregnancy-associated plasma protein A (PAPP-A) level in the case group was lower than that in the control group (P < 0.001). The AUC of AFP-L2 in predicting trisomy 21 was 0.797. After considering the maternal serum AFP-L2 level, the AUC, detection rate (DR), positive predictive value (PPV), negative predictive value (NPV), falsepositive rate (FPR), false negative rate (FNR), positive likelihood ratio (+LR), and negative likelihood ratio (-LR) were significantly improved. In this study, PAPP-A + free β-hCG + NT + AFP-L2 and PAPP-A + free β-hCG + AFP-L2 increased the integrated discrimination improvement (IDI) and net classification improvement (NRI) of predicting fetuses with trisomy 21 (1.10% and 5.27%; 11.07% and 2.78%) (1.10% and 5.27%; 11.07% and 2.78%), respectively, after considering the maternal serum AFP-L2 level. The maternal serum AFP-L2 level in early pregnancy had high sensitivity and specificity, and it was a good biomarker to predict fetuses with trisomy 21.

Cancer-associated fibroblasts educate normal fibroblasts to facilitate cancer cell spreading and T-cell suppression.

In some tumors, a small number of cancer cells are scattered in a large fibrotic stroma. Here, we demonstrate a novel mechanism for expansion of pro‐tumor fibroblasts via cancer‐associated fibroblast (CAF)‐mediated education of normal fibroblasts (NFs). When NFs were incubated with conditioned medium from CAFs, the resulting CAF‐educated fibroblasts (CEFs) generated reactive oxygen species, which induced NF‐κB‐mediated expression of inflammatory cytokines and the extracellular matrix protein asporin (ASPN), while expression of a common CAF marker gene, α‐SMA, was not increased. ASPN further increased CEF expression of downstream molecules, including indoleamine 2,3‐dioxygenase 1 (IDO‐1), kynureninase (KYNU), and pregnancy‐associated plasma protein‐A (PAPP‐A). These CEFs induce cytocidal effects against CD8+ T cells and IGF‐I activation in cancer cells. CEFs were generated without cancer cells by the direct mixture of NFs and CAFs in mouse xenografts, and once CEFs were generated, they sequentially educated NFs, leading to continuous generation of CEFs. In diffuse‐type gastric cancers, ASPNhigh/IDO‐1high/KYNUhigh/α‐SMA− CEFs were located at the distal invading front. These CEFs expanded in the fibrotic stroma and caused dissemination of cancer cells. ASPN may therefore be a key molecule in facilitating tumor spreading and T‐cell suppression.

Effect of Low-Dose Aspirin in Preventing Early-Onset Preeclampsia in the Taiwanese Population-A Retrospective Cohort Study.

PurposeTo evaluate the effect of low-dose aspirin on preventing early-onset preeclampsia during first-trimester screening using maternal factors and biochemistry.Patients and MethodsThis study was a retrospective cohort study of pregnant women with singleton pregnancies at a gestational age of 11–13+6 weeks from May 2017 to August 2019. Serum pregnancy-associated plasma protein A (PAPP-A)/placental growth factor (PLGF) and maternal demographic and clinical characteristics were collected and analyzed using a logistic regression model with a preset detection rate of 74% and a 10% false-positive rate. Low-dose aspirin was initiated for those screened positive for the prevention of early-onset preeclampsia.ResultsOf the 805 women who underwent preeclampsia screening, 78 were screened positive for early-onset preeclampsia. With a preset detection rate of 74% and a 10% false-positive rate, there were a total of 28 women with preeclampsia, of which 11 developed preterm preeclampsia (<37 GA) and three had early-onset preeclampsia with 72% and 75% sensitivity and specificity of 93% and 91%, respectively, resulting in an estimated 95% risk reduction for early-onset preeclampsia. Early-onset preeclampsia had lower serum PLGF (0.29 multiple of the median [MoM], range 0.1–0.67) compared with preterm preeclampsia (0.74 MoM, range 0.1–2.26). PLGF remains the only predictor of early-onset preeclampsia, while mean arterial pressure and chronic hypertension are predictors of preterm preeclampsia using multivariate regression. No variables accurately predicted the development of early-onset preeclampsia with the initiation of low-dose aspirin before the gestational age of 16 weeks.ConclusionA remarkable reduction in early-onset preeclampsia was observed with early initiation of low-dose aspirin in those screened positive for maternal characteristics and serum PAPP-A/PLGF.

A prospective cohort study on association of first-trimester serum biomarkers and risk of isolated foetal congenital heart defects

Background This study aims to assess the association between first-trimester biomarkers in foetuses with a non-chromosomal congenital heart defect (CHD) and compares it to the matched healthy foetuses. Method Nuchal Translucency (NT), Pregnancy-Associated Plasma Protein-A (PAPP-A) and free beta-human Chorionic Gonadotropin (β-hCG) were evaluated in 56 isolated foetal heart defects and 224 controls. The CHDs were further divided into Critical CHD (C-CHD) and Non-critical CHD (N-CHD) groups. Results The multiple of the median (MoM) values for PAPP-A were significantly lower (0.87 MoM vs. 0.92 MoM; p = 0.008) in the total CHD group than in controls. The median of foetal NT values was significantly higher in the total CHDs than in controls (1.16 MoM vs. 1.03 MoM; p < 0.001), especially for C-CHDs (1.28 MoM; P < 0.001). There were no significant differences in terms of PAPP-A (p = 0.779) and foetal NT values (p = 0.760) between the N-CHDs and control groups. There were no significant differences within the groups based on free β-hCG, except for a lower β-hCG in C-CHD group than in the control group (0.95 MoM vs. 1.11 MoM; p = 0.022). Conclusion Lower PAPP-A levels and increased NT thickness were associated with an increased risk of CHDs, especially the critical type of CHDs. Clinical significance Maternal serum PAPP-A, measured in the first trimester, is significantly lower in CHD. Foetal NT is significantly thicker in foetuses with CHD, especially those with critical CHD. Maternal serum β-hCG was only decreased among critical CHD group.

Prospective evaluation of first-trimester screening strategy for preterm pre-eclampsia and its clinical applicability in China.

To evaluate, in a Chinese population, the performance of a screening strategy for preterm pre-eclampsia (PE) using The Fetal Medicine Foundation (FMF)'s competing-risks model and to explore its clinical applicability in mainland China. This was a prospective, multicenter, observational cohort study including 10 899 women with singleton pregnancy who sought prenatal care at one of 13 hospitals, located in seven cities in mainland China, between 1 December 2017 and 30 December 2019. Mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and maternal serum levels of placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 to 13 + 6 weeks' gestation were measured and converted into multiples of the median using Chinese reference ranges. Individualized risk for preterm PE was calculated using the FMF algorithm. Prior risk was calculated based on maternal demographic characteristics and obstetric history. We evaluated the efficiency of the screening strategy using various combinations of biomarkers and analyzed its predictive performance for a composite of placenta-associated adverse pregnancy outcomes, including PE, placental abruption, small-for-gestational age (SGA) and preterm birth, at fixed false-positive rates for preterm PE. We identified 312 pregnancies that developed PE, of which 117 cases were diagnosed as preterm PE (< 37 weeks' gestation). There were 386 pregnancies complicated by severe composite placenta-associated adverse outcome, including preterm PE, 146 cases of severe SGA (birth weight < 3rd percentile) neonate, 61 cases with placental abruption and 109 cases of early preterm birth < 34 gestational weeks. The triple-marker model containing biomarkers MAP, UtA-PI and PAPP-A achieved, at fixed false-positive rates of 10%, 15% and 20%, detection rates for preterm PE of 65.0%, 72.7% and 76.1%, respectively, and detection rates for severe composite placenta-associated adverse outcome of 34.7%, 41.7% and 46.4%, respectively. Replacing PAPP-A with PlGF or adding PlGF to the model did not improve the performance. Of women screening positive for preterm PE at a fixed 5% false-positive rate, an estimated 30% developed at least one placenta-associated adverse pregnancy outcome, including PE, placental abruption, SGA (birth weight < 10th percentile) and preterm birth < 37 weeks. The FMF competing-risks model for preterm PE was found to be effective in screening a mainland Chinese population. Women who screened positive for preterm PE had increased risk for other placenta-associated pregnancy complications. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

A multivariate modeling method for the prediction of low fetal fraction before noninvasive prenatal testing.

To investigate factors associated with fetal fraction and to develop a new predictive method for low fetal fraction before noninvasive prenatal testing. The study was a retrospective cohort analysis based on the results of noninvasive prenatal testing, complete blood count, thyroxin test, and Down's syndrome screening during the first or second trimester in 14,043 pregnant women. Random forests algorithm was applied to predict the low fetal fraction status (fetal fraction < 4%) through individual information and laboratory records. The performance of the model was evaluated and compared to predictions using maternal weight. Of 14,043 cases, maternal weight, red blood cell, hemoglobin, and free T3 were significantly negatively correlated with fetal fraction while gestation age, free T4, pregnancy-associated plasma protein-A, alpha-fetoprotein, unconjugated estriol, and β-human chorionic gonadotropin were significantly positively correlated with fetal fraction. Compared to predictions using maternal weight as an isolated parameter, the model had a higher area under the curve of receiver operating characteristic and overall accuracy. The comprehensive predictive method based on combined multiple factors was more effective than a single-factor model in low fetal fraction status prediction. This method can provide more pretest quality control for noninvasive prenatal testing.

Upregulation of long non-coding RNA myocardial infarction-associated transcription is correlated with coronary artery stenosis and elevated inflammation in patients with coronary atherosclerotic heart disease.

Coronary atherosclerotic heart disease (CAD) is a chronic disease caused by multiple risk factors. Aberrant expression of long non-coding RNAs (lncRNAs) has been regarded as an independent risk factor of CAD. This study evaluated lncRNA myocardial infarction-associated transcription (MIAT) expression in CAD patients and its clinical significance. Totally, 155 CAD patients and 76 non-CAD controls were enrolled. MIAT expression was detected using reverse transcription quantitative polymerase chain reaction. The clinical diagnostic significance of MIAT was evaluated by plotting the receiver operating characteristic (ROC) curve. The levels of inflammatory cytokines were detected using enzyme-linked immunosorbent assay. microRNA (miR)-29b-3p expression and pregnancy-associated plasma protein A (PAPPA) level were detected. MIAT expression in CAD patients (4.23 [1.22-6.50]) was higher than that in non-CAD controls (1.64 [0.05-2.93]) (p < 0.01) and had an independent correlation with CAD. The area under ROC curve of predicting CAD was calculated as 0.790, the specificity as 71.40%, and the sensitivity as 70.00%. MIAT expression was positively correlated with the C-reactive protein level (r=0.769, p < 0.0001) and pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and IL-8 levels, while negatively correlated with the anti-inflammatory cytokine IL-10. MIAT was positively correlated with Gensini score and had an independent correlation with it. LncRNA MIAT sponged miR-29b-3p and miR-29b-3p targeted PAPPA. In conclusion, lncRNA MIAT was upregulated in the peripheral blood of CAD patients and elicited clinical diagnostic significance. MIAT participated in the development of CAD via miR-29b-3p/PAPPA axis. This study provides insights into a potential target for the diagnosis and treatment of CAD.

The Relationship Between First-Trimester Aneuploidy Markers and Birth Weight

OBJECTIVE: We aimed to determine the relationship between the first-trimester aneuploidy screeningma and the predicted weight at birth: Small for gestational age and large for gestational age. STUDY DESIGN: 594 low-risk pregnant women with a singleton pregnancy, who underwent first-trimester aneuploidy screening by measuring nuchal translucency, maternal serum free beta-human chorionic gonadotropin, and pregnancy-associated plasma protein-A were included in the study. Those weighing above the 3rd percentile and below the 10th percentile were defined as small for gestational age, and those over the 90th percentile were defined as large for gestational age. RESULTS: A total of 594 pregnant women were enrolled. The mean maternal age of the studied group was 28.8±5.5 years. Low maternal serum pregnancy-associated plasma protein-A levels and decreased nuchal translucency measurements were associated with the small for gestational age newborn (p&lt;0.001 and p=0.001, respectively). There is a significant correlation with large for gestational age for newborns only with an increase in maternal serum pregnancy-associated plasma protein-A levels (p=0.001). beta-human chorionic gonadotropin levels were not associated with the birth weight (p=0.735). CONCLUSION: Maternal serum pregnancy-associated plasma protein-A levels, one of the markers in first-trimester aneuploidy screening, can be used in the prediction of small for gestational age and large for gestational age However, due to its low correlation, it is not a suitable screening test for clinical practice.

ASPRE trial: risk factors for development of preterm pre-eclampsia despite aspirin prophylaxis.

To examine the possible risk factors amongst maternal characteristics, medical and obstetric history, pre-eclampsia (PE)-specific biomarkers and estimated-risk group, according to The Fetal Medicine Foundation (FMF) algorithm, that are associated with the development of preterm PE with delivery at < 37 weeks' gestation despite aspirin prophylaxis. This was a secondary analysis of data from the ASPRE trial. The study population consisted of women with singleton pregnancy who were deemed to be at high risk for preterm PE, based on the FMF algorithm that combines maternal factors, mean arterial pressure, uterine artery pulsatility index, serum pregnancy-associated plasma protein-A and placental growth factor (PlGF) at 11-13 weeks' gestation. High-risk women were randomized to receive aspirin (150 mg/day) vs placebo from 11-14 until 36 weeks' gestation. The primary outcome was PE with delivery at < 37 weeks' gestation (preterm PE). Multivariate logistic regression analysis was performed to identify independent predictors of preterm PE after adjusting for the use of aspirin and other covariates. Among 1592 high-risk women, the incidence of preterm PE was 3.0% (n = 48). The interaction between aspirin usage and history of chronic hypertension was significant in the prediction of preterm PE (P = 0.042), which indicated that there was no treatment effect in high-risk women who had chronic hypertension compared with those who did not. Adjusting for aspirin use, the interaction between aspirin and chronic hypertension and other covariates, independent predictors for the development of preterm PE were PlGF multiples of the median (MoM) (adjusted odds ratio (aOR), 0.226 (95% CI, 0.070-0.723)) and estimated-risk group based on the FMF algorithm. Compared to women with an estimated risk of 1 in 51 to 1 in 100, those with an estimated risk of 1 in 2 to 1 in 10 had a 7-fold higher risk of developing preterm PE (aOR, 6.706 (95% CI, 2.381-18.883)), and those with an estimated risk of 1 in 11 to 1 in 50 had a 3-fold higher risk of preterm PE (aOR, 2.769 (95% CI, 1.105-6.939)). PlGF MoM was an independent predictor for preterm PE among women with an estimated risk of 1 in 2 to 1 in 10 (aOR, 0.055 (95% CI, 0.005-0.668)). Among women with an estimated risk of 1 in 11 to 1 in 100, the use of aspirin was an independent predictor of preterm PE (aOR, 0.276 (95% CI, 0.111-0.689)). The cut-off for PlGF with the best performance for the prediction of preterm PE was 0.712 MoM, with an aOR of 3.677 (95% CI, 1.526-8.862). In pregnancies at high risk of preterm PE identified by screening at 11-13 weeks' gestation using the FMF algorithm, a very high-risk result (estimated risk ≥ 1 in 50), compared to an estimated risk of 1 in 51 to 1 in 100, chronic hypertension, compared to no chronic hypertension, and low PlGF concentration (< 0.712 MoM), compared to PlGF ≥ 0.712 MoM, were associated with the development of preterm PE despite aspirin prophylaxis. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Metabolomics Analysis of Amniotic Fluid in Euploid Foetuses with Thickened Nuchal Translucency by Gas Chromatography-Mass Spectrometry

Persistence of a fetal thickened nuchal translucency (NT), one of the most sensitive and specific individual markers of fetal disorders, is strongly correlated with the possibility of a genetic syndrome, congenital infections, or other malformations. Thickened NT can also be found in normal pregnancies. Several of its pathophysiological aspects still remain unexplained. Metabolomics could offer a fresh opportunity to explore maternal–foetal metabolism in an effort to explain its physiological and pathological mechanisms. For this prospective case-control pilot study, thirty-nine samples of amniotic fluids were collected, divisible into 12 euploid foetuses with an enlarged nuchal translucency (>NT) and 27 controls (C). Samples were analyzed using gas chromatography mass spectrometry. Multivariate and univariate statistical analyses were performed to find a specific metabolic pattern of >NT class. The correlation between the metabolic profile and clinical parameters was evaluated (NT showed an R2 = 0.75, foetal crown-rump length showed R2 = 0.65, pregnancy associated plasma protein-A showed R2 = 0.60). Nine metabolites significantly differing between >NT foetuses and C were detected: 2-hydroxybutyric acid, 3-hydroxybutyric, 1,5 Anydro-Sorbitol, cholesterol, erythronic acid, fructose, malic acid, threitol, and threonine, which were linked to altered pathways involved in altered energetic pathways. Through the metabolomics approach, it was possible to identify a specific metabolic fingerprint of the fetuses with >NT.

THE EXPRESSION OF PREGNANCY-ASSOCIATED PLASMA PROTEIN-A (PAPP-A) IN HUMAN BLASTOCOEL FLUID-CONDITIONED MEDIA

The aim of this study was to determine if pregnancy-associated plasma protein-A (PAPP-A), typically measured in maternal serum and a potential predictor of adverse maternal and fetal obstetric outcomes such as spontaneous miscarriage, pre-eclampsia, and stillbirth, is expressed in blastocoel fluid-conditioned media (BFCM) at the embryonic blastocyst stage.

Potential role of biochemical placentation markers - pregnancy associated plasma protein-A and human chorionic gonadotropin for early gestational diabetes screening - a pilot study.

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. The universal screening for GDM is usually performed between 24-28 weeks' gestation. This often delays the diagnosis and could increase the risk of adverse pregnancy outcomes. Some of the biochemical placental markers - pregnancy associated plasma protein A (PAPP-A) and free-β human chorionic gonadotropin (hCG), probably could provide a diagnostic value for GDM. The aim of our study was to assess if PAPP-A and hCG values were different among pregnant women with and without GDM and respectively, to tested their place in the early GDM screening. We conducted a retrospective, case-control study by reviewing the clinical database records of 662 pregnant women. The analysis includes the data for a two-year period. The patients included in the observation were divided into two groups - GDM group (n = 412) and Euglycemic group (n = 250). Early screening for GDМ between 9-12 weeks' gestation was performed in 173 of the women in the interventional group due to: registered fasting plasma glucose (FPG) above 5.1 mmol/L, obesity, macrosomia in previous pregnancies or family history for diabetes mellitus. The remaining 239 women underwent universal screening at 24-28 weeks' gestation. Mean serum levels of PAPP-A, hCG, FPG, and body mass index (BMI) were measured between 10-13 gestational weeks. Serum levels of PAPP-A and hCG are presented as multiples of the normal median (MoM), adjusted by maternal baseline characteristics and demographics. In patients who developed GDM during pregnancy, compared with the control group, we have found significantly lower MoM values of PAPP-A (p < 0.0001), higher levels of FPG (р < 0.0001) and higher BMI (р < 0.0001). Median hCG MoM was similar in both group of pregnant women. Our findings suggest that low-normal to low reference range values of PAPP-A might be associated with higher risk for GDM. PAAP-A levels can be used as an additional factor to recommend early screening for GDM.

Serum Inhibin-A and PAPP-A2 in the prediction of pre-eclampsia during the first and second trimesters in high-risk women.

Maternal serum inhibin-A, pregnancy associated plasma protein-A (PAPP-A) and PAPP-A2 together with placental growth factor (PlGF), maternal risk factors and uterine artery pulsatility index (UtA PI) were analysed to study their ability to predict pre-eclampsia (PE). Serial serum samples for the nested case-control study were collected prospectively at 12-14, 18-20 and 26-28weeks of gestation from 11 women who later developed early-onset PE (EO PE, diagnosis<34+0weeks of gestation), 34 women who developed late-onset PE (LO PE, diagnosis≥34+0weeks) and 89 controls. Gestational age -adjusted multiples of the median (MoM) values were calculated for biomarker concentrations. Multivariate regression analyses were performed to combine first trimester biomarkers, previously reported results on PlGF, maternal risk factors and UtA PI. Area under curve (AUC) values and 95% confidence intervals (CIs) for the prediction of PE and its subtypes were calculated. A high first trimester inhibin-A predicted PE (AUC 0.618, 95%CI, 0.513-0.724), whereas PAPP-A and PlGF predicted only EO PE (0.701, 0.562-0.840 and 0.798, 0.686-0.909, respectively). At 26-28weeks PAPP-A2 and inhibin-A predicted all PE subtypes. In the multivariate setting inhibin-A combined with maternal pre-pregnancy body mass index, prior PE and mean UtA PI predicted PE (0.811,0.726-0.896) and LO PE (0.824, 0.733-0.914). At first trimester inhibin-A show potential ability to predict not only EO PE but also LO PE whereas PlGF and PAPP-A predict only EO PE. At late second trimester inhibin-A and PAPP-A2 might be useful for short-term prediction of PE.

Analytical Comparison of Pregnancy-Associated Plasma Protein-A (PAPP-A) Immunoassays for Biochemical Determination of Gestational Age.

Accurate pregnancy dating is critical for maternal and child health and for counseling on safe and effective abortion methods. While last menstrual period and first trimester ultrasound are often used together to determine gestational age (GA), they have limited accuracy and availability, respectively. Prior studies have shown that pregnancy-associated plasma protein-A (PAPP-A) increases exponentially during pregnancy and has the potential to serve as a biochemical marker of GA. We aimed to analyze the relationship between sonographically determined GA and serum PAPP-A concentration measured by different immunoassays and to derive cutoff levels informative for the 70 days GA commonly recommended limit for medical abortion in outpatient settings. We compared technical characteristics of 4 commercially available PAPP-A immunoassays and tested 120 maternal serum samples (GA range: 34-231 days) along with contrived pool samples and traceable quality controls. These characteristics included area under the receiver operator characteristic (AUROC) plot, sensitivity and specificity based on cutoffs defined by the Youden Index, and likelihood ratios. All 4 immunoassays had sensitivities and specificities ≥80%, and AUROC values ranging from 0.948 to 0.968. Marked differences among absolute PAPP-A values were noted depending on immunoassay. PAPP-A cutoff values at 70 days GA for each individual immunoassay were established along with procedural recommendations that increase equivalence among immunoassays. Maternal serum PAPP-A levels correlated strongly with GA despite differences in immunoassay formats and absolute data output. Serum PAPP-A has biomarker potential for future development of a point-of-care test aimed at increasing access to medical abortion.