Pregnancy-associated Plasma protein-A Concentrations Research Articles

Navigating Uncertain Waters: First-Trimester Screening's Role in Identifying Neonatal Complications.

Background: Contemporary diagnostic methods aimed at assessing neonatal outcomes predominantly rely on the medical history of pregnant women. Ideally, universal biomarkers indicating an increased risk of delivering infants in poor clinical condition, with a heightened likelihood of requiring hospitalization in a Neonatal Intensive Care Unit (NICU), would be beneficial for appropriately stratifying pregnant women into a high-risk category. Our study evaluated whether biochemical and ultrasonographical markers universally used in first-trimester screenings for non-heritable chromosomal aberrations could serve this purpose. Methods: This study encompassed 1164 patients who underwent first-trimester screening, including patient history, ultrasound examinations, and biochemical tests for pregnancy-associated plasma protein-A (PAPP-A) and the free beta-HCG subunit (fbHCG), from January 2019 to December 2021. The research concentrated on the correlation between these prenatal test results and neonatal outcomes, particularly Apgar scores, umbilical blood pH levels, and the necessity for NICU admission. Results: In our cohort, neonates scoring lower than 8 on the Apgar scale at birth exhibited lower concentrations of PAPP-A in the first trimester, both in raw and normalized values (PAPP-A MoM 0.93 vs. 1.027, p = 0.032). We also observed a higher pulsatility index in the venous duct in the first trimester in full-term neonates born with <8 points on the Apgar scale. Additionally, newborns born with an umbilical blood pH < 7.2 had lower normalized first-trimester PAPP-A concentrations (0.69 vs. 1.01 MoM, p = 0.04). We also noted that neonates requiring NICU hospitalization post-delivery had lower first-trimester bHCG concentrations (0.93 MoM vs. 1.11 MoM, p = 0.03). However, none of the correlations in our study translated into a robust prognostic ability for predicting dichotomous outcomes. All areas under the curve achieved a value < 0.7. Conclusions: Low concentrations of PAPP-A and free bHCG subunit in the first trimester may be associated with poorer clinical and biochemical conditions in neonates post-delivery. However, the relationship is weak and has limited predictive capability. Further research evaluating these relationships is necessary for the appropriate stratification of pregnant women into high-risk categories for neonatological complications.

Abstract P357: Health Behaviors in Early Pregnancy Are Associated With Mid-Pregnancy Biomarkers of Placental Health and Function

Introduction: Placental blood biomarkers are dysregulated in adverse pregnancy outcomes (APO). While health behaviors are associated with APO risk, it is not well-characterized whether health behaviors impact placental blood biomarkers. Thus, we examined the associations between health behaviors and placental biomarkers of angiogenesis in mid-pregnancy. Hypothesis: Pregnant people engaging in healthier behaviors in the 1 st trimester would demonstrate more favorable 2 nd trimester concentrations of placental biomarkers. Methods: Data from 2,078 participants with available analytes from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be were included, representing an enriched sample of APO (preterm birth, preeclampsia/eclampsia, small-for-gestational age, or stillbirth; n=1,284) and 12% of those without these diagnoses (n=794). Health behaviors of physical activity, sleep, smoking, and diet assessed in the 1 st trimester were scored from 0-100 according to the Life’s Essential 8 algorithm; a higher score is more favorable. Biomarkers assayed included total endoglin, pregnancy-associated plasma protein A (PAPP-A), vascular endothelial growth factor, placental growth factor, and soluble FMS-like tyrosine 1. The association between health behaviors and each biomarker was examined using linear (continuous) or logistic (odds of concentration below multiple of the median [MoM] cut point) regression adjusted for demographics, BMI, resilience (Connor-Davidson Scale), and perceived discrimination (Krieger Racism Scale) using a backwards stepwise approach; analyses were repeated stratified by APO status. Bonferroni-corrected significance was p&lt;0.001. Results: The overall APO rate in this enriched sample was 62%; this was significantly lower in those with ≥150 min/week compared with no physical activity (58% vs 66%, p=0.04). Lower (worse) smoking score was associated with lower (adverse) PAPP-A concentration in those who developed APO (p&lt;0.001). Higher physical activity score (healthier) was associated with lower PAPP-A concentration (adverse) regardless of APO occurrence; for every 10-point higher physical activity score, odds of PAPP-A &lt; 0.3 MoM increased 10% (OR 1.10; 95% CI 1.05, 1.16). No associations were observed between the other health behaviors and biomarkers. Conclusions: Higher levels of physical activity were associated with lower APO occurrence. In contrast, PAPP-A concentrations were lower in those with higher physical activity regardless of pregnancy outcome. Lower 2 nd trimester PAPP-A was observed in those with higher smoking exposure who developed APO. Our findings support prior work demonstrating lower risk of APO with more physical activity in pregnancy, but also indicate that PAPP-A concentrations may be sensitive to physical activity and smoking. Further work to elucidate the mechanisms of these associations is warranted.

Can we improve the outcome of pregnancies with low serum PAPP-A in the first trimester?

Low birth weight is associated with various complications, and recent findings rely on the fact that micronized progesterone supplementation leads to improved birth weight, which is crucial for addressing concerns related to fetal growth. Objective This study aimed to assess the impact of micronized progesterone (VMP4) supplementation on pregnancies with low serum pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) values during first-trimester screening. Methods Out of 8933 patients evaluated, 116 pregnant women with low PAPP-A concentrations in their blood and no fetal chromosomal anomalies (CAs) were included. Three groups were formed: group 1 received VMP4 from 11 to 16 weeks (29 women, 25%), group 2 received VMP4 from 11 to 36 weeks (25 women, 21.5%), and group 3 (62 women, 53.5%) served as controls without receiving progesterone. Results Results indicated that group 3 had higher rates of complications, including miscarriages (16.37%), preterm delivery (17.8%), and fetal developmental abnormalities (19.4%). Birthweight variations were elevated in pregnancies without progesterone, contrasting with lower variations in VMP4 groups. Group 2, receiving VMP4 until 36 weeks, reported the lowest incidence of abortion and preterm birth (PB), along with the highest mean birth weight. Conclusions The conclusion suggests that 200 mg per day of VMP4 up to 36 weeks of supplementation led to fewer placental-related complications in women with very low PAPP-A at first-trimester screening (0.399 MoM). By reporting lower rates of miscarriages, PBs, and fetal developmental abnormalities in the micronized progesterone-treated groups, the study suggests a potential reduction in complications.

Correlation between PAPP-A serum levels in the first trimester of pregnancy with the occurrence of gestational diabetes, a multicenter cohort study

ObjectiveThis study aimed to investigate the association between first-trimester Pregnancy-associated plasma protein A (PAPP-A) levels and subsequent gestational diabetes mellitus (GDM) development.MethodThe study was conducted on 5854 pregnant women who attended routine prenatal care. Maternal biomarkers, including PAPP-A and free beta hCG, were measured for all women in a referral laboratory and converted to MoM values. Pregnant women were divided into two groups, based on the serum concentration of PAPP-A, (PAPP-A > 0.4 (normal) and PAPP-A < 0.4 (low)). Data on the screening test for GDM and pregnancy outcomes were collected and analyzed with appropriate tests.ResultOf the 5854 pregnant women, 889 (15.19%) developed GDM. The maternal PAPP-A MoM concentrations were significantly lower in GDM cases compared to controls. Indeed, gestational age at delivery and birth weight were significantly lower (p < 0.001) in PAPP-A MoM < 0.4, and the rate of intrauterine growth restriction (IUGR) was significantly higher (p < 0.001). ROC analysis revealed that the sensitivity and specificity of MoM concentration for predicting GDM were 53.3% and 51.9%, respectively.ConclusionLower maternal PAPP-A in early pregnancy can lead to glucose intolerance and increase the risk of subsequent GDM development. In addition, decreased serum concentration of PAPP-A is significantly correlated to lower birth weight and IUGR.

Adverse pregnancy outcome in low PAPP-A levels: First trimester screening hospital based study

To assess the adverse pregnancy outcome in Low Pregnancy Associated Plasma Protein -A (PAPP-A) levels in serum.This is a prospective cohort study, which included 2150 pregnant women who attended the antenatal clinic of Obstetrics and Gynecology in the Lok Nayak Hospital, New Delhi, India. Blood samples were collected by the venipuncture method for First trimester screening to assess free β-hCG and PAPP-A concentrations were measured by Auto DELFIA (Perkin Elmer, Turku, Finland).In this study a total of 210 women who have the low PAPP-A value less than 0.4 MoM were under the closer surveillance for serious pregnancy outcome. 33(15.6%) women had pre-eclempsia, 27 (12.9%) cases showed intra-utrine growth retardation (IUGR), 6 (3.0%) cases have intra-utrine death. 48 (22.8%) women have pregnancy induced hypertension, and 96(45.6%) cases have other pregnancy related complication. Low PAPP-A levels gives an indication of adverse pregnancy outcome in the early gestation age during the first trimester.

The STC2-PAPP-A-IGFBP4-IGF1 axis and its associations to mortality and CVD in T2D.

Physiologically, pregnancy-associated plasma protein-A (PAPP-A) serves to liberate bound IGF1 by enzymatic cleavage of IGF-binding proteins (IGFBPs), IGFBP4 in particular. Clinically, PAPP-A has been linked to cardiovascular disease (CVD). Stanniocalcin-2 (STC2) is a natural inhibitor of PAPP-A enzymatic activity, but its association with CVD is unsettled. Therefore, we examined associations between the STC2-PAPP-A-IGFBP4-IGF1 axis and all-cause mortality and CVD in patients with type 2 diabetes (T2D). We followed 1284 participants with T2D from the ADDITION trial for 5 years. Circulating concentrations of STC2, PAPP-A, total and intact IGFBP4 and IGF1 and -2 were measured at inclusion. End-points were all-cause mortality and a composite CVD event: death from CVD, myocardial infarction, stroke, revascularisation or amputation. Survival analysis was performed by Cox proportional hazards model. During follow-up, 179 subjects presented with an event. After multivariable adjustment, higher levels of STC2, PAPP-A, as well as intact and total IGFBP4, were associated with all-cause mortality; STC2: hazard ratio (HR) = 1.84 (1.09-3.12) (95% CI); P = 0.023, PAPP-A: HR = 2.81 (1.98-3.98); P < 0.001, intact IGFBP4: HR = 1.43 (1.11-1.85); P = 0.006 and total IGFBP4: HR = 3.06 (1.91-4.91); P < 0.001. Higher PAPP-A levels were also associated with CVD events: HR = 1.74 (1.16-2.62); P = 0.008, whereas lower IGF1 levels were associated with all-cause mortality: HR = 0.51 (0.34-0.76); P = 0.001. This study supports that PAPP-A promotes CVD and increases mortality. However, STC2 is also associated with mortality. Given that STC2 inhibits the enzymatic effects of PAPP-A, we speculate that STC2 either serves to counteract harmful PAPP-A actions or possesses effects independently of the PAPP-A-IGF1 axis. PAPP-A has pro-atherosclerotic effects and exerts these most likely through IGF1. IGF1 is regulated by the STC2-PAPP-A-IGFBP4-IGF1 axis, where STC2, an irreversible inhibitor of PAPP-A, has been shown to reduce the development of atherosclerotic lesions in mice. We examined the association of this axis to mortality and CVD in T2D. We demonstrated an association between PAPP-A and CVD. All components of the STC2-PAPP-A-IGFBP4-IGF1 axis were associated with mortality and it is novel that STC2 was associated with mortality in T2D. Our study supports that inhibition of PAPP-A may be a new approach to reducing mortality and CVD. Whether modification of STC2 could serve as potential intervention warrants further investigation.

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

The significance of maternal blood pregnancy-associated plasma protein A (PAPP-A) and free beta-subunit of human chorionic gonadotropin (β-hCG) levels for the risk assessment of fetal trisomy 18 during the first prenatal testing between 11 and 13+6 weeks of pregnancy.

The aim of the study was to evaluate the significance of the maternal blood level of pregnancy-associated plasma protein A (PAPP-A) and free beta-subunit of human chorionic gonadotropin (β-hCG), to estimate the risk of fetal trisomy 18 and their correlation with the assessment of nuchal translucency (NT) during the first prenatal testing. Examinations of 93 pregnant women between 11 and 13+6 weeks of pregnancy were conducted, which included determination of β-hCG and PAPP-A concentrations in the maternal serum and ultrasound assessment of fetal nuchal translucency. Concentrations of biochemical parameters were expressed as multiples of median (MoM) for the appropriate gestational age. The risk assessment of trisomy 18 was analyzed using Astraia software. Pregnant women with a high (≥ 1:300) risk of trisomy 18 were offered a genetic amniocentesis with an examination of fetal karyotype. Twenty cases were healthy and 23 with trisomy 18. PAPP-A and β-hCG MoM values < 0.3 were found in 61% cases of fetal trisomy 18. In 26% of cases, PAPP-A and β-hCG MoM values < 0.2 were NT-independent risk factors for trisomy 18. There were no significant differences between groups with normal fetal karyotype (40%) and trisomy 18 (35%) in PAPP-A and β-hCG MoM 0.2-0.5 range. Maternal free β-hCG MoM was found to change parallelly to fetal NT widening in case of trisomy 18 diagnosis. Maternal β-hCG and PAPP-A MoM results presented less then 0.2 might be used independently of NT widening in fetus for trisomy 18 risk evaluation. Above 0.2 for PAPP-A and β-hCG MoMs, fetal NT measurement was an requirment.

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.

Associations between First Trimester Maternal Nutritional Score, Early Markers of Placental Function, and Pregnancy Outcome.

This study investigated the associations between maternal adherence to a healthy diet, first trimester placental markers, and pregnancy outcome. Singleton spontaneous pregnancies were enrolled at 11+0–13+6 gestational weeks in a prospective cohort study. A nutritional score (0–10) measuring the adherence to a healthy diet was calculated. A transabdominal ultrasound scan for placental marker assessment was performed (uterine artery (UtA) doppler, placental volume). Biochemical placental markers were recorded (Pregnancy Associated Plasma Protein A (PAPP-A), free β- Human Chorionic Gonadotropin (HCG)). Birth outcomes were obtained from medical records. Associations between the maternal nutritional score, first trimester placental markers, and pregnancy outcome were investigated by using multi-adjusted general linear models. In total, 112 pregnancies were enrolled with a median nutritional score of 7 (range 3–10). Median gestational age at birth was 277 days (range 203–296). The nutritional score was positively associated with PAPP-A concentrations, whereas a negative association was detected with the UtA mean pulsatility index and placental volume. A positive association was detected between nutritional score and gestational age at birth. This study demonstrates that a first trimester nutritional score as a measure of adherence to a healthy diet is significantly associated with early biochemical and ultrasound markers of placental development, with further association with gestational age at birth.

Cut-off values for Gaussian first-trimester screening for early-onset preeclampsia with maternal history, biochemical markers and uterine artery Doppler

IntroductionSeveral algorithms for first-trimester screening for preeclampsia are available; however, the Gaussian model algorithm is more likely to match the characteristics of different populations. It is recommended to validate a screening strategy before being implemented in clinical practice; unfortunately, the validation process might not be feasible in all settings. Thus, the aim of this study was to provide cut-off values for the Gaussian model for its use in clinical practice. Material and methodsThis prospective cohort study was conducted at Vall d’Hebron University Hospital (Barcelona) from October 2015 to September 2017. A total of 2641 women with singleton pregnancies were recruited. Recorded at the first-trimester scan were demographic characteristics, maternal obstetric history, maternal history, uterine artery Doppler and arterial blood pressure. Serum concentrations of pregnancy-associated plasma protein-A and placental growth factor were assessed from the first-trimester blood test. Detection rates and cut-off values for fixed 5%, 10 %, 15 %, 20 %, 25 % and 30 % false-positive rates were calculated for all combinations of markers. ResultsNinety (3.41 %) of the 2641 women developed preeclampsia, which was early-onset in 11 (0.42 %). The cut-off values and their respective detection rates, for the screening of early-onset PE by all possible combinations of markers involved in this model, are provided. DiscussionWhen external validation of first-trimester screening for preeclampsia before its clinical implementation is not feasible, the cut-off values from the Gaussian model algorithm provided in this study could be used and median values corrected prospectively if necessary.

Health technology assessment in obstetrics: advantage of tailored conservative strategy vs surgical therapies of monochorionic twin complicated by TRAP-sequence

Introduction.Twin reversed arterial perfusion (TRAP) syndrome is one of the types of complications of monochorial twins (MT) with a frequency of occurrence of 1:35000 births. It is characterized by the presence of the main vessel instead of a normal 4 chambers heart and intrauterine developmental abnormalities. This pregnancy requires monitoring using dynamic ultrasound diagnostics every 7 days, in accordance with current recommendations. The treatment is intrauterine laser coagulation of blood vessels of the “acardial fetus” (AP) in order to prevent the development of a threatening condition for the “fetal pump” (PP). Aim: to demonstrate the possibilities of comprehensive conservative management of monochorial pregnancy complicated by TRAP.Materials and methods. An ultrasound examinations were performed on a weekly basis in monochorionic pregnancy, complicated by TRAP within the period 12-38 weeks. Serum concentrations of biochemical markers PAPP-A (pregnancy-associated plasma protein-A) and β-hGC (β-subunit of human chorionic gonadotropin) were studied in the first trimester to predict adverse perinatal outcomes.Results. The possibility of prolonging a pregnancy complicated by TRAP without performing intrauterine surgical intervention, during which quite serious complications can occur in this category of pregnancies, has been demonstrated. In a patient with monochorionic twins complicated by TRAP, totally 27 ultrasound examinations were performed within the period 12-38 weeks. This approach made it possible to dynamically monitor the condition of a pregnant and healthy fetus and to prolong pregnancy without surgery until the full term.Conclusions.Following the existing guidelines, without tailoring for individual risk, may lead to an unreasonable increase in surgical interventions. In turn, surgery is not only accompanied by a high risk of complications (up to 15%), but also constitute a certain financial burden on the budget, determined by the state on the level of 208,000 rubles. Performing routine ultrasound examinations according to the examination protocol for monochorionic pregnancy will contribute to avoiding the complications associated with surgery and better selection for surgery as well as reducing the government costs.

Sensitivity and specificity of placental proteins for gestational age screening: An exploratory study

ObjectiveTo examine the possibility that serum or urine concentrations of pregnancy-associated plasma protein A (PAPP-A), a disintegrin and metalloproteinase 12 (ADAM-12), placental growth factor (PlGF), human placental lactogen (HPL), glypican-3, pregnancy specific beta-1-glycoprotein 1 (PSG-1) or prolactin could predict gestational age (GA) >70 days, the currently recommended limit for medical abortion in the United States. Study designIn this exploratory observational study, we collected serum and urine specimens from 245 healthy individuals with singleton intrauterine pregnancies at GA <40 weeks by ultrasound. We assayed the serum specimens for all seven proteins and the urine specimens for PAPP-A and ADAM-12. We used scatterplots and receiver operating characteristic curves to identify a concentration for each protein that would differentiate GAs above and below 70 days. ResultsAll seven proteins showed significant ability to distinguish GAs >70 days from earlier gestations. A PAPP-A concentration ≥5.591 ng/ml provided 100% sensitivity and 90% specificity for identifying GAs >70 days. An ADAM-12 concentration of ≥3.11 ng/ml provided 98.5% sensitivity and 77% specificity for identifying GAs >70 days. Serum concentrations of the other compounds showed less diagnostic discrimination. PAPP-A was not detected in urine, and urinary ADAM-12 concentrations were not useful in identifying GAs above 70 days. ConclusionPAPP-A and ADAM-12 showed considerable promise as bases for a sensitive and specific serum test for identifying pregnancies with GA >70 days. If these results are confirmed by future research, such a test could obviate the need for routine ultrasound before medical abortion. ImplicationsTwo placental proteins, PAPP-A and ADAM-12, showed considerable promise as bases for a serum test for identifying pregnancies with gestational age >70 days. Such a test could be highly useful in screening patients for eligibility for medical abortion.

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 IGF system in patients with inflammatory bowel disease treated with prednisolone or infliximab: potential role of the stanniocalcin-2 / PAPP-A / IGFBP-4 axis

BackgroundPatients with inflammatory bowel disease (IBD) present with reduced serum insulin-like growth factor I (IGF-I). Anti-inflammatory treatment with prednisolone or infliximab ameliorates symptoms and increases circulating IGF-I, but prednisolone induces catabolism, whereas infliximab may promote protein synthesis. Recently, stanniocalcin-2 (STC2) was discovered as a novel inhibitor of the enzyme pregnancy-associated plasma protein-A (PAPP-A), which modulates IGF-I activity. PAPP-A can cleave IGF binding protein-4 (IGFBP-4), upon which IGF-I is liberated. We hypothesized that prednisolone and infliximab exert different effects on levels of STC2, PAPP-A, and IGFBP-4, thereby explaining the distinct metabolic effects of prednisolone and infliximab.MethodsThirty-eight patients with active IBD treated with either prednisolone (n = 17) or infliximab (n = 21) were examined before and after 7 days of treatment. Circulating levels of IGF-I, IGF-II, IGFBP-3, PAPP-A, and STC2 were measured by immunoassays. Intact IGFBP-4 and two IGFBP-4 fragments were determined by a novel immunoassay. Bioactive IGF was assessed by cell-based IGF receptor activation assay. Concentrations of IGFBP-4, PAPP-A, and STC2 on day 0 and 7 were compared to healthy control subjects.ResultsFollowing seven days of prednisolone treatment, total and bioactive IGF-I were increased (p < 0.001 and p < 0.05, respectively). Upon infliximab treatment, total IGF-I levels were augmented (p < 0.05), yet IGF bioactivity remained unaltered. Intact IGFBP-4 and the two IGFBP-4 fragments generated upon cleavage by PAPP-A were all decreased following treatment with either prednisolone or infliximab (all p < 0.05). PAPP-A levels were only increased by infliximab (p = 0.005), whereas the inhibitor STC2 did not respond to any of the treatments.ConclusionIGF-I and IGFBP-4 concentrations were markedly altered in patients with IBD and near-normalized with disease remission following treatment with prednisolone or infliximab. Thus, IGFBP-4 may modulate IGF bioavailability in IBD. The effect of immunosuppression did not appear to extend beyond the regulation of IGF and IGFBP-4, as neither PAPP-A nor STC2 were discernibly affected.Trial registrationClinicalTrials.gov: NCT00955123. Date of registration: August 7, 2009 (retrospectively registered).

The Impact of Assisted Reproduction on First Trimester Biochemical Markers in Singleton and Twin Pregnancies

The objective was to determine the effect of in vitro fertilization (IVF) on nuchal translucency, free beta-human chorionic gonadotropin (Free b-HCG) and pregnancy-associated plasma protein-A (Papp-A) measurements for singleton and twin pregnancies. This was a retrospective population-based register study that included 2921women with 11-13 weeks of gestation singleton and twin pregnancies. All patients were evaluated for the first trimester Down syndrome combined screening. We identify the effect of assisted reproductive technologies (ART) such as in vitro fertilization (IVF) on the nuchal translucency (NT), free beta-human chorionic gonadotropin (b-HCG) and pregnancy-associated plasma protein-A (PAPP-A) values. The study included 2921 patients: 2526 with spontaneous conception (86.5%) and 395 following IVF (13.5%); in our study singleton pregnancies were 2660 (91.1%), dichorionic twin pregnancies 232 (7.9%) and 12 (0.4%) monochorionic twin pregnancies. The mean b-HCG were about 56.67 IU/l (95%CI: 54.98-58.36) in singleton pregnancies and 128.08 IU/l (95%CI: 115.72-140.45) in twin pregnancies. PAPP-A mean values in singleton pregnancies were 3.54 IU/l (95%CI: 3.42-3.66) and 5.25 IU/l (95%CI: 4.46-6.08) in twin pregnancies. The results were statistically significant with p value p�01. There were also significant differences between b-HCG values in spontaneous pregnancies HCG 63.35 IU/l (95%CI: 60.14-64.10) and IVF pregnancies HCG 99.9 IU/l (95%CI: 91.8-107.99) with p value p � 0.01. In our study the IVF had no impact on nuchal translucency values. Free b-HCG levels were higher in twin pregnancies and IVF pregnancies. PAPP-A concentrations were exceeded in twin pregnancies.

Matrix Metalloproteinases and Their Tissue Inhibitors: an Evaluation of Novel Biomarkers in ANCA-Associated Vasculitis

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) may play an important role in both inflammation with subsequent fibrosis and in repair and healing in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We evaluated the circulating levels of MMPs, including pregnancy-associated plasma protein A (PAPP-A), and TIMPs in patients with AAV. PAPP-A, MMP-2, MMP-3, MMP-7, MMP-9, TIMP-1, TIMP-2 and selected parameters were measured in 100 AAV patients (36 patients with active disease and 64 patients in remission) and 34 healthy subjects. The levels of MMP-2, MMP-3, MMP-7, MMP-9, TIMP-1, TIMP-2, and PAPP-A in AAV were all found to be different to those of the controls. The MMP-7 and PAPP-A concentrations were increased in active disease in comparison to the controls (MMP-7: 13 ±.7 vs. 2 ± 0.6 ng/ml, PAPP-A: 14 ± 18 vs. 6.8 ± 2.6 ng/ml, both P &lt; 0.005). The MMP-2 and TIMP-2 levels were increased in remission when compared to the controls (MMP-2: 242 ± 50 ng/ml vs. 212 ± 26 ng /ml, TIMP-2: 82 ± 14 ng/ml vs. 68 ± 93 ng/ml) and to the active AAV (MMP-2: 242 ± 50 vs. 219 ± 54 ng/ml, TIMP-2: 82 ± 14 ng/ml vs. 73 ± 15 ng/ml, all P &lt; 0.005). MMP-3, MMP-7, TIMP-1, and PAPP-A correlated with serum creatinine. The serum levels of MMPs, TIMPs and PAPP-A are all altered in AAV. MMP-2, MMP-7 and TIMP-2 appear to be promising markers in distinguishing active AAV from remission. MMP-3, MMP-7, TIMP-1, and PAPP-A are associated with kidney function in AAV. Further studies are needed to delineate the exact roles of circulating MMPs, TIMPs and PAPP-A in patients with AAV.