Serum Pregnancy-associated Plasma protein-A Concentrations Research Articles

Low first trimester maternal serum PAPP-A concentrations in women with non-cavity-distorting intramural uterine fibroids.

Reliable aneuploidy risk estimation in first trimester is prominently interconnected with accurate assessment of maternal serum biomarkers. Some maternal factors like insulin-dependent diabetes, weight, and rhesus status are known to alter levels of these biomarkers. Adjustment of biomarker values for specific factor is crucial to avoid excessive invasive procedures or missed diagnoses. We aimed to investigate the effects of noncavity distorting intramural uterine fibroids on first trimester aneuploidy screening test maternal serum biomarkers. Pregnant women who underwent first trimester aneuploidy screening test in a single tertiary center between 2011 and 2020 were retrospectively assessed. One hundred ninety-eight women were found to have at least one noncavity distorting intramural uterine leiomyoma (Figo type 3-6) of at least 2cm diameter and remaining women were assigned as controls. First trimester aneuploidy screening test parameters were compared. Pregnancy associated plasma protein-A (PAPP-A) MoMs were found significantly lower in leiomyoma group in comparison to control group (1.19 ± 0.60 MoM vs. 1.40 ± 0.73 MoM, p=0.002). PAPP-A MoMs in women with leiomyomas larger than 5.5cm were significantly lower in comparison to both control group and women with ≤5.5cm leiomyomas (0.82 ± 0.376 vs. 1.40 ± 0.73, p < 0.001; 0.82 ± 0.376 vs. 1.33 ± 0.61 p < 0.001, respectively). PAPP-A MoM and size of leiomyoma were found inversely correlated when fibroid size exceeds 5.5cm (r=-0.467, p < 0.001). Noncavity distorting intramural uterine leiomyomas >5.5cm are associated with low first trimester PAPP-A MoMs (<0.5). PAPP-A concentrations are inversely correlated with fibroid size in women with >5.5cm intramural uterine leiomyomas. Fibroids ≤5.5cm are not associated with alterations in first trimester aneuploidy screening test parameters.

Maternal serum pregnancy-associated plasma protein-A concentration at 11–14 weeks of gestation and preeclampsia risk of women with common congenital anatomic uterine abnormalities

To evaluate maternal serum pregnancy-associated plasma protein-A (PAPP-A) levels at 11–14 weeks of gestation and preeclampsia risk in women with common congenital anatomic uterine abnormalities (AUAs). First trimester screening markers were compared between 12 AUA pregnancies, 60 age matched controls and 12 cases of early preeclampsia. PAPP-A level and birth weight were significantly lower in AUA compared to control and early preeclampsia group (p<.001). Preeclampsia was absent in the AUAs pregnancies group. Birth weight were similar in AUA group when we compared AUA and control group regarding weeks of gestation at delivery and lower but not significantly, when we compared AUA and early preeclampsia group. Our findings suggest that AUA pregnancies are associated with low first trimester maternal serum PAPP-A concentrations not predictive of susceptibility to preeclampsia. Impact statement What is already known on this subject? During first trimester screening for preeclampsia based on maternal pregnancy-associated plasma protein A (PAPP-A) levels, various parameters are used, such as the somatometric characteristics of pregnant woman, single or multiple pregnancy, smoking status, family history, diabetes, hypertension and measurement of blood pressure and uterine artery Dopplers. What do the results of this study add? Our pioneer study revealed that there is drastic difference in PAPP-A concentration in women with common anatomic uterine abnormalities (AUAs), in comparison with their age matched control women with normal uterus. What are the implications of these findings for clinical practice and further research? Based on our results, uterine anatomical deviations, is another factor which must be taken in account for preeclampsia risk calculation and further clinical consultation and follow up in those pregnancies. Lower PAPP-A levels in AUA cases is a weak predictor of susceptibility to preeclampsia and could be associated to smaller placental size rather than poor placentation and in future research the calculation of the uterine cavity functional dimension may lead to a more accurate clinical assessment.

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.

Maternal serum pregnancy-associated plasma protein-A concentration at 11–14 weeks of gestation of women with common congenital anatomic uterine abnormalities

Maternal serum pregnancy-associated plasma protein-A concentration at 11–14 weeks of gestation of women with common congenital anatomic uterine abnormalities

Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer

Pregnancy-associated plasma protein-A (PAPP-A) and its homolog PAPP-A2 are enzymes that modulate the availability and mitogenic activity of insulin-like growth factor-I (IGF-I). PAPP-A has been implicated in numerous cancers but reports on PAPP-A2 in malignancy are non-existent. In a prospective observational study of 689 patients under suspicion of lung cancer, we examined levels of PAPP-A and PAPP-A2 and their relationship with mortality. Serum PAPP-A and PAPP-A2 concentrations were determined in pre-diagnostic blood samples using ELISA, and immunohistochemical staining of PAPP-A and PAPP-A2 was performed in malignant tissue from five operable patients. A total of 144 patients were diagnosed with lung cancer, whereas the diagnosis was rejected in 545 subjects, who served as a control group. PAPP-A2 concentrations were higher in patients with lung cancer [median (IQR): 0.33 (0.21–0.56) ng/mL] than in controls [0.27 (0.17–0.39) ng/mL], p < 0.001, whereas PAPP-A levels did not differ. Presence of PAPP-A and PAPP-A2 were confirmed in tumor specimens, and staining occurred in a heterogeneous pattern. Patients were observed for a median (range) of 7 (6; 8) years, during which 114 patients (79.2%) died. Patient mortality differed according to PAPP-A2 tertile (p < 0.001). PAPP-A2 was associated with mortality with an unadjusted hazard ratio (95% CI) per doubling in protein concentration of 1.30 (1.12; 1.53), p = 0.001. In a multivariable model adjusted for age, sex, and BMI, PAPP-A2 remained predictive of the endpoint with a hazard ratio per doubling in protein concentration of 1.25 (1.05; 1.48), p = 0.013. Collectively, PAPP-A2, but not PAPP-A, is elevated in patients with lung cancer and associated with mortality. This novel role of PAPP-A2 in cancer warrants further functional studies as well as validation in external cohorts.

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.

First-Trimester Uterine Artery Pulsatility Index and Maternal Serum PAPP-A and PlGF in Prediction of Preeclampsia in Primigravida.

Preeclampsia is a heterogeneous disorder affecting different body systems and frequently associated with morbidity and mortality. Early preeclampsia prediction will reduce this associated morbidity and mortality as it will give the chance for frequent maternal and fetal surveillance and application of prophylactic procedures. The aim of this work is to evaluate the role of mean pulsatility index (PI) of the uterine arteries and maternal serum concentrations of pregnancy-associated plasma protein A (PAPP-A) and placental growth factor (PlGF) in early preeclampsia prediction in primigravida. Three hundred primigravida attending the antenatal care clinic in Zagazig University Hospitals were included in the study. The mean PI of the uterine arteries was calculated. Maternal serum levels of PAPP-A and PIGF were analyzed by specific immunoassay. Three hundred women were included in the final analysis, of them 30 patients (10%) suffered from preeclampsia. There was a significant difference between preeclamptic and normal women as regards the mean PI of the uterine arteries and levels of PAPP-A and PIGF at 11-13weeks. When combining the cutoff levels of the three methods, mean PI of the uterine arteries ≥1.69, PAPP-A assay <0.96 multiple of median (MoM) and PlGF assay <0.91 MoM, the sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy were 56.7, 99.3, 89.5, 95.4 and 67%, respectively. The combined measurement of maternal serum PAPP-A and PlGF concentrations and mean PI of the uterine arteries at 11-13weeks of pregnancy may help to predict preeclampsia in primigravida when other parameters of preeclampsia prediction are normal. However, we need more studies on larger and variable populations to evaluate the use of those combined methods in preeclampsia prediction.

Pregnancy-associated plasma protein-A (PAPP-A) and the proform of the eosinophil major basic protein (ProMBP) are associated with increased risk of death in heart failure patients

Risk stratification and patient management in heart failure (HF) is difficult due to the unpredictable progression of the disease, necessitating the development of reliable diagnostic biomarkers to facilitate decision-making in clinical practice. Pregnancy-associated plasma protein-A (PAPP-A) is a marker of arteriosclerotic heart disease. PAPP-A is a serum protease, which is involved in the insulin-like growth factor 1 (IGF-1) axis where it is inhibited by the proform of the eosinophil major basic protein (proMBP). In this study, we evaluated serum PAPP-A and proMBP as long-term prognostic biomarkers of all-cause mortality in HF. Serum PAPP-A and proMBP concentrations were determined in 683 patients with NYHA III–IV HF recruited in the EchoCardiography and Heart Study (ECHOS) in Denmark. The mean age of the patients (73% male) was 70 at admission. During 7 years of follow-up, 516 patients died. In univariate analysis, both PAPP-A and proMBP, divided into quartiles, showed significant association with mortality. Using a Cox proportional hazard model, hazard ratios for continuous values of PAPP-A and proMBP were HR = 1.42 (CI = 1.23–1.64, p < 0.0001) and HR = 1.36 (CI = 1.22–1.51, p <0.0001), respectively. However, neither PAPP-A nor proMBP were significant independent predictors when the model included age, gender, brain-type natriuretic peptide, medical history of HF, ischemic heart disease, chronic obstructive pulmonary disease, and diabetes mellitus. In conclusion, high levels of PAPP-A and proMBP are associated with increased risk of death from all causes in HF and are potential prognostic markers of adverse outcomes in HF patients.

Predictive value of serum pregnancy-associated plasma protein A for patients with ischemic cerebrovascular disease.

To investigate the role of pregnancy-associated plasma protein A (PAPP-A) in the outcome of ischemic cerebrovascular disease. We analyzed the levels of PAPP-A in the transient ischemic attack (TIA) patients, ischemic stroke (IS) patients and normal control, and followed up the outcome of the patients in the following 2years. Blood samples were drawn at admission, prior to treatment with heparins. The levels of PAPP-A in TIA patients, IS patients and normal control were 4.91 (2.11, 6.48) mIU/L, 6.77 (3.31, 10.23) mIU/L and 4.25 (1.76, 5.22) mIU/L, respectively. The follow-up results of TIA patients and IS patients indicated the PAPP-A concentration in the poor prognosis group were higher than those in the good prognosis group (5.90 vs 4.46mIU/L, P<.05, 10.06 vs 5.12mIU/L, P<.05, respectively). Serum PAPP-A concentration emerged as a predictor of risk stratification with an OR of 1.41 and 1.25 (P<.05, P<.05). Higher PAPP-A concentration has a forecasting value on prognosis in ischemic cerebrovascular disease.

Does Endometriosis Affect PAPP-A Concentration in First Trimester Fetal Screening Test?

Objective Pregnancy-associated plasma protein A (PAPP-A) is a macromolecular glycoprotein. The peritoneal fluid of women affected by endometriosis shows a significant increase of PAPP-A levels. Given the important role of PAPP-A in first trimester screening test, we wondered if its presence in the peritoneal fluid of women with endometriosis could affect biochemical parameters of the test performed during pregnancy. Methods A prospective study enrolled 78 women with singleton pregnancy who performed combined test between 11 + 0 and 13 + 6 weeks of gestation: 25 women with previous histological diagnosis of endometriosis and 53 women without. All patients were sampled to determine PAPP-A concentrations. Serum levels of PAPP-A were expressed in UI/L and in MoM (multiples of median). The two groups – endometriosis women and non-endometriosis women – were compared in order to find a possible different concentration of serum PAPP-A. Results We found an increased concentration of both PAPP-A UI/L and PAPP-A MoM in deep endometriosis patients versus ovarian endometriosis with significant difference in PAPP-A MoM (p = 0.018). We also found a significant association between the stage of the disease and PAPP-A UI/L and MoM levels (PAPP-A UI/L p = 0.05, PAPP-A MoM p = 0.01). Conclusions Women with deep endometriosis show increased serum PAPP-A concentrations compared to women with ovarian endometriosis. Likewise, women with moderate or severe stage of the disease show increased serum PAPP-A concentrations compared to women with minimum or mild disease. This increase could affect first trimester aneuploidy screening test and endometriosis could represent a confounding factor in the calculation of aneuploidy risk.

P05.03: Ischemia modified albumin in pregnancy

In normal pregnancies, a hypoxic intrauterine environment seems necessary for the early trophoblast development. In this context, mother's serum levels of ischemia modified albumin (IMA) are elevated reflecting the oxidative stress associated with placental development. The aim of this study is to evaluate serum levels of IMA and pregnancy associated plasma protein-A (PAPP-A) in mothers bearing small-for-gestational age (SGA) fetuses compared to normal pregnancies. A prospective study was performed between June 2013 and May 2014. Serum total albumin, IMA and PAPP-A concentrations were determined in 81 pregnant women in 3 different periods: 1st trimester, 2nd trimester and in the postpartum. Two groups of subjects were identified: group 1) mothers bearing appropriate-for-gestational-age fetuses (AGA) and group 2) mothers bearing SGA fetuses. Serum total albumin and IMA concentrations were determined in 198 non-pregnant women as controls. Serum IMA concentrations increase during the gestation. IMA/Albumin serum levels in the 1st trimester were significantly higher in subjects of group 2 (p < 0.05), whereas values of serum PAPP-A MoM were significantly lower (p < 0.05). Elevated IMA serum levels together with low levels of PAPP-A were detected in the 1st trimester in mothers bearing SGA fetuses and that may reflect early placental changes occurring before clinical manifestation of SGA.

First-Trimester Risk Factors for Preeclampsia Development in Women Initiating Aspirin by 16 Weeks of Gestation

The residual risk of preeclampsia in high-risk women on aspirin prophylaxis exceeds that of low-risk populations, and this study aimed to identify first-trimester maternal characteristics associated with aspirin prophylaxis failure. This is a nested cohort study of prospectively enrolled women with verified initiation of risk-indicated aspirin prophylaxis by 16 weeks of gestation. First-trimester maternal history, demographics, anthropometry, ultrasound parameters, and serum analytes were compared between women who developed preeclampsia and those who did not. Blood pressure measurements were classified as prehypertension or hypertension according to the Joint National Committee on Hypertension guidelines. Chi square, nonparametric, and logistic regression analyses were used to determine the contributors to preeclampsia development. Six hundred fourteen women prospectively enrolled at 9-14 weeks of gestation initiated aspirin by 16 weeks of gestation. The 59 (9.6%) women who developed preeclampsia were more likely to have chronic hypertension, diabetes, and obesity and had higher first-trimester blood pressure and lower serum pregnancy-associated plasma protein-A concentrations (all P<.05). Having first-trimester Joint National Committee on Hypertension prehypertension or hypertension was associated with a 2.18-fold increased risk of developing preeclampsia, whereas normotension was associated with a reduction of risk of 56%. Women who develop preeclampsia while taking aspirin prophylaxis are more likely to have elevated first-trimester blood pressures. Conversely, first-trimester normotension is associated with a reduced risk of preeclampsia.

Association of E-Selectin Gene Polymorphism and Serum PAPP-A with Carotid Atherosclerosis in End-Stage Renal Disease

Atherosclerotic vascular disease represents a significant cause of morbidity and mortality in patients with end-stage renal disease (ESRD). The endothelium plays a crucial role in vascular inflammation. E-selectin is exclusively expressed on activated endothelial cells and is upregulated following an inflammatory response and oxidative stress, while serum pregnancy-associated plasma protein-A (PAPP-A) concentrations are related to the presence and stability of carotid atherosclerotic plaques. The aim of this study was to investigate whether there is an association between SELE rs5355C>T gene polymorphism, serum PAPP-A level and the presence of carotid atherosclerosis in ESRD patients. Seventy subjects were recruited into this study; 40 ESRD patients [age (mean±SD) 43.42±13.94years] and 30 age- and gender-matched healthy individuals assigned to the control group. Polymerase chain reaction-restriction fragment length polymorphism was performed for the analysis of SELE rs5355C>T gene polymorphism, while serum PAPP-A concentrations were measured using electro-chemiluminescence immunoassay. Routine laboratory tests were measured on an automated chemistry analyzer. Carotid ultrasonographic studies were performed by a bilateral high-resolution B-mode ultrasound. There was no significant relationship between the SELE rs5355C>T gene polymorphism and ESRD incidence. Serum PAPP-A levels were significantly higher in ESRD patients compared with controls [median (interquartile range) 5.8 (5.1-11.6) and 5.1 (4.1-6.7), respectively; p=0.005]. Serum PAPP-A correlated positively with urea, creatinine, systolic and diastolic blood pressure (DBP). Serum PAPP-A showed a statistically significant increase in SELE rs5355TT versus CC in both patients and controls. There was no association on comparing right intima-media thickness (IMT), left IMT, right cross-sectional area (CSA) and left CSA with the CC, CT and TT genotypes of SELE rs5355C>T. No correlation between serum PAPP-A with each of the above-mentioned carotid doppler findings was observed. There was a statistically significant increase in DBP in TT genotype carriers when compared with CC genotype carriers (p=0.009). Serum PAPP-A levels were higher in hypertensive ESRD patients when compared with normotensive ESRD patients. There was a statistically significant decrease in high-density lipoprotein cholesterol (HDL-C) in TT genotype carriers when compared with CT genotype carriers in the whole study group (p=0.003). Serum PAPP-A correlated negatively with HDL-C. The lack of a direct association between SELE rs5355C>T gene polymorphism, serum PAPP-A level and IMT suggests that their hypothesized association with carotid atherosclerosis might reflect an indirect mechanism of SELE rs5355C>T gene polymorphism and serum PAPP-A with cardiovascular risk factors such as blood pressure and HDL-C rather than a direct effect on the vasculature.

Ischemia-modified albumin in pregnancy

ObjectiveIn normal pregnancies, a hypoxic intrauterine environment seems necessary for early trophoblast development. In this context, maternal serum levels of ischemia-modified albumin (IMA) are elevated, reflecting the oxidative stress associated with placental development. The aim of this study was to evaluate IMA and pregnancy-associated plasma protein A (PAPP-A) in mothers bearing small-for-gestational-age (SGA) fetuses compared to normal pregnancies. Study designA prospective study was performed between June 2010 and June 2011. Serum total albumin, IMA and PAPP-A concentrations were determined in 81 pregnant women in three different periods: 1st trimester, 2nd trimester and postpartum. Two groups of subjects were retrospectively identified: Group (1) mothers bearing appropriate-for-gestational-age (AGA) fetuses, and Group (2) mothers bearing SGA fetuses. Serum total albumin and IMA concentrations were determined in 198 non-pregnant women as controls. ResultsSerum IMA concentrations increase during gestation. IMA/albumin serum levels in the 1st trimester were significantly higher in subjects of Group (2) (p<0.05), whereas values of serum PAPP-A MoM were significantly lower (p<0.05). ConclusionsElevated IMA serum levels together with low levels of PAPP-A were detected in the 1st trimester in mothers bearing SGA fetuses, and this may reflect early placental changes occurring before clinical manifestation of SGA.

Elevated pregnancy-associated plasma protein A predicts myocardial dysfunction and death in severe sepsis

Pregnancy-associated plasma protein A (PAPPA) is an emerging biomarker used in various medical fields but has yet to be evaluated in critical care medicine. This study evaluates the value of PAPPA as a biomarker in predicting myocardial dysfunction and 28-day mortality in patients with severe sepsis. Serum concentrations of PAPPA and traditional cardiac biomarkers including cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP) were measured on admission in 118 severely septic patients. The value of PAPPA for the diagnosis of sepsis-related myocardial dysfunction (SRMD) and for the prediction of 28-day mortality was subsequently evaluated using statistical methods. PAPPA was elevated (≥4.5 ng/mL) in 76 (64.4%) patients; patients with elevated PAPPA were more likely to have SRMD (76.3% vs. 38.1%, P < 0.001). By comparison of the area under the curve (AUC) in receiver operating characteristics analysis, PAPPA had comparable value (AUC 0.661, P = 0.003) to conventional biomarkers (BNP: AUC 0.699, P < 0.001; cTnI: AUC 0.647, P = 0.007) in the diagnosis of SRMD and offered superior value (AUC 0.771, P < 0.001) over them (all AUC<0.7, P > 0.05) in the prediction of 28-day death. Increased PAPPA (≥5.4 ng/mL) was associated with lower 28-day survival (χ(2) = 19.78, P < 0.001) and independently predicted 28-day mortality in septic patients. Serum PAPPA concentration frequently increases in patients with severe sepsis and appears to be associated with SRMD. PAPPA can be used as a novel biomarker for the diagnosis of SRMD and the prediction of outcomes in critically ill patients.

Temporal effects of maternal and pregnancy characteristics on serum pregnancy‐associated plasma protein‐A and free β‐human chorionic gonadotropin at 7–14 weeks' gestation

The aim of this study was to investigate gestational age-dependent effects of racial origin, smoking status and mode of conception on maternal serum levels of free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 7-14 weeks' gestation. This was an analysis of data from prospective first-trimester combined screening for aneuploidies in singleton pregnancies, with β-hCG and PAPP-A measured at 7 + 1 to 14 + 3 weeks' gestation. We included 27,908 pregnancies from three centers in the U.K. and 125,461 pregnancies from 22 centers in Denmark, all with known normal fetal karyotype or resulting in the birth of a phenotypically normal neonate. Multiple regression modelling of log10 -transformed marker concentrations was used to produce log10 multiple of the median (MoM) values for free β-hCG and PAPP-A and to examine pregnancy characteristics that have significant effects on marker concentrations. Serum free β-hCG and PAPP-A concentrations were significantly affected by gestational age, maternal weight, racial origin, parity, smoking and mode of conception. There were significant gestational age-dependent effects attributed to Afro-Caribbean race, smoking and conception through in-vitro fertilization (IVF) on PAPP-A and free β-hCG levels. In women of Afro-Caribbean race there was a weekly increase in PAPP-A of 5.3% and in free β-hCG of 1.8%. In smokers there was a weekly decrease in PAPP-A of 2.4% and in free β-hCG of 1.6%. In cases of IVF conceptions there was a weekly increase in PAPP-A of 4.5% and in free β-hCG of 4.6%. Serum free β-hCG and PAPP-A concentrations at 7-14 weeks' gestation are affected by several pregnancy characteristics. The effects of Afro-Caribbean race, smoking and IVF conception change with gestational age.

Reference interval of pregnancy-associated plasma protein-A in healthy men and non-pregnant women

ObjectiveThe serum pregnancy-associated plasma protein-A (PAPP-A) concentration is a predictor of ischemic cardiac events and renal impairment. However, the reference interval of PAPP-A has not been determined. This study determined the reference interval of PAPP-A in men and non-pregnant women. MethodsThe study enrolled 126 apparently healthy individuals (52 males and 74 females). The mean age of the men and women was 34.7 (range 20–66) years and 34.6 (range 18–65) years, respectively. Serum PAPP-A concentrations were determined using an ultrasensitive enzyme-linked immunoassay kit. Reference intervals were calculated using the bootstrap method. ResultsThe results for three subjects were outliers, so the reference interval of PAPP-A was calculated using the data for 123 subjects. PAPP-A was undetectable in 26 subjects. The reference interval of PAPP-A for men and women (with the 90% confidence interval) was <22.9ng/mL (19.7–23.3) and <33.6ng/mL (25.2–36.7), respectively. In male subjects, serum PAPP-A levels of smokers [3.10 (UD, 7.30)ng/mL] were significantly lower than that of non-smokers [11.00 (UD, 24.4)ng/mL] (p<0.001) and there was a positive correlation between serum PAPP-A levels and subjects’ age (r=0.439; p<0.001). ConclusionsThe reference interval of PAPP-A differed for men and non-pregnant women. In clinical practice, <22.9ng/mL for men and <33.6ng/mL for non-pregnant women may be used as reference intervals for PAPP-A.

Diagnostic Accuracy of Maternal Serum Macrophage Inhibitory Cytokine-1 and Pregnancy-Associated Plasma Protein-A at 6–10 Weeks of Gestation to Predict Miscarriage

To determine whether serum macrophage inhibitory cytokine-1, pregnancy-associated plasma protein-A (PAPP-A), anandamide, or β-human chorionic gonadotropin (hCG) measured in an asymptomatic population in the middle of the first trimester with a viable fetus predicts subsequent miscarriage. We undertook a prospective cohort study at Mercy Hospital for Women between 2004 and 2008. Participants (N=782) were recruited from prenatal clinics, where samples were taken from asymptomatic women at 6 0/7 to 10 6/7 weeks of gestation. We collected samples from only those women for whom we were able to obtain ultrasound evidence of a singleton with fetal cardiac activity. Serum macrophage inhibitory cytokine-1, PAPP-A, anandamide, and β-hCG concentrations were assayed. Twenty-one (2.7%) miscarried and 761 did not. Among those who miscarried, macrophage inhibitory cytokine-1 and PAPP-A were significantly decreased at 63% (multiples of the median (MOM) 0.63, 25th-75th percentiles 0.33-0.88) and 23% (MOM 0.23, 25th-75th percentiles 0.12-0.48) of levels seen among those with ongoing pregnancies (P<.001 for both comparisons). In contrast, neither serum β-hCG (MOM 0.99, 25th-75th percentiles 0.46-1.86) nor anandamide (MOM 1.07, 25th-75th percentiles 0.87-1.19) was elevated or decreased among those who miscarried compared with those with ongoing pregnancies. At a fixed 10% false-positive rate (90% specificity), a test combining macrophage inhibitory cytokine-1 and PAPP-A yielded 63% sensitivity and a 6.6 positive likelihood ratio in predicting miscarriage. Low serum levels of macrophage inhibitory cytokine-1 and PAPP-A measured from asymptomatic women at 6-10 weeks of gestation with viable pregnancies can predict subsequent miscarriage. These analytes are likely to have an important biological role in early pregnancy and are likely to be useful clinical biomarkers for miscarriage and other early pregnancy complications. II.

La pregnancy-associated plasma protein A (PAPP-A)

Summary Pregnancy-associated plasma protein A (PAPP-A), metalloglycoprotein isolated from pregnancy serum, has been also found in different cell systems (vascular cells of smooth muscle, osteoblasts…). Two forms exist: a high-molecular-weight heterotetrameric complex particularly during pregnancy, and an active free form. PAPP-A has been found to proteolytically cleave insulin-like growth factor (IGFBP-4). Automated techniques have been developed particularly for use in prenatal Down's syndrome (DS) screening. Serum PAPP-A concentrations increase during pregnancy, and decreased PAPP-A values have been found to be associated with fetal DS. It is used, in association with free βhCG and measurement of nuchal translucency, in first trimester DS screening. PAPP-A has also been used as a marker of aneuploidies or preeclampsia and predictor of adverse outcome. Moreover, PAPP-A has been described as a marker of instability of atherosclerotic plaque activity and might predict complications in cardiology. But this application requires more sensitive tests in comparison with prenatal diagnosis.

The significance of fetal maxillary length in the first trimester screening for trisomy 21

The present study aims to specify the significance of fetal maxillary length by establishing a nomogram for a Turkish population and by investigating its relationship with the ultrasonographic and biochemical parameters which are commonly used to screen trisomy 21 in the first trimester of pregnancy. The present observational study investigates 1,308 Turkish women who had 11- to 14-week-old singleton healthy pregnancies. Fetal crown-rump length (CRL), nuchal translucency (NT), nasal bone length (NBL) and maxillary length are measured by ultrasonography and maternal serum concentrations of pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (HCG) are determined. A positive and significant correlation was detected between the fetal maxillary length and gestational age (r = 0.309, P < 0.001) as was the case with fetal CRL (r = 0.357, P < 0.001) and NBL (r = 0.487, P < 0.001). Although there was a significant and positive correlation between fetal maxillary length and maternal serum PAPP-A levels (r = 0.201, P < 0.001), a significant and negative correlation was found between fetal maxillary length and the maternal serum concentrations of free beta-HCG (r = -0.238, P < 0.001). Fetal maxillary length increased in accordance with the advancing gestational age and increasing CRL. Maternal serum PAPP-A concentrations and fetal CRL and NBL were addressed as independent predictors of fetal maxillary length. The length of fetal maxillary bone is a promising biometrical parameter which can be reliably and efficiently used to screen trisomy 21 in first trimester. Fetal maxillary length is also found to correlate with gestational age, CRL, NBL and PAPP-A significantly. It would be rational to use a combination of nasal and maxillary bone length measurements in case serum concentrations of PAPP-A or beta-HCG cannot be assessed.