Pregnancy-associated Plasma Protein Research Articles

Сучасні погляди на етіологію, патогенез і клінічний перебіг спонтанних передчасних пологів, тактику ведення та профілактику ускладнень (огляд літератури)

A review of medical literature regarding modern views on premature birth, the main issues of etiology and pathogenesis of this pathology, diagnostic signs, clinical features of the course, management tactics and perinatal consequences, investigated prognostic markers. A review of the medical literature regarding modern views on premature birth, the main issues of etiology and pathogenesis of this pathology, diagnostic signs, clinical features of the course, management tactics and perinatal consequences, investigated prognostic markers is provided. Despite the active and relentless development of medical science, the issue of premature births and their impact on short- and long-term consequences for mothers and children remains an urgent issue. Purpose - to highlight the scientists’ understanding of the etiology, pathogenesis, clinical management of premature birth, as well as to examine the available data on promising tocolytic drugs and methods of predicting premature birth. Among the tocolytic drugs currently undergoing clinical trials, the following groups are distinguished - broad-spectrum chemokine inhibitors, prostaglandin F2α-receptor target drugs, interleukin 1 receptor antagonists, and nanoparticle platforms. If the research is successful, obstetricians and gynecologists may have a targeted drug for the treatment of preterm labor with a better safety profile than the range of drugs we have today. Research into new laboratory prognostic markers of preterm birth, such as pregnancy-associated plasma protein A, human chorionic gonadotropin, alpha-fetoprotein, estriol, ferritin, ceruloplasmin, alkaline phosphatase, hematological markers, is also ongoing. The implementation of the above prognostic markers in clinical medicine will allow obtaining new opportunities in the early prediction of premature birth. Sonographic approaches to predicting premature birth are being updated. In addition to the measurement of the length of the cervix, the measurement of the uterine-cervical angle and the use of cervical elastography are used. Modern scientific achievements will allow doctors in the future at earlier stages of pregnancy to predict the possibility of premature birth and more effectively treat premature birth that has begun. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

A-331 Prenatal Maternal First Trimester Screening and Establishing the Multiple of Medians of Double Marker Tests in Tertiary Care Hospital in India

Abstract Background Down's syndrome, Edwards syndrome, and Patau syndrome (trisomy 21, 18, 13 respectively) in a fetus can be screened by prenatal testing using the maternal serum. Prenatal testing can provide an accurate assessment of the patient's risk of carrying an affected fetus. Double marker testing which includes the levels of free β- Human Chorionic Gonadotropin and Pregnancy Associated Plasma Protein A in the maternal serum along with the measurement of Crown Rump Length and Nuchal Translucency helps in determining the risk of Trisomy 21. Prenatal testing prevents the need for invasive methods. Methods This is a study conducted in Kokilaben Dhirubhai Ambani Hospital and Research Centre, Mumbai, Maharashtra, India from January 2012 to December 2018 for 628 pregnant women. The data for 1st trimester was divided into 3 groups: 11 to 11.6 weeks(86 patients), 12 to 12.6 weeks (421 patients), and 13 to 13.6 weeks (121 patients) based on their gestational age. This study included the determination of levels of double markers like free β- Human Chorionic Gonadotropin and Pregnancy Associated Plasma Protein A using maternal serum along with the ultrasound studies which included the Crown Rump Length and Nuchal Translucency measurements. Additional factors like a history of chromosomal abnormalities, smoking habits, insulin-dependent diabetes, and other dichotomous markers like the presence of nasal bone, abnormal ductal flow, and tricuspid regurgitation are also considered in calculating the risk. The concentration of biochemical parameters was expressed in Multiple of Median (MOM) with respect to maternal age. The risk assessment was analyzed using SSDW 5 and SSDW 6 software and the cut-off was set at 1:250 for age as well as trisomy 21, 18, and 13. Results The total number of positive patients for trisomy 21 and trisomy 13/18 were represented in percentage which turned out to be 2.86% and 1.11% respectively in association with the gestational age, dichotomous markers, double marker test, and ultrasound studies. The MOM for β-HCG, PAPPA, and NT were compared in SSDW5 and SSDW6. The mean β-HCG MOM negative and positive patients (trisomy 21) were found to be 1.34 ± 0.945 and 2.74 ± 1.685 respectively indicating the levels increase above normal. The mean PAPPA MOM negative and positive patients (trisomy 21) were found to be 1.47 ± 0.9125 and 0.77 ± 7667 respectively indicating the levels decrease below the normal. The NT mom for negative and positive patients was 0.91 ± 1879 and 1.88 ± 1.6508 respectively which suggests that the thickness of nuchal translucency increases with the increased risk for trisomy 21. Conclusion 18 out of 628 patients tested positive for trisomy 21 which was assessed using double marker testing and ultrasound studies. The levels of free β-HCG were seen to be increased and the levels of PAPPA were decreased in the patients who showed higher risks. Prenatal testing provides an advantage for early detection of this disorder.

Myocardial infarction and pregnancy

The article presents an analysis of circulatory disorders in the coronary vessels during pregnancy, childbirth, and the postpartum period. In recent years, there has been a tendency towards an increase in the level of maternal mortality associated with cardiovascular diseases. There has been a rise in the incidence of myocardial infarction and acute coronary syndrome both during pregnancy and childbirth. These indicators are associated with physiological changes in the main parameters of hemodynamics and the hemostatic system at different stages of gestation, which often provokes or complicates the development of coronary heart disease. The main pathogenetic mechanisms responsible for the development of cardiac catastrophe, such as atherosclerosis, spontaneous dissection of the coronary arteries, coronary thrombosis, and vasospasm, are considered. Particular attention is paid to the characteristic features of the clinical picture and the importance of modern diagnostic methods in establishing an accurate diagnosis, including determining the level of troponin, pregnancy-associated plasma protein A, transthoracic and transesophageal echocardiography, and coronary angiography. The basic principles of managing pregnancy with coronary heart disease at different stages have been determined, including the choice of delivery method and management in the postpartum period. The issues of pharmacological therapy are considered, taking into account the possible negative impact on the health of the mother and fetus.

Role of First Trimester Screening Biochemical Markers to Predict Hypertensive Pregnancy Disorders and SGA Neonates-A Narrative Review.

Early recognition of high-risk pregnancies through biochemical markers may promote antenatal surveillance, resulting in improved pregnancy outcomes. The goal of this study is to evaluate the possibilities of using biochemical markers during the first trimester of pregnancy in the prediction of hypertensive pregnancy disorders (HPD) and the delivery of small-for-gestational-age (SGA) neonates. A comprehensive search was conducted on key databases, including PubMed, Scopus, and Web of Science, for articles relating to the use of biochemical markers in the prediction of HPD and SGA. The findings show that changes in the levels of biomarkers in the early pregnancy phases could be an important indicator of adverse pregnancy outcomes. The literature shows that low PAPP-A (pregnancy-associated plasma protein A) and PlGF (placental growth factor) levels, low alkaline phosphatase (AP), higher sFlt-1 (soluble fms-like Tyrosine Kinase-1) levels, higher AFP (alfa fetoprotein) levels, and elevated levels of inflammatory markers such as β-HGC (free beta human chorionic gonadotropin), interferon-gamma (INF-γ), and tumor necrosis factor-α (TNF-α) may be associated with risks including the onset of HPD, fetal growth restriction (FGR), and delivery of SGA neonates. Comparatively, PAPP-A and PlGF appear to be the most important biochemical markers for the prediction of SGA and HPD.

Screening for Preeclampsia and Fetal Growth Restriction in the First Trimester in Women without Chronic Hypertension.

Nowadays, it is possible to identify a group at increased risk of preeclampsia (PE) and fetal growth restriction (FGR) using the principles of the Fetal Medicine Foundation (FMF). It has been established for several years that acetylsalicylic acid (ASA) reduces the incidence of PE and FGR in high-risk populations. This study aimed to evaluate the implementation of ASA use after the first-trimester screening in a Polish population without chronic hypertension, as well as its impact on perinatal complications. A total of 874 patients were enrolled in the study during the first-trimester ultrasound examination. The risk of PE and FGR was assessed according to the FMF guidelines, which include the maternal history, mean arterial pressure (MAP), uterine artery pulsatility index (UtPI), pregnancy-associated plasma protein A (PAPP-A) and placental growth factor (PLGF). Among patients with a risk higher than >1:100, ASA was administered at a dose of 150 mg. Perinatal outcomes were assessed among the different groups. When comparing women in the high-risk group with those in the low-risk group, a statistically significantly higher risk of pregnancy complications was observed in the high-risk group. These complications included pregnancy-induced hypertension (PIH) (OR 3.6 (1.9-7)), any PE (OR 7.8 (3-20)), late-onset PE (OR 8.5 (3.3-22.4)), FGR or small for gestational age (SGA) (OR 4.8 (2.5-9.2)), and gestational diabetes mellitus type 1 (GDM1) (OR 2.4 (1.4-4.2)). The pregnancies in the high-risk group were more likely to end with a cesarean section (OR 1.9 (1.2-3.1)), while the newborns had significantly lower weights (<10 pc (OR 2.9 (1.2-6.9)), <3 pc (OR 10.2 (2.5-41.7))). The first-trimester screening test for PE and FGR is a necessary and effective tool in identifying high-risk pregnancies. ASA prophylaxis among high-risk patients may have the most beneficial effect. Furthermore, this screening tool may significantly reduce the incidence of early-onset PE (eo-PE).

"Low Pregnancy Associated Plasma Protein A as a Predictive Tool for Pregnancy Outcome"

"Low Pregnancy Associated Plasma Protein A as a Predictive Tool for Pregnancy Outcome"

Implementing Preeclampsia Screening in Switzerland (IPSISS): First Results from a Multicentre Registry

Introduction: The Fetal Medicine Foundation (FMF) London developed a first trimester combined screening algorithm for preterm preeclampsia (pPE) that allows a significantly higher detection of pregnancies at risk compared to conventional screening by maternal risk factors only. The aim of this trial is to validate this screening model in the Swiss population in order to implement this screening into routine first trimester ultrasound and to prescribe low-dose aspirin 150 mg (LDA) in patients at risk for pPE. Therefore, a multicentre registry study collecting and screening pregnancy outcome data was initiated in 2020; these are the preliminary results. Methods: Between June 1, 2020, and May 31, 2021, we included all singleton pregnancies with pPE screening at the hospitals of Basel, Lucerne, and Bern. Multiple of medians of uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP), placental growth factor (PlGF), and pregnancy-associated plasma protein A (PAPP-A) as well as risks were analysed as calculated by each centre’s software and recalculated on the FMF online calculator for comparative reasons. Statistical analyses were performed by GraphPad Version 9.1. Results: During the study period, 1,027 patients with singleton pregnancies were included. 174 (16.9%) had a risk >1:100 at first trimester combined screening. Combining the background risk, MAP, UtA-PI, and PlGF only, the cut-off to obtain a screen positive rate (SPR) of 11% is ≥1:75. Outcomes were available for 968/1,027 (94.3%) of all patients; 951 resulted in live birth. Fifteen (1.58%) developed classical preeclampsia (PE), 23 (2.42%) developed PE according to the International Society for the Study of Hypertension in Pregnancy (ISSHP) definition. Conclusion: First trimester combined screening for PE and prevention with LDA results in a low prevalence of PE. The screening algorithm performs according to expectations; however, the cut-off of >1:100 results in a SPR above the accepted range and a cut-off of ≥1:75 should be considered for screening. More data are needed to evaluate, if these results are representative for the general Swiss population.

First and second trimester maternal serum markers for prenatal aneuploidy screening: An update on the adjustment factors for race, smoking, and insulin dependent diabetes mellitus

ObjectivesThe concentrations of maternal serum markers for aneuploidy screening are influenced by maternal characteristics such as race, smoking, insulin dependent diabetes mellitus (IDDM), and in vitro fertilization (IVF). Accurate risk estimation requires adjustment of initial values for these characteristics. This study aims to update and validate adjustment factors for race, smoking, and IDDM. MethodsThe study included singleton pregnancies that received multiple marker screening in Ontario, Canada between January 2012, and December 2018, and had their information collected in the Better Outcomes Registry & Network (BORN) Ontario. Serum markers assessed included first trimester pregnancy-associated plasma protein A (PAPP-A), free β and total human chorionic gonadotropin (hCG), placental growth factor (PlGF) and αlpha-fetoprotein (AFP); second trimester AFP, unconjugated estriol (uE3), total hCG and inhibin A. The Mann-Whitney U test was used to assess the differences in the median multiple of the median (MoM) of serum markers between study and reference groups. New adjustment factors were generated by dividing the median MoM of a particular race, individuals who smoke tobacco, or have IDDM by those of the reference groups. ResultsThe study included 624,789 pregnancies. There were statistically significant differences in serum marker concentrations among pregnant individuals who were Black, Asian, or First Nations compared to a White group, those who smoked compared to Non-smoking individuals, and those with IDDM compared to Non-IDDM group. New adjustment factors for race, smoking, and IDDM were validated by comparing median MoM of serum markers corrected using the current adjustment factors and new adjustment factors generated in this study. ConclusionThe adjustment factors generated in this study can adjust the effects of race, smoking, and IDDM on serum markers more accurately.

Impact of COVID-19 and vaccination on first and second trimester screening results

COVID-19 has been shown to affect pregnant women. Since pregnant women are at risk of this infection, vaccination against COVID-19 has been suggested as an imperative way to diminish rate of COVID-19 in this population. In the current observational study, we have collected data of first and second trimester screening (FTS and STS) from pregnant women who were infected with SARS-CoV-2 and/or vaccinated against COVID-19 during their pregnancy, and compared this data with a group of control pregnant women. The cohort included 4612 and 2426 women referred for FTS and STS, respectively. There was no significant difference in median values of Pregnancy-associated plasma protein A (PAPP-A) and human chorionic gonadotropin-beta subunit (βHCG) between infected women and controls. Moreover, these levels were not different between “Infected + vaccinated” and “Only vaccinated” groups. However, median values of PAPP-A and βHCG were higher in “Infected + vaccinated” and “Only vaccinated” groups compared with “Infected” and “Control” groups (P < 0.001). Median values of unconjugated Estriol (uE3) and βHCG markers were not different between “Only vaccinated” and “Control” groups, yet both markers were elevated in “Infected” and “Infected + vaccinated” groups compared with other groups. AFP values were higher in “Infected” group (P = 0.012). However, multiple of the median (MoM) and risk of open spina bifida (OSB) were not affected. Finally, median of calculated risk of trisomy 18 was lower in “Infected” and “Vaccinated” groups compared with controls (P = 0.007). Moreover, AstraZeneca and Sinopharm vaccines were associated with elevation of the calculated risk values of trisomy 21 and trisomy 18 (P < 0.001). While Sinopharm did not affect nuchal translucency (NT) and NT MoM (P = 0.13), AstraZeneca and Barakat increased and decreased these values, respectively (P values = 0.0027 and 0.015, respectively). Taken together, COVID-19 during pregnancy might be associated with some adverse obstetric outcomes. Besides, vaccination against this infection might affect the results of STS or FTS.

Erken Gebelikte Vajinal Kanamanın İlk Trimester Tarama Testi, Uterin Arter Doppler İndeksleri ve Perinatal Sonuçlara Etkisi

Aim: We aimed to prospectively investigate the effect of first trimester vaginal bleeding on first trimester screening test, uterine artery (UtA) Doppler results and perinatal outcomes. Material and Methods: Fifty cases that presented with vaginal bleeding in the first trimester between 2019 and 2020 constituted the early vaginal bleeding (abortus imminens-threatened abortion) group and fifty cases without a history of vaginal bleeding in pregnancy constituted the control group. Demographic datas were noted at the first visit. Both groups were followed up until birth. First trimester screening test (double screening test) between 11-14 weeks and UtA Doppler examination between 20-24 weeks of gestation was performed. Perinatal outcomes and values of nuchal translucency (NT), free β human chorionic gonadotropin (f β-hCG), pregnancy-associated plasma protein A (PAPP-A), and UtA Doppler were compared between the two groups. Results: There was no statistically significant difference was found between the two groups in terms of NT and PAPP-A among the first trimester screening test results (p=0.741 and p=0.937, respectively). In the group with threatened miscarriage, f β-hCG value was numerically higher, but there was no statistically significant difference (1.24±0.59 vs. 1.1±0.93, p=0.057). In the Doppler examination of the UtA, there was no statistically significant difference between the groups in terms of systolic/diastolic ratio, pulsatility index, resistive index and the presence of a notch (p=0.713, p=0.528, p=424, p=0.538, respectively). Perinatal complication rate was statistically significantly higher in the study group (p=0.013; Odds Ratio:3.2, 95% CI 1.2-8.3). Conclusion: Contrary to some different studies, we believe that first trimester screening test parameters or uterine artery Doppler flow indices do not have a place in predicting perinatal outcomes of pregnant women with a history of vaginal bleeding in the first trimester. In addition, early vaginal bleeding does not significantly affect screening parameters. Perinatal complication rate was found to be statistically significantly higher in the group with a history of threatened miscarriage.

The role of serum markers PAPP-A β-hCG, AFP, and uE3 in predicting the risk of preeclampsia in early, middle, and late pregnancy.

Preeclampsia (PE) has adverse effects on pregnant women, fetuses, and newborns [1], and accounts for 3%-10% of pregnancy-related diseases globally. This study aimed to screen a series of prenatal markers (pregnancy-associated plasma protein [PAPP-A], β-human chorionic gonadotropin [β-hCG], alpha fetoprotein [AFP], and estriol [uE3]) to establish a risk model and evaluate the diagnostic values of the markers for predicting PE. Sixty-five pregnant women were enrolled in this study. They were divided into two groups containing healthy pregnant women (n= 51, the non-PE group) and pregnant women with PE (n= 14, the PE group). According to the stage of pregnancy, the pregnant women in each group were divided into early, middle, and late pregnancy groups for statistical analysis. The levels of PAPPA-A β-hCG, AFP, and uE3 were compared among these groups. Then, a risk model was established, and PE was diagnosed using receiver operating characteristic (ROC) curve results. In the early pregnancy group, the differences in the levels of PAPP-A, AFP, and uE3 between the PE and non-PE groups were statistically significant (P< 0.001, P= 0.029, and P= 0.033, respectively), while the difference in the single remaining marker was not statistically significant. A ROC curve analysis revealed that in early pregnancy, the sensitivity and specificity of PAPP-A were 76.5% and 71.4%, respectively, and the sensitivity and specificity of β-hCG were 82.4% and 57.1%, respectively. The sensitivity and specificity of the combination of the two markers for diagnosing PE were 86.3% and 57.1%, respectively. This study demonstrated that the combination of PAPP-A and β-hCG has diagnostic value for PE in pregnant women. Accordingly, we should formulate innovative PE screening strategies to target the prevention of PE and create important conditions for predictive and preventive personalized medical treatments.

PAPP-A-Specific IGFBP-4 Proteolysis in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

The insulin-like growth factors IGF-I and IGF-II-as well as their binding proteins (IGFBPs), which regulate their bioavailability-are involved in many pathological and physiological processes in cardiac tissue. Pregnancy-associated plasma protein A (PAPP-A) is a metalloprotease that preferentially cleaves IGFBP-4, releasing IGF and activating its biological activity. Previous studies have shown that PAPP-A-specific IGFBP-4 proteolysis is involved in the pathogenesis of cardiovascular diseases, such as ischemia, heart failure, and acute coronary syndrome. However, it remains unclear whether PAPP-A-specific IGFBP-4 proteolysis participates in human normal cardiomyocytes. Here, we report PAPP-A-specific IGFBP-4 proteolysis occurring in human cardiomyocytes derived from two independent induced pluripotent cell lines (hiPSC-CMs), detected both on the cell surface and in the cell secretome. PAPP-A was measured by fluoroimmune analysis (FIA) in a conditioned medium of hiPSC-CMs and was detected in concentrations of up to 4.3 ± 1.33 ng/mL and 3.8 ± 1.1 ng/mL. The level of PAPP-A-specific IGFBP-4 proteolysis was determined as the concentration of NT-IGFBP-4 proteolytic fragments using FIA for a proteolytic neo-epitope-specific assay. We showed that PAPP-A-specific IGFBP-4 proteolysis is IGF-dependent and inhibited by EDTA and 1,10-phenanthroline. Therefore, it may be concluded that PAPP-A-specific IGFBP-4 proteolysis functions in human normal cardiomyocytes, and hiPSC-CMs contain membrane-bound and secreted forms of proteolytically active PAPP-A.

Associations between nausea and vomiting in pregnancy, disgust sensitivity, and first-trimester maternal serum free β-hCG and PAPP-A

Elevated levels of nausea and vomiting in pregnancy (NVP) and disgust sensitivity have been observed in the first trimester and both are thought to have a protective function for the mother and her fetus. Their aetiology is not clear, however, with previous studies attributing elevated NVP and disgust to various factors including endocrine changes, immunological changes, and psychological variables. To date, no study has directly assessed the relationship between disgust and NVP. Here, we prospectively collected two independent samples (S1 and S2; n1 = 201, n2 = 391) of women in the first trimester of pregnancy, who completed the Index of Nausea, Vomiting, and Retching and the Disgust Scale-Revised. We also measured free β-human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein A (PAPP-A) in maternal serum. Our results did not confirm any association between NVP and disgust; in addition, they indicate that NVP and disgust may have different proximate causes. Disgust sensitivity was significantly negatively correlated with free β-hCG and (only in S1) with PAPP-A. In contrast, NVP was significantly positively associated with free β-hCG levels and (only in S1) with PAPP-A. While low hCG levels seem to be an important indicator for activation of the behavioral immune system in the first trimester, increased hCG levels play a role in stronger symptoms of NVP, a result consistent with previous studies. Levels of PAPP-A are likely part of a larger network of immunological and endocrine responses and do not appear to provide sufficient information for predicting women's NVP and disgust sensitivity.

Validation of a preeclampsia early screening test in a Mexican population.

No preeclampsia screening test has been validated in our country. To assess the fit and performance of the FMF 4.0 Bayesian algorithm in a Mexican population. Cohort study in singleton pregnancies, according to the competing risks model for preeclampsia. A priori risk was calculated based on medical history. Mean blood pressure (MBP), uterine artery mean pulsatility index (UtAmPI) and pregnancy-associated plasma protein A (PAPP-A) were measured at 11-14 weeks of gestation using standardized methodology. The value of each marker was transformed into multiples of the median (MoM) by the originala algorithm and by population-correctionb. Multivariate normal distribution and Bayes theorem were applied to obtain post-test probabilities. There was 5.0% (40/807) of preeclampsia. Distributions in women without preeclampsia were MBP = 0.927a vs. 0.991b, UtAmPI = 0.895a vs. 1.030b and PAPP-A = 0.815a vs. 0.963b (p < 0.001). The AUC was 0.821a vs. 0.823b. For a detection rate of 69 %, cutoff points were 1 in 240a and 1 in 120b, with false positive rates of 31 %a and 29 %b. The model has to be adjusted to the target population.

Study on the Relationship and Predictive Value of First-Trimester Pregnancy-Associated Plasma Protein-A, Maternal Factors, and Biochemical Parameters in Gestational Diabetes Mellitus: A Large Case-Control Study in Southern China Mothers.

To investigate the relationship and predictive value of first-trimester pregnancy-associated plasma protein A (PAPP-A), maternal factors, and biochemical parameters with gestational diabetes mellitus (GDM) in southern China mothers. This study recruited 4872 pregnant women. PAPP-A, the free beta subunit of human chorionic gonadotropin (free β-HCG), fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), and high- and low-density lipoproteins (HDL, LDL) were measured at 11-13+ weeks of gestation. GDM was diagnosed based on a 75 g oral glucose tolerance test at 24-28 weeks of gestation. We performed stepwise logistic regression analysis to determine the odds ratio (OR) and the 95% confidence interval (CI) of GDM. We used Receiver Operating Characteristic (ROC) curves with the area under the curve (AUC) to evaluate the predictive value of PAPP-A, maternal factors, and biochemical markers. The significance of the differences between the AUC values was assessed using the DeLong test. GDM was diagnosed in 750 (15.39%) women. Independent factors for GDM were age, pre-gestational BMI, GWG before a diagnosis of GDM, previous history of GDM, family history of diabetes, FPG, TG, LDL, PAPP-A, and TC. The AUC of PAPP-A was 0.56 (95% CI 0.53-0.58). The AUC of a model based on combined maternal factors, biochemical markers, and PAPP-A was 0.70 (95% CI 0.68-0.72). Differences in AUC values between PAPP-A alone and the model based on combined maternal factors, biochemical markers, and PAPP-A were statistically significant (Z= 9.983, P<0.001). A Low serum PAPP-A level in the first trimester is an independent risk factor for developing GDM later in pregnancy. However, it is not a good independent predictor although the predictive value of a low serum PAPP-A level increases when combined with maternal factors and biochemical markers.

First-trimester screening for Down syndrome using quadruple maternal biochemical markers.

Placental growth factor (PlGF) is used for first-trimester preeclampsia screening and could be combined with other biochemical markers for Down syndrome screening. We aim to estimate the predictive value of the combination of pregnancy-associated plasma protein (PAPP-A), free β-human chorionic gonadotropin (free β-hCG), placental growth factor (PlGF) and α-fetoprotein (AFP) with and without nuchal translucency. Singleton pregnancies recruited at 11-14weeks and followed until delivery. The four maternal markers were measured using Kryptor (ThermoFisher-BRAHMS) and adjusted for gestational age and maternal characteristics. The risk of Down syndrome was calculated using the Fetal Medicine Foundation algorithm and multivariate linear regression analyses in all cases and in 2,200 controls. Receiver-operator characteristic (ROC) curves were used to calculate the detection and false-positive rates. Twenty-six (0.2%) cases of Down syndrome were diagnosed among 13,386 participants. The combination of the four biomarkers could have detected 88% (95% CI: 72-97%) of the cases at a false-positive rate of 13% (95% CI: 12-15%). The addition of nuchal translucency would have increased the detection rate to 96% (95% CI: 82-99%) at a false-positive rate of 4% (95% CI: 4-5%) using a 1:300 cut-off and to 100% (95% CI: 89-100%) at a false-positive rate of 6% (95% CI: 5-8%) using a 1:500 cut-off. First-trimester screening using biochemical markers allows the identification of approximately 88% of Down syndrome cases for a false-positive rate of 13%. The addition of nuchal translucency raises the detection rate above 95% with a false-positive rate below 5%.

Fetal Growth Restriction Is Associated with Pregnancy Associated Plasma Protein A and Uterine Artery Doppler in First Trimester

Fetal growth restriction (FGR) is a major cause of stillbirth and poor neurodevelopmental outcomes. The early prediction may be important to establish treatment options and improve neonatal outcomes. The aim of this study was to assess the association of parameters used in first-trimester screening, uterine artery Doppler pulsatility index and the development of FGR. In this retrospective cohort study, 1930 singleton pregnancies prenatally diagnosed with an estimated fetal weight under the third percentile were included. All women underwent first-trimester screening assessing maternal serum pregnancy-associated plasma protein A (PAPP-A), free beta-human chorionic gonadotrophin levels, fetal nuchal translucency and uterine artery Doppler pulsatility index (PI). We constructed a Receiver Operating Characteristics curve to calculate the sensitivity and specificity of early diagnosis of FGR. In pregnancies with FGR, PAPP-A was significantly lower, and uterine artery Doppler pulsatility index was significantly higher compared with the normal birth weight group (0.79 ± 0.38 vs. 1.15 ± 0.59, p < 0.001 and 1.82 ± 0.7 vs. 1.55 ± 0.47, p = 0.01). Multivariate logistic regression analyses demonstrated that PAPP-A levels and uterine artery Doppler pulsatility index were significantly associated with FGR (p = 0.009 and p = 0.01, respectively). To conclude, these two parameters can predict FGR < 3rd percentile.

Prenatal screening for preeclampsia: the roles of placental growth factor and pregnancy–associated plasma protein A in the first trimester and placental growth factor and soluble fms-like tyrosine kinase 1–placental growth factor ratio in the early second trimester

Professional societies have recommended universal first trimester screening for preeclampsia and a second or third trimester soluble fms-like tyrosine kinase-1-placental growth factor ratio test to assess for preeclampsia and its severity. However, it may not be feasible to implement the most optimal screening protocol for preeclampsia in the first trimester which uses a combination of maternal characteristics, maternal biophysical and biochemical markers due to limitations in the access to uterine artery doppler ultrasound. There are inconsistent findings on how early in the second trimester the fms-like tyrosine kinase-1-placental growth factor ratio begins to provide useful information in preeclampsia prediction. This study aimed to assess the accuracy of (1) a combination of maternal characteristics, maternal serum pregnancy-associated plasma protein A, and placental growth factor in the screening for preeclampsia in the first trimester; and (2) placental growth factor or soluble fms-like tyrosine kinase-1-placental growth factor ratio in the prediction of preeclampsia in the early second trimester. This retrospective case-control study used frozen residual blood samples from women who had aneuploidy screening and delivered at a tertiary center. The case group included pregnancies with gestational hypertension or preeclampsia (further classified as early-onset [birth at <34 weeks' gestation] and preterm preeclampsia [birth at <37 weeks' gestation]). Each case was matched with 3 control pregnancies by date of blood sample draw, gestational age at first blood sample draw, maternal age, maternal ethnicity, type of multiple-marker screening, and amount of residual sample. Mann-Whitney U tests were used to assess the associations between serum markers and the risk of preeclampsia. Logistic regressions were used to assess if the risk of preeclampsia can be predicted using a combination of maternal characteristics and serum markers. The case group included 146 preeclampsia and 295 gestational hypertension cases. Compared with the controls, preeclampsia cases had significantly lower first-trimester pregnancy-associated plasma protein A and placental growth factor. At a 20% false-positive rate, 71% of early-onset and 58% of preterm preeclampsia cases can be predicted using maternal characteristics, pregnancy-associated plasma protein A, and placental growth factor. Preeclampsia cases had lower second-trimester placental growth factor and a higher soluble fms-like tyrosine kinase-1-placental growth factor ratio. At a 10% false-positive rate, 80% and 53% of early-onset preeclampsia can be predicted using maternal characteristics and placental growth factor or soluble fms-like tyrosine kinase-1-placental growth factor ratio, respectively. The current first-trimester aneuploidy screening programs may be expanded to identify women at increased risk of developing preeclampsia. Early in the second trimester, placental growth factor alone provided better prediction for preeclampsia compared with the soluble fms-like tyrosine kinase-1-placental growth factor ratio.

IL-1β knockdown inhibits cigarette smoke extract-induced inflammation and apoptosis in vascular smooth muscle cells.

This study was aimed to investigate the role of interleukin-1β (IL-1β) in cigarette smoke extract (CSE)-induced apoptosis in vascular smooth muscle cells and the underlying mechanism in a rat derived cell line. Rat thoracic aortic smooth muscle cells (A7r5) were divided into six groups including control, CSE (model), CSE+ overexpression empty vector (OvExp-EV), CSE+IL-1β knockdown (KD), and CSE+ IL-1β knockdown empty vector (KD-EV). The mRNA expression levels of IL-1β and pregnancy-associated plasma protein A (PAPP-A) were detected by quantitative polymerase chain reaction (qPCR). The apoptosis of A7r5 cells was detected by flow cytometry. The expression levels of inflammatory mediators (TNFα, IL-6 and IL-8) and apoptotic proteins (Bax and Bcl-2) were determined by western blot. CSE induced significant apoptosis in vascular smooth muscle cells (P < 0.01) and elevated the mRNA levels of IL-1β and PAPP-A (P < 0.01). CSE administration increased protein expression of Bax, TNF-α, IL-6, and IL-8, with significantly reduced Bcl-2 expression (P < 0.01). IL-1β knockdown significantly decreased cell apoptosis via regulating the expression of these proteins (P < 0.05 or P < 0.01). IL-1β is involved in CSE-induced PAPP-A expression and apoptosis in vascular smooth muscle cells, which might be considered as a target for preventing of cardiovascular diseases caused by cigarette smoking.

Preeclampsia: Recent Advances in Predicting, Preventing, and Managing the Maternal and Fetal Life-Threatening Condition.

Preeclampsia accounts for one of the most common documented gestational complications, with a prevalence of approximately 2 to 15% of all pregnancies. Defined as gestational hypertension after 20 weeks of pregnancy and coexisting proteinuria or generalized edema, and certain forms of organ damage, it is life-threatening for both the mother and the fetus, in terms of increasing the rate of mortality and morbidity. Preeclamptic pregnancies are strongly associated with significantly higher medical costs. The maternal costs are related to the extra utility of the healthcare system, more resources used during hospitalization, and likely more surgical spending due to an elevated rate of cesarean deliveries. The infant costs also contribute to a large percentage of the expenses as the babies are prone to preterm deliveries and relevant or causative adverse events. Preeclampsia imposes a considerable financial burden on our societies. It is important for healthcare providers and policy-makers to recognize this phenomenon and allocate enough economic budgets and medical and social resources accordingly. The true cellular and molecular mechanisms underlying preeclampsia remain largely unexplained, which is assumed to be a two-stage process of impaired uteroplacental perfusion with or without prior defective trophoblast invasion (stage 1), followed by general endothelial dysfunction and vascular inflammation that lead to systemic organ damages (stage 2). Risk factors for preeclampsia including race, advanced maternal age, obesity, nulliparity, multi-fetal pregnancy, and co-existing medical disorders, can serve as warnings or markers that call for enhanced surveillance of maternal and fetal well-being. Doppler ultrasonography and biomarkers including the mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), and serum pregnancy-associated plasma protein A (PAPP-A) can be used for the prediction of preeclampsia. For women perceived as high-risk individuals for developing preeclampsia, the administration of low-dose aspirin on a daily basis since early pregnancy has proven to be the most effective way to prevent preeclampsia. For preeclamptic females, relevant information, counseling, and suggestions should be provided to facilitate timely intervention or specialty referral. In pregnancies complicated with preeclampsia, closer monitoring and antepartum surveillance including the Doppler ultrasound blood flow study, biophysical profile, non-stress test, and oxytocin challenge test can be arranged. If the results are unfavorable, early intervention and aggressive therapy should be considered. Affected females should have access to higher levels of obstetric units and neonatal institutes. Before, during, and after delivery, monitoring and preparation should be intensified for affected gravidas to avoid serious complications of preeclampsia. In severe cases, delivery of the fetus and the placenta is the ultimate solution to treat preeclampsia. The current review is a summary of recent advances regarding the knowledge of preeclampsia. However, the detailed etiology, pathophysiology, and effect of preeclampsia seem complicated, and further research to address the primary etiology and pathophysiology underlying the clinical manifestations and outcomes is warranted.