Serum Pregnancy-associated Plasma protein-A Research Articles

Missed Down Syndrome Cases after First Trimester False-Negative Screening-Lessons to be Learned.

Background and Objectives: Here, we performed a descriptive analysis of Down syndrome (DS) cases that were misdiagnosed and/or false-negative diagnosed after first trimester traditional screening via risk evaluation using ultrasound, biochemical markers, and different software programs. Our objective was to demonstrate the clear need to improve the application of prenatal DS screening programs using standardized ultrasound measurements, accurate pregnancy dating, analytical immunoassay performance, and properly selected medians. Materials and Methods: We performed a database search for the period 2010–2015 to analyze DS cases that were false-negative diagnosed after the first trimester of pregnancy, before the introduction of cell free fetal DNA-based tests by Romanian laboratories in 2015. First-trimester screening was performed using two software programs for prenatal DS risk calculation: Astraia and Prisca. The rationale for using both software programs was to assess the full risk using the maternal age combined test (based on nuchal translucency thickness, nasal bone, ductus venosus flow, tricuspid flow, free beta-human chorionic gonadotropin level, and serum pregnancy-associated plasma protein-A) and, in some cases, the triple test. Results: We identified seven DS cases that exhibited low risk for trisomy 21, and 6540 cases with a low risk for trisomy 21 and euploid fetus in the first trimester. Using Astraia software, 14 cases were diagnosed, and three cases were missed after risk calculation. Using Prisca software, four cases were missed. Additionally, one neonate had a missed prenatal diagnosis of atrio-ventricular canal defect. Conclusion: In Romania, the evaluation of DS risk depends on patient choice (without knowing the accuracy of the utilized tests) and on the operators’ skills. Both Astraia and Prisca software were developed by experts, who can prove their performance in DS screening. However, even in an ideal situation, false-negative results are possible. The application of first and second-trimester combined screening based on biochemical markers could be improved by the implementation of standardized protocols, professional guidelines for test application, and audit control.

The relationship between serum pregnancy-associated plasma protein-A level in patients with aortic valve stenosis: a case-control study

Objective Calcific aortic stenosis (AS) is the most common form of calcific aortic valve disease. Many matrix metalloproteinase (MMP) have been shown to be expressed in aortic sclerosis and contribute to valve fibrosis and calcification. We investigated the relationship between Pregnancy-Associated Plasma Protein-A (PAPP-A) and AS. Methods Sixty-one patients who referred to our cardiology clinic having AS diagnosed with transthoracic echocardiography and thirty control subjects were included in this study. The patient group was divided into two groups as mild and moderate-severe AS in terms of echocardiography results. Levels of C-reactive protein (CRP), insulin-like growth factor-1 (IGF-1) and PAPP-A were measured. Results There was statistically significant difference between the patient and control group for PAPP-A (p = 0.009). In addition, the difference between MPV, IGF-1 and PAPP-A levels of control and AS groups was found. We found that serum PAPP-A level was an independent predictor of AS (B = 0.107, p = 0.01) by logistic regression analysis. In linear regression analysis, a significant correlation was found for AS severity with MPV, IGF-1 and PAPP-A levels, respectively (p = 0.025, p = 0.004, p = 0.035). It was revealed that PAPP-A and IGF-1 were negatively correlated (r = −0.327, p = 0.002). Correlation of serum PAPP-A level with echocardiographic parameters was no observed. Conclusion The level of PAPP-A may be a marker used in diagnosis rather than a marker used to determine the severity of AS. Studies with larger patient populations may further explain the role of PAPP-A in the diagnosis and treatment of AS.

The evaluating of pregnancy-associated plasma protein-A with the likelihood of small for gestational age.

ObjectiveRecently, strong evidences were obtained on the association between low pregnancy-associated plasma protein-A (PAPP-A) levels in the first trimester and poor outcomes of pregnancy.MethodsThis cross-sectional study was conducted on all pregnant women who were referred to the Obstetrics and Gynecology Clinic at Imam Hossein Hospital in Tehran, Iran in 2014. Women were asked to attend clinical examinations and screening at 11–14 weeks of gestation.ResultsBased on the definition, 14.5% of neonates found to be small for gestational age (SGA). There was a strong association between PAPP-A levels and birth weight. The mean PAPP-A level in the mothers of neonates who were SGA was significantly lower than those without this poor outcome. Based on the receiver operating characteristic curve analysis, serum PAPP-A level was a main determinant in the prediction of SGA neonates.ConclusionThe serum PAPP-A level at 11–13 weeks of gestation can effectively predict the increased risk for fetal growth retardation. In patients in this study, the best cutoff value for PAPP-A was 0.75 MOM, which signifies that lower levels of this marker can predict fetal growth restriction with high sensitivity and specificity.

First trimester prenatal screening in multiple pregnancies. Part II: serum proteins PAPP-A and β-hCG as markers of adverse pregnancy outcomes

Aim: to evaluate the ability of serum biochemical markers in pregnant woman - PAPP-A (pregnancy-associated plasma protein-A) and β-hCG (the в-subunit of human chorionic gonadotropin) studied in the first trimester (11 +0 -13 +6 ) during combined prenatal screening to predict adverse perinatal outcomes of multiple pregnancy that occurred spontaneously and as a result of in vitro fertilization (IVF). Materials and methods . The main group consisted from 65 women with pregnancy occurred as a result of IVF; comparison group included 56 women with spontaneous pregnancy. All pregnancies were multiple and their outcomes were known. Serum PAPP-A and β-hCG levels were measured in the first trimester. The results were expressed in absolute values and in MoM (multiples of median). Subgroups were compared with mono- and dichorionic pregnancies, complicated and uncomplicated pregnancies, distributed according to MoM index: within the reference values (0.5-2.0), below or above the reference values. Results . PAPP-A MoM values in the spontaneous pregnancy group were 1.12 [0.8; 1.57], in the IVF group - 1.35 [1.11; 1.72] (p = 0.01). In subgroup of low PAPP-A MoM antenatal fetal death occurred in 50 %, in subgroup of normal PAPP-A MoM - in 14.58 %, in subgroup of high PAPP-A MoM - in 5.88 % (p = 0.011). In addition, a positive correlation was found between serum PAPP-A level and time of fetal death (r s = 0.564; p = 0.036). Low PAPP-A MoM values were associated with 50 % fetal mortality, 75 % of them were attributable to pregnancy as a result of IVF. Conclusion . Identification of adverse outcomes in multiple pregnancies is still a difficult task, but evaluation of serum biochemical markers during the first trimester screening can help in early diagnosis of necessity and extent of timely prophylaxis.

Association between first-trimester maternal level of pregnancy-associated plasma protein-A and adverse pregnancy outcomes

Objectives To study the association between low first-trimester pregnancy-associated plasma protein-A (PAPP-A) and adverse pregnancy outcomes. Background PAPP-A is produced by the placenta during pregnancy. Low plasma level of this protein has been suggested as a biochemical marker for pregnancies with aneuploidy fetuses. Other studies found associations between low PAPP-A and adverse pregnancy outcomes during the first-trimester screening. Patients and methods The present study was conducted at Al-Amrya General Hospital, Gynecology and Obstetrics Department, after informed consent from participants was taken. The research ethics committee at Faculty of Medicine, Menoufia University, approved it. The study included 90 pregnant women booked for routine antenatal care while they were in their first-trimester after fulfilling the inclusion criteria. A blood sample (3–4 ml of venous blood) was withdrawn from all study participants. Then, samples were collected in plain tubes, followed by centrifugation of the samples, where the sera were collected for PAPP-A assay and stored at −20°C. Actual assay of PAPP-A would not be done except after development of any of adverse pregnancy outcome, including preeclampsia, gestational hypertension, intrauterine growth restriction, intrauterine fetal death, or spontaneous preterm. Results There is an association between low PAPP-A less than or equal to 0.41 in the first-trimester and development of adverse pregnancy outcomes. Conclusion Maternal serum PAPP-A level was significantly lower during the first-trimester in women who developed adverse pregnancy outcomes than women who did not develop.

Are the first-trimester levels of PAPP-A and fb-hCG predictors for obstetrical complications in diabetic pregnancy?

Objective To assess the levels of pregnancy-associated plasma protein-A (PAPP-A) and β-human chorionic gonadotropin (fb-hCG) in cases of diabetic pregnancy, to determine whether these biomarkers can be considered significant predictors for macrosomia, preeclampsia (PE), intrauterine growth restriction (IUGR), and preterm birth in mothers with different types of pregestational diabetes mellitus (DM). Methods It was a retrospective cohort study. Study groups were presented: type 1 DM (n = 100), type 2 DM (n = 50), and controls (n = 25). At 11 + 0 to 13 + 6 week’s gestation, we recorded maternal characteristics and medical history, and performed a combined test for the detection of risk of chromosomal abnormalities. To assess the performance of the markers in the prediction of the main obstetrical complications (PE, IUGR, preterm birth, and macrosomia), receiver-operating characteristic (ROC) curves were produced and area under the curves was calculated. Results The study has shown that DM is associated with a high rate of perinatal complications: PE, IUGR, macrosomia, and preterm birth. The median level of PAPP-A was significantly lower in case of type 1 DM- 0.89 (inter quartile range (IQR), 0.51–1.1), and type 2 DM-0.88 (IQR, 0.42–1.15) compared to the unaffected group 1.03 (IQR, 0.96–1.12; p = .025). There were no significant differences in the fb-hCG multiples of the normal median (MoM; p = .14) between the diabetic and unaffected groups. More significant results were obtained when calculated by percentile: in diabetic pregnancies, PAPP-A and fb-hCG MoMs values were lower in the 5–10% ranges and higher in the 95% range, compared to the control group. ROC-analysis did not show any significant data that first-trimester PAPP-A and fb-hCG serum levels are predictors for PE, IUGR, macrosomia, and preterm birth. Conclusion The routine first-trimester serum screening of fetal Down syndrome cannot be used as a tool of risk identification for PE, IUGR, macrosomia, and preterm birth in case of diabetic pregnancy.

First trimester PAPP-A serum levels and long-term metabolic outcome of mothers and their offspring

Low maternal serum levels of pregnancy associated plasma protein A (PAPP-A) are known to be associated with the development of pregnancy-related complications like small for gestational age infants, intrauterine fetal demise, gestational diabetes and preeclampsia. The study aims to find possible long-term correlations with the development of metabolic and cardiovascular complications in the mothers and their progeny in later life. This is a retrospective cohort study conducted on consecutive unselected women screened for chromosomal anomalies in the first trimester of pregnancy between 2004 and 2010. PAPP-A values as well as clinical data collected at childbirth were considered. A maternal and neonatal follow-up was performed through a telephone interview with the mother during 2015. The body-mass-index and the presence of cardiovascular diseases, dyslipidaemia and diabetes mellitus were evaluated. The analysis included 988 patients. The median time of follow-up was 7 years (IQR 6–9). Lower first trimester maternal blood PAPP-A quartiles were associated with small stature of the offspring (z-score 1st-2nd quartile 0.37 IQR −0.42 and 1.17 vs 3rd-4th quartile 0.67 IQR −0.17 and 1.36, p < 0.05). Furthermore, low first trimester PAPP-A in pregnancy without other gestations following the index one, in Kaplan-Meier analysis was associated to a significant increase of hypoglycemic agents use at 7 and 10 years (respectively 1.12% CI.95 0–2.38% and 5.45% CI.95 0–10.82%) compared to the control group of high first trimester PAPP-A values (0% CI.95 0–0%) (p < 0.05). Low PAPP-A serum levels in the first trimester of pregnancy are associated with short stature in offspring and de-novo development of maternal diabetes mellitus in later life.

Study on the correlation and predictive value of serum pregnancy-associated plasma protein A, triglyceride and serum 25-hydroxyvitamin D levels with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a concern due to its rapid increase in incidence in recent years. To investigate the correlation and predictive value of serum pregnancy-associated plasma protein A (PAPP-A), triglyceride (TG), and 25-hydroxyvitamin D [25-(OH)D] with GDM in early pregnancy. A total of 99 patients in early pregnancy admitted to Peking University International Hospital from November 2015 to September 2017 were included, and underwent a fasting glucose test and oral glucose tolerance test screening at 24-28 wk of pregnancy. Of these cases with GDM, 51 were assigned to group A and the remaining 48 cases without GDM were enrolled in group B. Serum PAPP-A, TG and 25-(OH)D in the two groups were compared and their correlation with blood sugar was analyzed. In addition, their diagnostic value in GDM was determined using receiver operating characteristic (ROC) curve analysis. Group A had markedly lower serum PAPP-A and 25-(OH)D levels and a significantly higher serum TG level than group B, with statistical significance (P < 0.05). Furthermore, Pearson analysis identified that PAPP-A and 25-(OH)D levels were negatively correlated with fasting blood glucose (FBG) levels (r = -0.605, P < 0.001), (r = -0.597, P < 0.001), while TG and FBG levels were positively correlated (r = 0.628, P < 0.001). The sensitivity, specificity, area under the curve (AUC) and optimal cut-off value of serum PAPP-A level in the diagnosis of GDM were 72.55%, 82.35%, 0.861 and 16.340, respectively, while the sensitivity of TG in diagnosing GDM was 86.27%, the specificity was 66.67%, the AUC was 0.813, with an optimal cut-off value of 1.796. The corresponding sensitivity, specificity, AUC and optimal cut-off value of serum 25-(OH)D were 64.71%, 70.59%, 0.721 and 23.140, respectively. Moreover, multivariate logistic regression analysis revealed that FBG, vascular endothelial growth factor, Flt-1, serum PAPP-A, TG, and 25-(OH)D were related risk factors leading to GDM in patients. Serum PAPP-A, TG, and 25-(OH)D levels are all correlated with blood glucose changes in GDM, and are independent factors affecting the occurrence of GDM and have certain value in the diagnosis of GDM.

Screening for Hypertensive Pregnancy Complications through Maternal Serum PAPP-A 5th and 10th Percentiles during the 11-14 Weeks Gestational Age Interval

The aim of our study was to assess the predictive values for hypertensive complications of pregnancy of the multiples of median (MoM) of serum pregnancy associated plasma protein A (PAPP-A), measured in 128 pregnant patients between 11 and 14 weeks gestational age. The 5th and the 10th percentile for MoM PAPP-A were 0.27 and 0.33, respectively. The detection rate for pregnancy induced hypertension, mild preeclampsia, severe preeclampsia, all preeclampsia and all hypertensive complications was 0%, 9.09%, 0%, 7.69%, and 6.25% for MoM PAPP-A below the 5th percentile (for a false positive rate of 5%), and 33.33%, 9.09%, 0%, 7.69%, and 12.5% for MoM PAPP-A below the 10th percentile (for a false positive rate of 10%), respectively. The specificity ranged from 89.57% to 95.73%, the positive predictive value from 0% to 16.67%, and the negative predictive value from 87.70% to 98.36%.

First-trimester screening for trisomies in pregnancies with vanishing twin.

To examine multiples of the median (MoM) values of serum free beta-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in a large series of pregnancies with a vanishing twin, determine the association of these values with the interval between embryonic death and blood sampling, and develop a model that would allow incorporation of these metabolites in first-trimester combined screening for trisomy. This was a retrospective study comparing maternal serum free β-hCG and PAPP-A levels at 11-13 weeks' gestation in 528 dichorionic pregnancies with a vanishing twin, including 194 (36.7%) with an empty gestational sac and 334 (63.3%) with a dead embryo, with those in 5280 normal singleton pregnancies matched for method of conception and date of examination. In vanishing-twin pregnancies with a dead embryo, marker levels were examined in relation to the estimated time between embryonic death and maternal blood sampling. First, in pregnancies with a vanishing twin, median free β-hCG MoM was not significantly different from that in normal singleton pregnancies (1.000; 95% CI, 0.985-1.016 vs 0.995; 95% CI, 0.948-1.044; P = 0.849). Second, PAPP-A MoM was higher in vanishing-twin pregnancies than in normal singleton pregnancies (1.000; 95% CI, 0.985-1.015), both in the group with an empty gestational sac (1.165; 95% CI, 1.080-1.256; P = 0.0001) and in that with a dead embryo (1.175; 95% CI, 1.105-1.249; P < 0.0001). Third, in vanishing-twin pregnancies with a dead embryo, PAPP-A MoM was related inversely to the interval between estimated gestational age at embryonic demise and blood sampling (P < 0.0001). Fourth, in first-trimester screening for trisomy 21 in singleton pregnancies, the estimated detection rate, at a 5% false-positive rate, was 82% in screening by a combination of maternal age and fetal nuchal translucency thickness, and this increased to 86% with the addition of serum free β-hCG and to 91% with the addition of serum PAPP-A. Fifth, similar performance of screening can be achieved in pregnancies with a vanishing twin, provided the appropriate adjustments are made to the level of PAPP-A for the interval between estimated gestational age at embryonic demise and blood sampling. First-trimester screening for trisomy in pregnancies with a vanishing twin should rely on a combination of maternal age, fetal nuchal translucency thickness and serum free β-hCG, as in singleton pregnancy, without the use of serum PAPP-A. Alternatively, PAPP-A can be included but only after appropriate adjustment for the interval between estimated gestational age at fetal demise and blood sampling. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

A new model for screening for early-onset preeclampsia

Early identification of women with an increased risk for preeclampsia is of utmost importance to minimize adverse perinatal events. Models developed until now (mainly multiparametric algorithms) are thought to be overfitted to the derivation population, which may affect their reliability when applied to other populations. Options allowing adaptation to a variety of populations are needed. The objective of the study was to assess the performance of a first-trimester multivariate Gaussian distribution model including maternal characteristics and biophysical/biochemical parameters for screening of early-onset preeclampsia (delivery <34 weeks of gestation) in a routine care low-risk setting. Early-onset preeclampsia screening was undertaken in a prospective cohort of singleton pregnancies undergoing routine first-trimester screening (8 weeks 0/7 days to 13 weeks 6/7 days of gestation), mainly using a 2-step scheme, at 2 hospitals from March 2014 to September 2017. A multivariate Gaussian distribution model including maternal characteristics (a priori risk), serum pregnancy-associated plasma protein-A and placental growth factor assessed at 8 weeks 0/7 days to 13 weeks 6/7 days and mean arterial pressure and uterine artery pulsatility index measured at 11.0-13.6 weeks was used. A total of 7908 pregnancies underwent examination, of which 6893 were included in the analysis. Incidence of global preeclampsia was 2.3% (n= 161), while of early-onset preeclampsia was 0.2% (n= 17). The combination of maternal characteristics, biophysical parameters, and placental growth factor showed the best detection rate, which was 59% for a 5% false-positive rate and 94% for a 10% false-positive rate (area under the curve, 0.96, 95% confidence interval, 0.94-0.98). The addition of placental growth factor to biophysical markers significantly improved the detection rate from 59% to 94%. The multivariate Gaussian distribution model including maternal factors, early placental growth factor determination (at 8 weeks 0/7 days to 13 weeks 6/7 days), and biophysical variables (mean arterial pressure and uterine artery pulsatility index) at 11 weeks 0/7 days to 13 weeks 6/7 days is a feasible tool for early-onset preeclampsia screening in the routine care setting. Performance of this model should be compared with predicting models based on regression analysis.

First-trimester screening for fetal growth restriction using Doppler color flow analysis of the uterine artery and serum PAPP-A levels in unselected pregnancies

Purpose To explore an early diagnostic model for fetal growth restriction (FGR) at 11–13 (+6 days) gestational weeks using Doppler analysis of the uterine artery and measurements of pregnancy-associated plasma protein-A (PAPP-A). Methods This was a prospective study which included 1796 singleton pregnant women, who received routine pregnancy examination at 11–13 (+6 days) gestational weeks in Shanghai Changning Maternity and Infant Health Hospital between 1 June 2017 and 31 July 2018. Uterine artery pulsatility index (PI), uterine resistance index (RI), and notching were recorded using the Doppler ultrasound detector (Voluson E8; GE Healthcare, Kretztechnik, Zipf, Austria). Maternal serum PAPP-A was assayed using time-resolved fluorescence immunoassay (Perkin-Elmer Life Sciences, Waltham, MA, USA) and analyzed using Fetal Medicine Foundation software. Maternal and neonatal outcomes were followed. Results Out of 1796 pregnant women aged 18–42 years, 76 (4.2%) mothers had FGR fetus. In the FGR fetuses, the mean uterine artery PI and RI were higher, the PAPP-A levels were 0.42-fold lower (all p values < .05), and notching was 40% higher (p < .0001) than in non-FGR fetuses. The sensitivity and specificity of early diagnosis of FGR and the area under the curve for the combination of uterine artery PI and PAPP-A were 0.788 (95% CI: 0.735, 0.842), 0.816, and 0.758, respectively. A combination of PAPP-A and Doppler analysis of uterine artery was better than individual measurements for predicting FGR (all p values < .05), and the specificity was significantly improved after including serum PAPP-A. Conclusion The combination of uterine artery PI and PAPP-A measured at 11–13 (+6 days) gestational weeks provides a sensitive and specific predictor for early diagnosis of FGR.

From first-trimester screening to risk stratification of evolving pre-eclampsia in second and third trimesters of pregnancy: comprehensive approach.

Preeclampsia and associated hypertensive disorders of pregnancy represent a leading cause of global maternal and neonatal morbidity and mortality. Identification of women at high risk for developing preterm-preeclampsia and prophylaxis with low-dose aspirin has the potential to significantly reduce the rate of preterm-preeclampsia. In addition, risk assessment and monitoring of women in the second and third trimester of pregnancy, to aid in early detection of evolving disease, timely referral to specialist care, and active monitoring of women with confirmed or suspected preeclampsia is essential for improving maternal and neonatal outcomes. The angiogenesis-related biomarkers sFlt-1 and PlGF have been shown to have clinical value to aid in the prediction, diagnosis, and risk stratification of preeclampsia when used either alone or in combination with other risk factors. However, currently there is no consensus on the optimum strategy to link first trimester screening for preterm-preeclampsia with appropriate second and third trimester risk assessment strategies. This opinion paper will outline the current evidence for first trimester preeclampsia screening and prevention, as well as the evidence for various risk stratification approaches for detection of evolving preeclampsia through the second and third trimesters of pregnancy, and proposes a potential model integrating these tools. This article is protected by copyright. All rights reserved.

Free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A levels – late markers of abnormal implantation and placentation. Comparison between spontaneous and IVF singleton pregnancies

Background. During the late first trimester, between 11-13 weeks of gestation, it is recommended for all pregnant women to have a screening for Down syndrome and for other chromosomal abnormalities like trisomy 13 or 18, because it estimates the potential risk and allows patients to make an informed choice about the continuation of pregnancy. The combined test analyzes three markers along with the maternal age: maternal serum beta-human chorionic gonadotropin (beta-hCG or free beta-hCG subunit), maternal serum pregnancy-associated plasma protein-A (PAPP-A) and an ultrasound measurement of nuchal translucency (NT). Objectives. To determine if there are differences regarding serum markers and pregnancy outcomes between spontaneous pregnancies and pregnancies obtained by assisted reproductive techniques (ART). Materials and method. We performed a literature review by searching MEDLINE and Cochrane databases using the keywords: beta-hCG, PAPP-A, screening, IVF, ICSI, ART, implantation. Results. Assisted reproduction techniques, such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), can alter serum markers levels and mimic the pattern associated with Down syndrome: maternal serum beta-hCG and inhibin A levels tend to be increased, while estradiol and PAPP-A levels are decreased. When comparing spontaneously conceived (SC) singleton pregnancies with in vitro fertilization/intracytoplasmic sperm injection, cohort studies confirm an increased risk of perinatal complications for the latter. The most frequent adverse outcomes are: preterm birth, intrauterine growth restriction, perinatal mortality, congenital malformations and higher risks for preeclampsia and placenta praevia. Conclusions. Overall, the risk of complications is significantly higher in ART pregnancies, but the reasons for this increase are still uncertain. The possible cause of this difference might be the increased maternal age and the particularities that occur during the implantation and placentation.

Pregnancy-associated plasma protein A as a predictor of all-cause mortality and cardiovascular events in patients with chronic kidney disease: a meta-analysis of prospective studies.

IntroductionThe aim of the study was to assess the association of elevated serum pregnancy associated plasma protein A (PAPP-A) and the risk of all-cause mortality, cardiovascular events and mortality due to infection in patients with chronic kidney disease (CKD).Material and methodsWe systematically searched the Medline database up to March 2017. A random effects model was used to pool the relative risks (RRs) and their 95% confidence intervals (CIs). Sensitivity analysis and subgroup analysis were performed to explore the potential sources of heterogeneity.ResultsSix studies involving 2034 subjects were included. The pooled RRs for the risk of all-cause mortality and cardiovascular events were 1.50 (95% CI: 1.17–1.92), 1.26 (95% CI: 0.95–1.69), respectively. Sensitivity analysis by excluding each individual study showed no influence on the main results. Subgroup analysis showed that age, male proportion, follow-up term, and assay methods were not modifiable factors.ConclusionsOur study suggests that elevated serum PAPP-A is associated with the risk of all-cause mortality in patients with CKD.

Serum Levels of Angiogenic Factors Distinguish Between Women with Preeclampsia and Normotensive Pregnant Women But Not Severity of Preeclampsia in an Obstetric Center in Turkey.

BackgroundThis study aimed to compare serum levels of vascular endothelial growth factor (VEGF) and the VEGF receptors, VEGFR-1 and VEGFR-2, free placental growth factor (fPGF), endostatin, and serum pregnancy-associated plasma protein-A (PAPP-A) levels in women with mild and severe preeclampsia and healthy pregnant women.Material/MethodsA included patients diagnosed with mild preeclampsia (n=32), severe preeclampsia (n=32), and healthy pregnant women (n=24). Serum levels of VEGF-A, VEGFR-1, VEGFR-2, fPGF, endostatin, and PAPP-A levels were measured by enzyme-linked immunosorbent assay (ELISA).ResultsIn women with mild and severe preeclampsia, the gestation age at birth and birth weight were found to be significantly lower than the control group (p<0.001). Serum levels of endostatin, VEGFR-1, and VEGF-A levels were significantly increased in pregnant women with preeclampsia compared with healthy pregnant women (p<0.001). Serum levels of PAPP-A, VEGFR-2, and fPGF were significantly higher in healthy pregnant women when compared with women with preeclampsia (p=0.024, p<0.001, and p<0.001, respectively), but there were no significant differences between women with mild and severe preeclampsia.ConclusionsReduced serum levels of the angiogenic factors PAPP-A, VEGFR-2, and fPGF distinguished between women with preeclampsia and normotensive pregnant women but did not significantly distinguish between mild and severe 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.

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.

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.