Pregnancy-associated Plasma protein-A Research Articles

PAPP-A and the IGF system in atherosclerosis: what's up, what's down?

Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase with a well-established role in releasing bioactive insulin-like growth factor-1 (IGF-1) from IGF-binding protein-2, -4, and -5 by proteolytic processing of these. The IGF system has repeatedly been suggested to be involved in the pathology of atherosclerosis, and both PAPP-A and IGF-1 are proposed biomarkers and therapeutic targets for this disease. Several experimental approaches based on atherosclerosis mouse models have been undertaken to obtain causative and mechanistic insight to the role of these molecules in atherogenesis. However, reports seem conflicting. The literature suggests that PAPP-A is detrimental, while IGF-1 is beneficial. This raises important questions that need to be addressed. Here we summarize the various studies and discuss potential underlying explanations for this seemingly inconsistency with the objective of better understanding complexities and limitations when manipulating the IGF system in mouse models of atherosclerosis. A debate clarifying what's up and what's down is highly warranted going forward with the ultimate goal of improving atherosclerosis therapy by targeting the IGF system.

Pregnancy-Associated Plasma Protein A Induces Inflammatory Cytokine Expression by Activating IGF-I/PI3K/Akt Pathways.

Pregnancy-associated plasma protein A (PAPP-A) was previously reported to be an inflammatory biomarker and a prognostic marker of acute coronary syndrome (ACS) and involved in the process of atherosclerosis and plaque rupture. However, the role of PAPP-A in inflammation is poorly understood. In this study, we aimed to investigate the role of PAPP-A in macrophage activation and inflammatory cytokine production. RAW264.7 macrophages were treated with or without PAPP-A. Reverse-transcriptase quantitative real-time PCR (RT-qPCR) and Western blot were performed to detect gene and protein expressions. The concentration of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in culture supernatants was determined by ELISA. Results showed that PAPP-A significantly stimulated the expression of MCP-1, TNF-α, and IL-6 at both transcriptional and translational levels in a dose-dependent and time-dependent manner. The secretion of these inflammatory cytokines by macrophages was also increased after PAPP-A treatment. Moreover, PAPP-A activated the IGF-I/PI3K/Akt signaling pathway in macrophages. The PAPP-A-mediated upregulation of MCP-1, TNF-α, and IL-6 mRNA and protein levels were strongly inhibited by PI3K inhibitors or IGF-IR siRNA, indicating that the upregulation of MCP-1, TNF-α, and IL-6 could involve the IGF-I/PI3K/Akt pathway. Together, this study demonstrates that PAPP-A activates the macrophage signaling pathway (IGF-I/PI3K/Akt), which drives the expression and production of inflammatory cytokines known to contribute to the initiation and progression of ACS. These findings indicate that PAPP-A may play a proinflammatory role in the pathophysiology of ACS and serve as a potential therapeutic target.

Serum level of PAPPA-A (pregnancy associated plasma protein-A) at first trimesterand its relation with adverse pregnancy outcome

Background: PAPP-A is a preterm marker for undesirable pregnancy diagnosis. The relationship between PAPP-A serum levels and maternal health, especially gestational diabetes, which is the most common outcome of pregnancy, is a major issue that needs to be studied. The aim of this study were to evaluate the serum level of PAPP-A and pregnancy outcomes. Methods: in this study all pregnant women who referred to the pregnancy care clinics during their first 3 months, serum levels of PAPP-A were evaluated. As their PAPP-A serum level were less than 0.4 Mom, they were considered as risk-positive and pregnant women with a serum PAPP-A level of more than 0.4 MM as a control group. In the subjects, maternal age, serum PAPP-A level, type of delivery, gestational age, intrauterine growth restriction, preeclampsia, spontaneous abortion, and gestational diabetes were evaluated. Results: The mean age of pregnant women were 26.85 ±4.74 years. There were a significant reverse correlation between serum concentration of first trimesters PAPP-A and preeclampsia (p=0.003), pregnancy Diabetes (p=0.003), restriction of intrauterine growth (p=0.005) and spontaneous abortion (p=0.04), but there were not significant corrections between serum level of PAPP-A with early birth (p=0.102) and gestation type (p=0.583). Conclusion: A reduced amount of first trimester PAPP-A would used as a probable risk factor in complications of pregnancy or embryo including preeclampsia, Gestational Diabetes, restriction of intrauterine growth and spontaneous abortion.

Impact of <i>Plasmodium falciparum</i> malaria infection on serum cortisol, adrenocorticotropic hormone, pregnancy associated plasma protein-A and alpha-fetoprotein in pregnant women at Nnewi

The present study assessed the maternal cortisol, Adrenocorticotropic hormone (ACTH), Pregnancy associated plasma protein-A (PAPP-A) and alpha-fetoprotein (AFP) concentrations in malaria infected pregnant women. A total of 76 (40 apparently healthy pregnant and 36 malaria-infected pregnant) women aged 18-40 years were prospectively recruited. Early morning blood samples (5 ml) were collected from each subject at 1st and 2nd trimesters. 1 ml of whole blood was used for the diagnosis of P. falciparum malaria using malaria Plasmodium falciparum Rapid Test Device (RTD) and Giemsa stained thick blood smears for microscopic detection of P. falciparum parasites while the remaining 4 ml was centrifuged, separated and serum used for estimation of cortisol, ACTH, AFP and PAPP-A using ELISA-based method. The mean cortisol (125.80 ±30.80 ng/ml) and AFP (1.9 ±0.7 MoM) concentrations in malaria-infected pregnant women were significantly (p<0.05) higher than those of normal pregnant women (86.70 ±3.30 and 1.5 ±0.7 respectively). Malaria-infected pregnant women had higher percentage of low birth weight babies (27.8%), preeclampsia (11.1%), premature rupture of membrane (11.1%), preterm delivery (30.6%), miscarriages (27.8%) and low APGAR score at one minute (2.8%). This shows the possible impact of malaria infection on pregnancy and birth outcomes. The increased cortisol concentration in malaria infected pregnant women shows that malaria infection in pregnancy increases the stress pregnant women are exposed to but the placental defect associated with increased placental permeability to AFP is not related to the effect of the stress (cortisol) and thus does not influence birth outcomes. Keywords: Plasmodium falciparum, pregnancy, cortisol, maternal serum markers, pregnancy outcome.

Use of pregnancy-associated plasma protein-A during oocyte in vitro maturation increases IGF-1 and affects the transcriptional profile of cumulus cells and embryos from Nelore cows.

Insulin-like growth factor 1 (IGF-1) activity is established by the regulation of IGF binding protein activity, which blocks IGF-1 functions, whereas pregnancy-associated plasma protein-A (PAPP-A) improves IGF-1 bioavailability and facilitates binding to IGF receptors. To further extend our understanding of the effect of exogenous PAPP-A on bovine embryo production, we added this protein during in vitro maturation of cumulus-oocyte complexes (COCs); moreover, we assessed its effects on IGF-1 quantity in the maturation medium, embryonic yield and postwarming survival, blastocyst quality, and transcript abundance. Bovine COCs were matured in a serum-free medium, either with PAPP-A supplementation (100 ng/ml) or without (control). The treatment group produced higher IGF-1 concentrations in the maturation medium; however, showed no difference on cleavage, blastocysts rates, and embryonic survival 3 and 24 hr postcryopreservation. Regarding gene expression, VNN1 was upregulated, whereas AGPAT9, FASN, EGFR, HAS2, and IMPDH1 were downregulated in PAPP-A treated. PAPP-A treated, CPT2, DNMT3A, and TFAM were upregulated, whereas ATF4 and IFITM3 were downregulated. We concluded that although the addition of PAPP-A did not affect embryo yield and blastocyst survival, higher IGF-1 levels may affect embryo competence through differential expression of genes involved in lipid metabolism, oocyte competence, and mitochondrial function.

The Role of Insulin-Like Growth Factor-1 and Pregnancy-Associated Plasma Protein-A in Diagnosis of Acute Coronary Syndrome and Its Related Morbidities.

Introduction:Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that plays a role in atherosclerotic plaque destabilization. In recent studies, insulin-like growth factor-1 (IGF-1) has been introduced as a mediator of atherosclerosis. PAPP-A and IGF-1 level may be important diagnostic indicators of acute coronary syndrome (ACS).Objective:The present study tried to assess the diagnostic role of IGF-1 and PAPP-A biomarkers in ACS spectrum.Methods:The serum level of IGF-1, PAPP-A and troponin I was determined in 121 consecutive patients with ACS. Relationships were assessed by t-test, ANOVA and the non-parametric equivalent. Accuracy of biomarkers was measured by the area under the ROC curve (AUC) and optimal cut-off points to diagnose STEMI and NSTEMI using Youden index.Results:In patients with acute ST segment elevation myocardial infarction (STEMI), all of these three biomarkers were significantly higher than those in patients with unstable angina (P= 0.028 for IGF-1, P<0.001 for PAPP-A and Troponin-I). Mean level of IGF-1 in patients with renal failure was significantly higher than that in patients without renal failure (137.9±35.1 vs 105.1±46.9, P=0.003), but PAPP-A and serum Troponin-I level had no significant difference in renal failure groups (P>0.05). ROC curve analysis showed that after Troponin-I, PAPP-A was a good discriminator between patients with STEMI and patients with unstable angina (AUC=0.79). Optimum cut-off value for PAPP-A was found to be 89.2 ng/ml, with sensitivity and specificity of 66.7% and 83.8%, respectively.Conclusion:PAPP-A can be a novel biomarker for both identification of patients with STEMI and risk stratification in patients with ACS.

Early prediction of preeclampsia and small-for-gestational-age via multi-marker model in Chinese pregnancies: a prospective screening study

BackgroundRecent evidence suggests early screening of preeclampsia and small-for-gestational-age (SGA) would benefit pregnancies followed by subsequent prophylactic use of aspirin. Multi-marker models have shown capability of predicting preeclampsia and SGA in first trimester. Yet the clinical feasibility of combined screening model for Chinese pregnancies has not been fully assessed. The aim of this study is to evaluate the applicability of a multi-marker screening model to the prediction of preeclampsia and SGA in first trimester particularly among Chinese population.MethodsThree thousand two hundred seventy pregnancies meeting the inclusion criteria took first-trimester screening of preeclampsia and SGA. A prior risk based on maternal characteristics was evaluated, and a posterior risk was assessed by combining prior risk with multiple of median (MoM) values of mean arterial pressure (MAP), serum placental growth factor (PLGF) and pregnancy associated plasma protein A (PAPP-A). Both risks were calculated by Preeclampsia PREDICTOR™ software, Perkin Elmer. Screening performance of prior and posterior risks for early and late preeclampsia by using PREDICTOR software was shown by Receiver Operating Characteristics (ROC) curves. The estimation of detection rates and false positive rates of delivery with both preeclampsia and SGA was made.ResultsEight cases developed early preeclampsia (0.24%) and 35 were diagnosed as late preeclampsia (1.07%). Five with early preeclampsia and ten with late preeclampsia later delivered SGA newborns (0.46%); 84 without preeclampsia gave birth to the SGAs (2.57%). According to ROC curves, posterior risks performed better than prior risks in terms of preeclampsia, especially in early preeclampsia. At 10% false positive rate, detection rates of early and late preeclampsia were 87.50 and 48.57%, detection rates of early and late SGA were 41.67 and 28.00%, respectively. For SGA, detection rates in cases with preeclampsia were much higher than those in absence of it.ConclusionsThis study demonstrates that combined screening model could be useful for predicting early preeclampsia in Chinese pregnancies. Furthermore, the performance of SGA screening by same protocol is strongly associated with preeclampsia.

Efficacy of combined medication of nifedipine and magnesium sulfate on gestational hypertension and the effect on PAPP-A, VEGF, NO, Hcy and vWF.

ObjectiveTo investigate the effects of combined medication of nifedipine and magnesium sulfate on the blood pressure, pregnancy-associated plasma protein A (PAPP-A), vascular endothelial growth factor (VEGF), nitric oxide (NO), homocysteine (Hcy) and von Willebrand factor (vWF) in gestational hypertension patients.MethodsA total of 220 gestational hypertension patients were enrolled as the subjects, and divided into two groups randomly, i.e. the observation group and the control group. In observation group, patients took combined medication of nifedipine and magnesium sulfate, while those in the control group only took magnesium sulfate for treatment. Clinical efficacy, and the changes in blood pressure, PAPP-A, VEGF, NO, Hcy and vWF before and after treatment were compared between two groups.ResultsIn the observation group and the control group, total effectiveness rates were 92.7% and 70.9%, respectively (p < 0.05). After treatment, we found significant decreases in PAPP-A, VEGF, NO, Hcy and vWF in patients of two groups, with more significant decreases in the observation group (p < 0.05). Incidence rates of the adverse reactions in two groups were 5.5% and 6.4%, respectively, without any statistically significant differences (p > 0.05). In the observation group, patients had fewer complications (p < 0.05).ConclusionCombined medication of magnesium sulfate and nifedipine can decrease the levels of PAPP-A, VEGF, NO, Hcy and vWF in serum as well as the blood pressure of patients with gestational hypertension, with a reduction in incidence rate of complications and improvement in efficacy.

Pregnancy-associated plasma protein-A2 levels are increased in early-pregnancy gestational diabetes: a novel biomarker for early risk estimation.

To determine whether pregnancy-associated plasma protein-A2 levels are increased in early pregnancies complicated by gestational diabetes and whether gestation age influences levels. The possible use of pregnancy-associated plasma protein-A2 as a pre-screening biomarker to reduce the need for performing oral glucose tolerance tests in pregnant women was also investigated. Pregnant women were diagnosed with gestational diabetes in early pregnancy after a 2-hour 75 g oral glucose tolerance test in the catchment area of Skåne University Hospital, Lund, Sweden during 2011-2015 (n = 99). Age- and BMI-matched pregnant women without diabetes were recruited at similar gestational ages from maternal healthcare centres in the same geographical area during 2014-2015 to act as controls (n = 100). Circulating pregnancy-associated plasma protein-A2 was analysed in participant serum using commercially available enzyme-linked immunosorbent assay kits. Circulating pregnancy-associated plasma protein-A2 was increased in women diagnosed with gestational diabetes [13.5 (9.58-18.8) ng/ml] compared with controls [8.11 (5.74-11.3) ng/ml; P < 0.001]. Pregnancy-associated plasma protein-A2 was associated with gestational diabetes independent of age, BMI, C-peptide and adiponectin (P < 0.001). Pregnancy-associated plasma protein-A2 as a pre-screening biomarker to identify women at a decreased risk of gestational diabetes resulted in a negative predictive value of 99.7%, with a sensitivity of 96% and a specificity of 30% at a cut-off level of 6 ng/ml. This is the first study to show increased pregnancy-associated plasma protein-A2 levels in gestational diabetes. Pregnancy-associated plasma protein-A2 also shows promise as a pre-screening biomarker with the potential to reduce the need for performing oral glucose tolerance tests in early pregnancy. Future prospective cohort studies in a larger group of both high- and low-risk women are, however, needed to further confirm this observation.

Development of a bioaffinity SPR immunosensor based on functionalized graphene oxide for the detection of pregnancy-associated plasma protein A2 in human plasma.

BackgroundGraphene-like material such as functionalized carboxyl-graphene oxide (carboxyl-GO) can be intelligently tuned to achieve particular properties for biological and chemical sensing applications.MethodsIn this study, we propose a method to improve interference of non-specific proteins for use in human plasma assays. The highly specific interactions between molecules are an advantage of carboxyl-GO-based surface plasmon resonance (SPR) immunoassays, and this can be applied to spiked plasma samples with pregnancy-associated plasma protein A2 (PAPPA2).ResultsThe experiment results showed that carboxyl-GO could be used to modulate the plasmon resonance energy, work function and conductivity properties. In addition, carboxyl groups could be used to enhance the conduction of electrons between carboxyl-GO and Au electrodes due to the excellent conductivity and electron transfer rate. The carboxyl-GO-based SPR chip exhibited high sensitivity based on the electric field amplification effects of the composite dielectric material. Therefore, the surface electric field could be enhanced by electron transfer, thereby greatly improving the sensitivity of the sensing system. Enhanced electric field intensity was generated around the carboxyl-GO of 63.58 V/m, and the measured work function was 4.95 eV. The results showed that the carboxyl-GO-based SPR biosensor had high sensitivity, affinity and selective ability for PAPPA2 protein with a high association rate constant (ka) of 3.1 ×109 M-1 S-1 and a limit of detection of 0.01 pg/mL in spiked human plasma.ConclusionThe results showed a detection accuracy of protein in spiked plasma of >90% compared to PBS buffer, suggesting that the carboxyl-GO-based SPR biosensor could be used in assays of human plasma for early and late gynecological diseases. The future of this technology will be useful for the diagnosis and evaluation of the risk of early maternal preeclampsia and potentially in clinical applications for gestational diseases.

Cap-independent mRNA translation is upregulated in long-lived endocrine mutant mice.

It has been hypothesized that transcriptional changes associated with lower mTORC1 activity in mice with reduced levels of growth hormone and insulin-like growth factor 1 are responsible for the longer healthy lifespan of these mutant mice. Cell lines and tissues from these mice show alterations in the levels of many proteins that cannot be explained by corresponding changes in mRNAs. Such post-transcriptional modulation may be the result of preferential mRNA translation by the cap-independent translation of mRNA bearing the N6-methyl-adenosine (m6A) modification. The long-lived endocrine mutants - Snell dwarf, growth hormone receptor deletion and pregnancy-associated plasma protein-A knockout - all show increases in the N6-adenosine-methyltransferases (METTL3/14) that catalyze 6-methylation of adenosine (m6A) in the 5' UTR region of select mRNAs. In addition, these mice have elevated levels of YTH domain-containing protein 1 (YTHDF1), which recognizes m6A and promotes translation by a cap-independent mechanism. Consistently, multiple proteins that can be translated by the cap-independent mechanism are found to increase in these mice, including DNA repair and mitochondrial stress response proteins, without changes in corresponding mRNA levels. Lastly, a drug that augments cap-independent translation by inhibition of cap-dependent pathways (4EGI-1) was found to elevate levels of the same set of proteins and able to render cells resistant to several forms of in vitro stress. Augmented translation by cap-independent pathways facilitated by m6A modifications may contribute to the stress resistance and increased healthy longevity of mice with diminished GH and IGF-1 signals.

Does first-trimester serum pregnancy-associated plasma protein A differ in pregnant women with sickle cell disease?

To assess whether levels of first-trimester pregnancy-associated plasma protein A (PAPP-A) differ between women with and without sickle cell disease (SCD). Retrospective study of 101 singleton pregnancies in women with SCD (including 55 with genotype HbSS, 37 with genotype HbSC, and nine with other genotypes). Measured levels of PAPP-A were converted to multiple of the median (MoM) values corrected for gestational age and maternal characteristics. Median PAPP-A MoM in the SCD group was compared with that of 1010 controls. In the SCD group median, PAPP-A MoM was lower than in the non-SCD group (0.72, interquartile range [IQR] = 0.54-1.14 versus 1.09, IQR = 0.74-1.49; P < .001). Within the SCD group median PAPP-A MoM was lower for those with genotype HbSS than HbSC (0.62, IQR = 0.44-1.14 versus 0.94, IQR = 0.72-1.25; .006). In 7.3% (4/55) of the HbSS group, there was stillbirth, and in these cases, PAPP-A was less than or equal to 0.5 MoM; in the control group, the incidence of stillbirth was lower (1%; P < .001). In HbSS disease, the incidence of small for gestational age (SGA) neonates was increased. Pregnancies with HbSS have lower PAPP-A MoM values and higher incidence of stillbirth and birth of SGA neonates than in non-SCD controls.

The utility of pregnancy associated plasma protein-A MoM values in prediction of term respiratory distress syndrome

This study aimed to investigate if the pregnancy associated plasma Protein-A (PAPP-A) multiples of median (MoM) levels could be used as a marker for the early prediction of RDS. The present study was designed with data gathered from 1773 patients who were referred to our institution for first trimester fetal chromosomal anomaly screening. First trimester PAPP-A MoM values and postnatal RDS occurrences in these pregnancies were retrospectively analysed. Of the 1773 neonates that were included in the study, 28 were delivered at or beyond 37 weeks, and 42 were delivered less than 37 weeks of gestation. In the group of neonates at or beyond 37 weeks, the cut-off value for RDS prediction was determined as 1.02. For this cut-off value, sensitivity was 72.41% and specificity was 91.84%. The area under curve (AUC) was determined to be statistically significant (p < .01). In conclusion, it was determined that in neonates that were delivered at or beyond 37 weeks of gestation, RDS occurrence could be predicted at a significant rate by utilising PAPP-A MoM values.IMPACT STATEMENTWhat is already known on this subject? Respiratory distress syndrome (RDS) is one of the major global healthcare problems, and continues to effect newborns despite the improvements in diagnosis and treatments of the disease. Studies have shown that pregnancy associated plasma protein-A (PAPP-A) has a critical role in cellular proliferation and differentiation, and it is closely associated with many physiological and pathological processes via regulation of local insulin like growth factor (IGF) concentrations. In majority of the past studies in the literature regarding PAPP-A values in pregnancies, the association between low values of PAPP-A MoM and maternal-fetal complications were investigated.What do the results of this study add? This study retrospectively examines the PAPP-A MoM levels and the occurence of RDS. In neonates that were delivered at or beyond 37 weeks of gestation, RDS occurrence could be predicted at a significant rate by utilising PAPP-A MoM values which was measured at the first trimester fetal anomaly screening test.What are the implications of these findings for clinical practice and/or further research? In the light of these findings, in order to reduce RDS related neonatal morbidity and mortality, pregnancies with PAPP-A MoM values greater than 1.02 at the first trimester fetal anomaly screening should be more closely followed up and a higher rate of suspicion should be kept for RDS occurrence.

Early pregnancy reference intervals; 29 serum analytes from 4 to 12 weeks' gestation in naturally conceived and uncomplicated pregnancies resulting in live births.

Background Pregnancy introduces major physiological changes that also alter biochemical analytes. Maternal and perinatal health can be optimized by early intervention and therefore, pregnancy-specific reference intervals (RIs) for the local population are warranted. While the second and third trimester-specific changes are well described, the first trimester is less well characterized. We therefore wanted to facilitate early detection of abnormalities by generating first trimester reference values for 29 common analytes. Methods In a prospective early pregnancy (PEP) cohort (2016-2017), 203 pregnant women were recruited from 4 to 8 weeks' gestation. Consecutive blood samples were drawn every 2 weeks until an ongoing second trimester pregnancy (n = 164) or a miscarriage (n = 39) occurred. After exclusion of women with complicated pregnancies or deliveries (n = 42), 122 women were included. The serum samples collected at <6, 6-8, 8-10, 10-12 and >12 weeks' gestation were analyzed for 29 common analytes. Subsequently the RIs were calculated according to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) recommendations (2.5-97.5th percentiles) and compared with the conventional RIs for non-pregnant women. Results Human chorionic gonadotropin (hCG), progesterone (P4), estradiol (E2), pregnancy-associated plasma protein A (PAPP-A), cancer antigen 125 (CA125), thyroid stimulating hormone (TSH), creatinine (CREA) and albumin (ALB) showed an early pregnancy-dependent change compared with conventional limits. For ALB the change was seen at 5.5 weeks' gestation. Conclusions We report gestational age-specific RIs available from the early part of the first trimester applicable to everyday clinical care of pregnant women. Well-known alterations of RIs seen in later trimesters are also observed in the first.

PAPP-A concentrations change in patients with gestational diabetes

Our aim was to assess the relationship between gestational diabetes and glucose intolerance regarding maternal serum PAPP-A and free β‐hCG concentrations in first trimester pregnancies. This study was conducted on 278 women between 18–45 years old with singleton pregnancies. The subjects were divided into four groups, according to their 50 and 100 g OGTT results. Group 1 was the Control Group, Group 2 with positive 50 g OGTT results, but negative 100 g, Group 3 had gestational diabetes after testing with 50 g OGTT (≥180 mg/dl) or with 100 g OGTT. Finally Group 4 was made of women with a one single high glucose level after testing with 100 g OGTT. These groups were analysed in terms of OGTT results. In the GDM group, serum PAPP-A concentrations were significantly lower when compared with the Control Group’s (p = 0.015). There was either no significant differences regarding free β‐hCG concentrations among the groups. GDM rate is 21.1%, the patients with GDM had significantly low concentrations of serum PAPP-A but their f β‐hCG concentrations did not change. Our results are supported by several studies. However, we need greater numbered studies for exact results.IMPACT STATEMENTWhat is already known on this subject? Pregnancy associated plasma protein A (PAPP-A) is produced by the placenta in pregnancy. PAPP-A cleaves insulin-like growth factor (IGF) binding proteins. It would appear to have a role in regulating IGF bioavailability in pregnancy. This is important as the IGF axis plays a critical role in fetal growth, and placental growth and function during pregnancy. Some studies have reported that PAPP-A levels were impaired among women who subsequently developed GDM.What do the results of this study add? The patients with GDM had significantly low concentrations of serum PAPP-A but their free β-hCG levels did not change.What are the implications of these findings for clinical practice and/or further research? By looking at PAPP-A concentrations, we can predict patients that will be gestational diabetic and take precautions to protect the babies health, such as their diet or exercise.

The alteration of first trimester screening markers in fresh and frozen-thawed blastocyst transfers

Objective: The aim of this study was to investigate whether first trimester combined screening for major fetal trisomies is influenced by assisted reproduction techniques (ART) from blastocyst transfer, with or without cryopreservation. Methods: This study is a retrospective analysis involving 115 singleton pregnancies with euploid fetuses recruited between January 2017 and December 2017. Sixty-five women conceived with fresh blastocysts from in vitro fertilization (IVF) cycles (fresh-blasto), 50 with frozen-thawed blastocysts. All cases underwent ultrasound assessment at 11+0 - 13+6 weeks with measurements of crown rump length, nuchal translucency (NT) , free beta-human chorionic gonadotrophin (free β-hCG) and pregnancy-associated plasma protein A (PAPP-A) concentrations. Results: Baseline characteristics and pregnancy outcomes did not differ substantially among the study groups. The NT was not significantly different in the frozen-thawed -blasto compared to the fresh-blasto group (p = 0.741). The free β-hCG levels was not significantly different in frozen-thawed-blasto group compared to fresh-blasto group (p = 0.495). The two groups showed no significant difference in the PAPP-A levels (p = 0.139). The median delta crown rump length was also not significantly different among the two groups (p = 0.758). Conclusions: In ART pregnancies from blastocyst transfer, with or without cryopreservation, the NT measurement, free β-hCG concentration and PAPP-A levels did not show any significant difference. These features are apparently unrelated to the outcome of pregnancy and may be due to alterations or delays in embryogenesis or placentation with potential relevance for the screening test performance.

Association of pregnancy-associated plasma protein A and vascular endothelial growth factor with pregnancy-induced hypertension.

The present study aimed to evaluate changes of pregnancy-associated plasma protein A (PAPP-A) and vascular endothelial growth factor (VEGF) in pregnancy-induced hypertension (PIH). A total of 105 cases (observation group) with complete data that underwent delivery and suffered from PIH in The Affiliated Hospital of Xuzhou Medical University from February 2015 to February 2017 were retrospectively analyzed. The observation group was further divided into the mild observation and severe observation groups according to severity degree of the disease. Another 65 asymptomatic pregnant women were recruited as the healthy control group. Basic data, obstetric data, PAPP-A and VEGF and data of perinatal infants were compared and analyzed. The Logistic regression model was adopted to screen out risk factors for PIH. In the observation group, the rate of periodic antenatal care was lower, and there were more primigravidas and housewives, with lower education level and economic income (P<0.05). In the observation group, the occurrence rates of placental abruption as well as turbid and bloody amniotic fluid were higher than those in the healthy control group (P<0.05). The neonatal birth weight was lower in the observation group than that in the healthy control group, while the occurrence rates of neonatal department transfer, small for gestational age (SGA), neonatal asphyxia and survival rates of perinatal infants were higher (P<0.05). PAPP-A levels at 34–40 gestational weeks in the observation group were significantly higher than those in the healthy control group (P<0.05). VEGF levels were lower than those in the healthy control group (P<0.05). Multivariate analysis revealed that high PAPP-A value [odds ratio (OR)=3.736] and identity of housewife (OR=2.514) were risk factors for PIH, while high VEGF value (OR=5.258), non-primigravid (OR=2.173), higher economic income (OR=4.162) and periodic antenatal care (OR=1.201) were regarded as protective factors. Therefore, enhancement of gestational management, early discovery and early treatment are critical for improving the prognosis of pregnant women and infants.

Association of Low Maternal Pregnancy-associated Plasma Protein A with Adverse Perinatal Outcome.

The aim is to provide an overall view of the association of low pregnancy-associated plasma protein A (PAPP-A) levels with adverse perinatal outcomes. The available literature in PubMed/Medline regarding PAPP-A and adverse pregnancy outcomes was searched for related articles, including terms such as “PAPP-A,” “intrauterine growth restriction (IUGR),” “small for gestational age (SGA),” “stillbirth,” “adverse outcome,” and others. The fifth percentile is supported by many recent studies to be PAPP-A’s cutoff for adverse outcome detection and the increased risk seems to be extremely high below 0.2 PAPP-A MoM (multiple of the median). Apart from chromosomal abnormalities, preeclampsia, intrauterine fetal demise, and pregnancy loss have been associated with maternal serum PAPP-A. For results below the first centile, PAPP-A has a strong positive predictive value for SGA and IUGR. Except for its vital role on the cleavage of insulin-like growth factor binding proteins (IGFBP), PAPP-A has proven to be a reliable marker for prenatal screening. Even though PAPP-A as a single predictor proved to be valuable for the prediction of some adverse perinatal outcomes, in some cases, a combination of PAPP-A to other maternal serum markers led to an increase in detection rates. PAPP-A is a promising maternal serum marker for pregnancy outcome prediction with more studies needed in order for its potentials to be fully understood and exploited.

The effect of oral micronized progesterone on first trimester screening test markers and neonatal outcome

Objective: It was aimed to investigate whether or not nuchal translucency(NT) thickness, maternal serum free beta-human chorionic gonadotropin(β-hCG) and pregnancy-associated plasma protein-A(PAPP-A) levels may affected by the use of oral micronized progesterone(OMP) in first trimester pregnancies. Also we aimed to evaluate pregnancy outcome in pregnant women using OMP. Method: This study was performed retrospectively including 1192 pregnant women, between January 2015 and August 2017. Body mass index(BMI), maternal and gestational age, levels of maternal serum PAPP-A and free β-hCG, NT measurement and the crown–rump length(CRL), fetal sex, fetal birth weight, Apgar score 5thminute<7 and admission to neonatal intensive care unit(NICU) were evaluated. Results: Maternal characteristics, ultrasound and biochemical parameters, fetal characteristics and neonatal outcome were evaluated. There was no statistically significant difference for maternal age, BMI, gestational age, PAPP-A, β-hCG, CRL, NT thickness, fetal sex, fetal birth weight, Apgar score 5th minute <7 and the number of admission to NICU during the first 28 days. Conclusions: Our results suggest that in clinical practice, 1) it seems that using OMP cannot affect on NT, CRL and birth weight. 2) OMP cannot adversely affect on production of PAPP-A and β-hCG in vivo. 3) NT, serum PAPP-A and β-hCG levels and MoM values, which are markers of the first trimester screening test, do not change by using OMP. Therefore using OMP cannot affect reliability of the first trimester screening test in pregnancy with threatened abortion. 4) OMP does not look like adversely affect on poor neonatal outcome.

Abnormal expression of Pappa2 gene may indirectly affect mouse hip development through the IGF signaling pathway.

Developmental dysplasia of the hip (DDH) is a major cause of disability in children, and the genetic mechanism of this disease remains unclear. In our previous study, we found that pregnancy-associated plasma protein-A2 (PAPP-A2) was associated with DDH significantly. The aim of this study was to investigate the insulin-like growth factor (IGF) expression and collagen synthesis as well as cartilage proliferation-related proteins in the case of abnormal expression of Pappa2 in mice to research the relationship between PAPP-A2 and the pathological changes of DDH. In vivo animal experiments, the mice were directly injected with 50 µl of Cas9/PAPP-A2 sgRNA lentiviruses around the hip to downregulate the Pappa2 gene expression and injected with control lentiviruses on the other side, then to observe the expression and localization of related proteins. And in an in vitro experiment, mice fibroblasts and primary chondrocytes were cultured with insulin-like growth factor binding protein-5 (IGFBP-5) protein, PAPP-A2 protein and Cas9/PAPP-A2 sgRNA lentiviruses to detect of related proteins and mRNA expression. Cartilage proliferation-related proteins demonstrated a significant decrease in the PAPP-A2 knockdown hips acetabulum and femoral head cartilage, meanwhile the IGF expression was also downregulated in the soft tissue around the acetabulum compared with the control hips. Furthermore, the role PAPP-A2 played in chondrocytes and fibroblasts was the same as in the in vivo experiments, downregulation of PAPP-A2 expression or upregulation of IGFBP-5 expression can reduce collagen synthesis and cartilage proliferation. PAPP-A2 may be involved in the development of the mouse hip joint by interfering the fibrous and cartilaginous metabolism via IGF pathway-associated proteins pathway.