Maternal Plasma Protein Research Articles

Antenatal maternal serum biomarkers as a predictor for placenta accreta spectrum disorders

IntroductionPlacenta accreta spectrum (PAS) disorder, an abnormal adherence of the placenta to the uterine wall, with variable degrees of invasion, is a major cause of maternal morbidity and mortality associated with severe postpartum hemorrhage. PAS is diagnosed using ultrasonography or with magnetic resonance imaging; in many centers there is a lack of PAS diagnostic expertise in diagnosing. Hence, we investigated the performance of selected maternal plasma protein biomarkers, antithrombin-III (AT-3), plasminogen activator inhibitor-I (PAI-I), soluble vascular endothelial growth factor receptor-II (sVEGFR-2), and soluble Tie-II (sT-2) for prenatal screening in pregnancies at a high risk of PAS. MethodsThis prospective study, conducted in a tertiary hospital from September 2021 to May 2022, included pregnant women with placenta previa suspicious of PAS between 28 and 42 weeks of gestation. Four serum samples were collected from each woman to evaluate serum concentrations and compared between placenta previa (control) and PAS groups. The screening performances of the biomarkers were analyzed, and the best screening model for PAS was created. ResultsTwenty-two women with PAS and 18 with placenta previa alone were included (n = 40). The median concentrations of PAI-I, AT-3, sVEGFR-2, and sT-2 among the PAS group were 21.2, 6154.6, 7.5, and 12.8 ng/mL, respectively. The best screening model for PAS combined all four biomarkers with a history of cesarean delivery (77 % sensitivity, 89 % specificity, and an AUC of 0.87). DiscussionA combination of the four maternal serum biomarkers in women with a history of cesarean delivery presented the most promising model for prenatal screening of PAS. ConclusionA combination of the four maternal serum biomarkers with a history of cesarean delivery presented the most promising model for prenatal screening of PAS.

Longitudinal Assessment of Oxidative Stress Markers in Women with Preeclampsia.

Preeclampsia (PE) is a pregnancy-specific disorder and a major contributor to maternal and fetal morbidity and mortality. Role of oxidative stress in early pregnancy with the pathophysiology of the disorder is unclear. The current study aims to analyse maternal levels of oxidative stress markers (MDA and protein carbonyl) longitudinally across gestation and placental levels of oxidative stress markers (MDA, protein carbonyl and 8-oxo-2'-deoxyguanosine) in women with PE and compare them with non-PE women. 324 pregnant women (216 non-PE and 108 PE women) were longitudinally followed during pregnancy. Women with preeclampsia were stratified as early onset preeclampsia (EOP) and late onset preeclampsia (LOP) Maternal blood at four time points across gestation (11-14weeks, 18-22weeks, 26-28weeks, and at delivery) and placenta were collected. Maternal and placental levels of oxidative stress markers were assessed using commercially available kits. Maternal plasma MDA and protein carbonyl levels were comparable between the PE and non-PE group at all timepoints across gestation. Maternal plasma MDA were significantly higher levels at 26-28weeks in EOP women when compared to non-PE women (p < 0.05). Placental 8-oxo-dG levels were lower in the EOP group as compared to non-PE (p < 0.05). Elevated plasma MDA levels were positively associated with birth length at 18-22weeks and 26-28weeks in the PE group (p < 0.05 for both). Maternal plasma MDA levels were positively associated with systolic blood pressure at 18-22weeks. Oxidative stress in early pregnancy is not associated with risk of PE.

Quantitative Proteomics of Maternal Blood Plasma in Isolated Intrauterine Growth Restriction

Intrauterine growth restriction (IUGR) remains a significant concern in modern obstetrics, linked to high neonatal health problems and even death, as well as childhood disability, affecting adult quality of life. The role of maternal and fetus adaptation during adverse pregnancy is still not completely understood. This study aimed to investigate the disturbance in biological processes associated with isolated IUGR via blood plasma proteomics. The levels of 125 maternal plasma proteins were quantified by liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM MS) with corresponding stable isotope-labeled peptide standards (SIS). Thirteen potential markers of IUGR (Gelsolin, Alpha-2-macroglobulin, Apolipoprotein A-IV, Apolipoprotein B-100, Apolipoprotein(a), Adiponectin, Complement C5, Apolipoprotein D, Alpha-1B-glycoprotein, Serum albumin, Fibronectin, Glutathione peroxidase 3, Lipopolysaccharide-binding protein) were found to be inter-connected in a protein–protein network. These proteins are involved in plasma lipoprotein assembly, remodeling, and clearance; lipid metabolism, especially cholesterol and phospholipids; hemostasis, including platelet degranulation; and immune system regulation. Additionally, 18 proteins were specific to a particular type of IUGR (early or late). Distinct patterns in the coagulation and fibrinolysis systems were observed between isolated early- and late-onset IUGR. Our findings highlight the complex interplay of immune and coagulation factors in IUGR and the differences between early- and late-onset IUGR and other placenta-related conditions like PE. Understanding these mechanisms is crucial for developing targeted interventions and improving outcomes for pregnancies affected by IUGR.

Causes and Consequences of Preterm Birth, A Systematic Review

To systematically review the potential causes and possible effects of preterm birth [&lt;37 weeks gestational duration]. We searched PubMed, google scholar, clinicaltrials.gov and science direct for English language articles published from 2004 to march 2021. All kinds of study schemes were considered acceptable, comprising case –control, cohort studies, experimental and cross- sectional studies. Significant evidences indicate that social stress, elevated cadmium exposure, genomic variations, vitamin D deficiency, pre-conception hepatitis B infection, declined vaginal microbial community, intrauterine infection, reduction in cervical consistency index, strong exposure of creatinine corrected thallium, systemic autoimmune diseases, ozone, primary traffic air pollutants, road traffic noise, potential exposure of arsenic, HIV exposure, maternal thyroid dysfunction, maternal plasma protein level and COVID-19 exposure in pregnant females are the major risk factors for PTBs. Results of earlier investigations indicated prominent risk of insulin resistance, hypertension, neurological defects, heart failure, Chronic kidney disease, Lung function impairment, lower birth weight, thalamocortical system defects, cancer, altered cardiac phenotype and cardio metabolic diseases in survivors of preterm births. This review will help clinicians to isolate the fundamental etiology and to proactively identify, cope and improve outcomes of at-risk pregnancies.

The relationship between the first trimester maternal serum PAPP-A and β-hCG values and newborn intensive care needs in low-risk pregnancies.

The purpose of the study was to look at the connection between newborn intensive care requirements in low-risk pregnancies and maternal blood pregnancy-associated plasma protein (PAPP-A) and free human chorionic gonadotropin (hCG) levels, which are elements of screening tests within the first trimester. In the delivery unit of our hospital, pregnant women between the years of 18 and 35 had singleton pregnancies who delivered between 37 and 41 weeks of pregnancy between July 2021 and January 2022 were split into 2 groups. One hundred eighty two pregnant women with infants who required neonatal intensive care (NICU) were enrolled in the first group, whereas 890 pregnant women with infants who did not require NICU were enrolled in the second. These two groups' maternal blood PAPP-A and free hCG levels, which are among the first trimester screening procedures, were examined. Additionally, subgroup analysis were performed in terms of cesarean section indications and NICU admission indications. Logistic regression analysis and ROC analysis were performed with related variables for estimating NICU need. The mean serum PAPP-A value was found to be 0.91±0.34 multiples of the median (MoM) in the blood taken from the infant mothers who needed NICU, while the mean serum PAPP-A value in the blood taken from infant mothers who did not need NICU was 1.12±0.59 MoM (p<0.000). The PAPP-A MoM mean of the group with Apgar 5th minute score ≥8 (1.09±0.57) was higher than the PAPP-A mean (0.84±0.27) of the Apgar 5th minute score <7 group (p=0.013). According to the results of our study, in groups with a PAPP-A value below 0.95, the possibility of increased NICU need of newborns is higher. The low serum PAPP-A level, which is used as a screening test among pregnant women, demonstrates that it is successful in predicting perinatal outcomes in the low-risk pregnancy group.

In vivo pharmacokinetic analyses of placental transfer of three drugs of different physicochemical properties in pregnant rats

Although the use of medication during pregnancy is common, information on exposure to the developing fetus and potential teratogenic effects is often lacking. This study used a rat model to examine the placental transfer of three small-molecule drugs with molecular weights ranging from approximately 300 to 800 Da with different physicochemical properties. Time-mated Sprague Dawley (Hsd:SD) rats aged 11–13 weeks were administered either glyburide, rifaximin, or fentanyl at gestational day 15. Maternal blood, placentae, and fetuses were collected at 5 min, 30 min, 1 h, 4 h, 8 h, 24 h, 48 h, and 96 h post-dose. To characterize the rate and extent of placental drug transfer, we calculated several pharmacokinetic parameters such as maximum concentration (Cmax), time to maximum concentration (Tmax), area under the concentration–time curve (AUC), half-life (t1/2), clearance (CL), and volume of distribution (Vd) for plasma, placenta, and fetus tissues. The results indicated showed that fetal exposure was lowest for glyburide, accounting for only 2.2 % of maternal plasma exposure as measured by their corresponding AUC ratio, followed by rifaximin (37.9 %) and fentanyl (172.4 %). The fetus/placenta AUC ratios were found to be 10.7 % for glyburide, 11.8 % for rifaximin, and 39.1 % for fentanyl. These findings suggest that although the placenta acts as a protective shield for the fetus, the extent of protection varies for different drugs and depends on factors such as molecular weight, lipid solubility, transporter-mediated efflux, and binding to maternal and fetal plasma proteins.

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.

134 Placental dimethylarginine dimethylaminohydrolase and maternal and cord concentrations of asymmetric dimethylarginine in preeclampsia

Asymmetric dimethylarginine (ADMA) concentrations are reportedly increased in women with preeclampsia (preE). Dimethylarginine dimethylaminohydrolase (DDAH) degrades ADMA, but its placental expression and relationship with ADMA has not been well studied. The objective of this study was to compare ADMA concentrations at delivery in maternal plasma and DDAH protein expression in placenta in women with preE compared to matched controls. The secondary objective was to compare cord blood ADMA concentrations at delivery between pregnancies complicated by preeclampsia and controls. Placenta, cord plasma, and maternal plasma at delivery were obtained from women diagnosed with preE and controls matched by gestational age, race, and BMI enrolled in the Indiana University Building Blocks of Pregnancy Biobank. Placenta tissue was homogenized and DDAH-1 in placental homogenate and ADMA in plasma were measured by ELISA. Differences in DDAH and ADMA concentrations between women with preE and controls were assessed using t-tests. Stepwise logistic regression was used to evaluate covariates. 25 women with preE and 23 matched controls were studied. There was no difference in DDAH-1 between women with preE (1.60±0.79 ng/mL) compared to controls (1.75±0.75 ng/mL, p=0.5). Multivariable analysis did not show a difference in concentrations with gestational age, BMI, race, or age. Hispanic women had lower DDAH-1 than non-Hispanic women (1.25±0.39 ng/mL vs 1.77±0.80 ng/mL, respectively, p=0.009). Maternal ADMA concentrations did not differ between cases (0.092±0.049 μmol/L) and controls (0.082±0.049 μmol/L, p = 0.64). There was no difference in cord concentrations of ADMA in 16 infants born from moms with preE (0.80±0.17 ng/mL) compared to 16 controls (0.73±0.23 ng/mL, p = 0.34). No significant correlation was observed between maternal ADMA, cord ADMA and DDAH. There is no statistical difference in plasma ADMA, placental DDAH-1, and neonatal ADMA between women with preE and controls in a small retrospective study. ADMA through pregnancy and activity of DDAH-1 needs further study.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

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.

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

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

Performance of first trimester maternal screening biomarkers pregnancy-associated plasma protein a (PAPP-A) and free beta human chorionic gonadotropin (FBHCG) on the Atellica® IM Analyzer

Metabolic syndrome (MetS) has been associated with a procoagulant and hypofibrinolytic state. Current data exploring the role of MetS in venous thromboembolism (VTE) are limited. The objective was to measure the prevalence of MetS in patients with acute PE receiving catheter-directed thrombolysis (CDT) and to investigate its effect on mean pulmonary arterial pressure and overall treatment success.We used a 3-year prospective registry of ED patients with acute PE with severity qualifying for activation of a PE response team (PERT). All patients had CDT with catheter-measured mPAP and angiography. The presence or absence of MetS components were extracted from chart review based on the following criteria: 1. body mass index (BMI) > 30 kg/m2; 2. diagnosed hypertension; 3. diabetes mellitus (including HbA1c > 6.5%) and; 4. dyslipidemia (including triglycerides > 150 mg/dL or high-density lipoprotein < 40 mg/dL).Of the 134 patients, 85% met the criteria for at least one of four MetS components, with obesity being most common, present in 71%. Results demonstrated a positive concordance between the number of criteria for MetS and MPAP, both pre- and post-fibrinolysis, as pressures tended to increase with each additional MetS criterion. Multivariate regression analysis determined age (-), BMI (+) and hypertension (+) to be significant independent predictor variables for mPAP.MetS was common in patients with more severe manifestations of PE and was associated with higher mPAP values both at diagnosis and following treatment with CDT.

Analysis of bupivacaine enantiomers in plasma as total and unbound concentrations using LC-MS/MS: Application in a pharmacokinetic study of a parturient with placental transfer

Bupivacaine, a drug used in obstetric anesthesia and analgesia, is commercially available as a racemic mixture of the R-bupivacaine and S-bupivacaine enantiomers, which show differences in pharmacokinetics, efficacy and toxicity. Changes in bupivacaine plasma protein binding is of clinical relevance considering its high protein binding (approximately 95%) and its classification as an intermediate hepatic extraction ratio drug (E = 0.38). Furthermore, the plasma protein binding of bupivacaine is also of clinical relevance considering that pregnancy is a physiological condition associated with reduced plasma albumin concentration. Also, different pathological conditions, such as pre-eclampsia, can reduce the maternal plasma protein concentrations and consequently increase the bupivacaine placental transfer. This report describes the development and validation of analytical methods for the sequential analysis of the total and unbound concentrations of bupivacaine enantiomers in human plasma using liquid chromatography coupled to mass spectrometry (LC–MS/MS) with a sensitivity compatible with application in pharmacokinetic studies including placental transfer. Aliquots of 200 μL of plasma or plasma ultra-filtrate were extracted with n-hexane in alkaline medium after the deproteinization of the matrix with acetonitrile and water. The separation of bupivacaine enantiomers was obtained on a Chirex® 3020 chiral stationary phase column using as a mobile phase a mixture of 95% n-hexane:ethanol (80:20, v/v) at a flow rate of 0.8 mL/min. The lower limit of quantification was 0.25 ng of each enantiomer/mL of plasma as the total concentration and 0.125 ng of each enantiomer/mL of plasma as the unbound concentration. The methods were applied to study the pharmacokinetics of bupivacaine enantiomers after the administration of 2.5 mg of 0.5% racemic bupivacaine hydrochloride with 1:200,000 epinephrine via the epidural route to an HIV-positive parturient woman undergoing antiretroviral treatment. The parturient showed lower AUC0−∞ (25.42 vs. 30.57 ng.h/mL) and higher volume of distribution (841.96 vs 655.05 L) and total clearance (98.34 vs 81.79 L/h) for the R-bupivacaine enantiomer. The pharmacokinetics of bupivacaine were enantioselective displaying a lower plasma proportion of the enantiomer R-bupivacaine (AUC(R)/(S) ratio equal to 0.83). The placental transfer was approximately 60% for both bupivacaine enantiomers. The unbound fraction (Fu) for the R-bupivacaine enantiomer was higher (10.84%) than the eutomer S-bupivacaine (6.29%).

The maternal plasma proteome changes as a function of gestational age in normal pregnancy: a longitudinal study

Pregnancy is accompanied by dramatic physiological changes in maternal plasma proteins. Characterization of the maternal plasma proteome in normal pregnancy is an essential step for understanding changes to predict pregnancy outcome. The objective of this study was to describe maternal plasma proteins that change in abundance with advancing gestational age and determine biological processes that are perturbed in normal pregnancy. A longitudinal study included 43 normal pregnancies that had a term delivery of an infant who was appropriate for gestational age without maternal or neonatal complications. For each pregnancy, 3to6 maternal plasma samples (median, 5) were profiled to measure the abundance of 1125 proteins using multiplex assays. Linear mixed-effects models with polynomial splines were used to model protein abundance as a function of gestational age, and the significance of the association was inferred via likelihood ratio tests. Proteins considered to be significantly changed were defined as having the following: (1) >1.5-fold change between 8 and 40 weeks of gestation; and (2) a false discovery rate-adjusted value of P < .1. Gene ontology enrichment analysis was used to identify biological processes overrepresented among the proteins that changed with advancing gestation. The following results were found: (1) Ten percent (112 of 1125) of the profiled proteins changed in abundance as a function of gestational age; (2) of the 1125 proteins analyzed, glypican-3, sialic acid-binding immunoglobulin-type lectin-6, placental growth factor, C-C motif-28, carbonic anhydrase 6, prolactin, interleukin-1 receptor 4, dual-specificity mitogen-activated protein kinase 4, and pregnancy-associatedplasma protein-A had more than a 5-fold change in abundance across gestation (these 9 proteins are known to be involved in a wide range of both physiological and pathological processes, such as growth regulation, embryogenesis, angiogenesis immunoregulation, inflammation etc); and (3) biological processes associated with protein changes in normal pregnancy included defense response, defense response to bacteria, proteolysis, and leukocyte migration (false discovery rate, 10%). The plasma proteome of normal pregnancy demonstrates dramatic changes in both the magnitude of changes and the fraction of the proteins involved. Such information is important to understand the physiology of pregnancy and the development of biomarkers to differentiate normal vs abnormal pregnancy and determine the response to interventions.

Low maternal pregnancy-associated plasma protein A during the first trimester of pregnancy and pregnancy outcomes.

To assess the association between pregnancy-associated placental protein A (PAPP-A) levels in the first trimester of pregnancy and adverse pregnancy outcomes. A retrospective study included data from a group of patients in the first trimester of pregnancy with PAPP-A levels below 0.3 multiples of median who attended the Helsinki University Hospital, Finland, between January 1, 2009 and December 31, 2012; an age-matched control group of patients with PAPP-A levels 0.9-1.1 multiples of median was also enrolled. The incidences of adverse pregnancy outcomes in the two groups were compared. There were 961 patients included in each of the groups. Significantly increased risks of aneuploidies (odds ratio [OR] 116.0; 95% confidence interval [CI] 16.2-836.6) and spontaneous abortion (OR 7.7; 95% CI 2.7-22.0) were observed among patients with low PAPP-A (both P<0.001). Preterm delivery (OR 2.5, 95% CI 1.8-3.5), pre-eclampsia (OR 10.9, 95% CI 4.3-27.6), and small for gestational age neonates (OR 4.9, 95% CI 3.2-7.5) were also observed more frequently among patients with low PAPP-A (all P<0.001). There were 9 (0.9%) stillbirths recorded among patients with low PAPP-A and none recorded in the control group. Low PAPP-A was associated with adverse pregnancy outcomes and aneuploidy. These risks should be considered when planning follow-up for patients with low PAPP-A pregnancies.

First Trimester Screening for Preeclampsia and Intrauterine Growth Restriction Using Uterine Artery Doppler and Maternal Serum Placental Growth Factor and Pregnancy Associated Plasma Protein- A

Objective: To assess the accuracy of first-trimester uterine artery Doppler indices combined with maternal serum placental growth factor (PlGF) and pregnancy associated plasma protein- A (PAPP-A) in the prediction of preeclampsia (PE) and intrauterine growth restriction (IUGR) in low risk pregnancy. Design: Prospective observational study. Patients and methods: A total of 266 low risk singleton pregnant women at12-14 weeks’ gestation were recruited and completed the study. Uterine artery (UtA) color Doppler study was estimated on the two sides, the mean pulsatility index (PI) was calculated and dicrotic diastolic notches were recorded. Estimation of maternal serum PlGF and PAPP-A were performed on the same day. The cut-off of Ut Ar PI was 2.35, the cut-off of PlGF was 12pg/ml and the cut off of PAPP-A was 0.42 MoM. The patients were followed up to detect PE and IUGR. PE developed in 14 cases (5.26 %), 2 cases early-onset 2 cases and late-onset 12 cases and IUGR in 19 cases (7.14 %), early-onset 3 cases and late-onset 16 cases. The sensitivity, specificity, positive and negative value (PPV and NPV) and accuracy were calculated. The higher sensitivity and PPV and accuracy for prediction of PE and IUGR were found when first trimester UtA PI and PlGF were combined. The addition of PAPR-A did not improve the accuracy. Conclusion: The ideal first trimester markers for prediction of PE and IUGR in low risk pregnant women may be a combination of UtA PI and maternal serum PlGF.

TRAIL Is Decreased Before 20 Weeks Gestation in Women with Hypertensive Disorders of Pregnancy.

ObjectiveThe present study evaluated maternal plasma protein profiles before the onset of hypertensive disorders of pregnancy (HDP) to assess the relationship between maternal plasma tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and HDP before 20 weeks gestation and to evaluate the discriminatory performance of plasma TRAIL levels for HDP.MethodsA 2-phase discovery/validation study was designed. In the discovery phase, a nested case-controlled study was performed using plasma sampled at 8 to 20 weeks gestation from 20 women who later developed HDP and from 20 age- and gestational week-matched controls. Plasma was analyzed using a human protein microarray technology designed to simultaneously detect 507 proteins. The functional annotation and clustering of the differentially expressed proteins were performed using DAVID and the GO database. TRAIL levels were further validated in an independent study using plasma obtained at 8 to 20 weeks gestation from 53 women who later developed HDP and from 106 matched controls, and 62 clinical risk factors were investigated.ResultsIn the protein microarray analysis, 23 proteins were differentially expressed between the two groups. The ELISA showed that women who later developed HDP had significantly lower TRAIL levels compared to women with uncomplicated pregnancies. The multivariable Cox regression analysis identified the following three factors that were entered into the final Cox regression model: gravidity (OR = 2.02, 95% CI 1.00–4.09), pre-pregnancy BMI (OR = 1.46, 95% CI 1.21–1.76) and TRAIL levels (OR = 0.97, 95% CI 0.94–0.99). The model had a significantly better discriminatory power (AUC = 0.83, 95% CI 0.75–0.88) compared to TRAIL alone as an independent predictor of HDP (AUC = 0.59, 95% CI 0.51–0.67).ConclusionTwenty-three differentially expressed proteins before 20 weeks gestation might be associated with the pathogenesis of HDP. Plasma TRAIL levels were associated with the development of HDP, and the combination of plasma TRAIL levels with pre-pregnancy BMI and gravidity had a good discriminatory performance for HDP before 20 weeks gestation.

Prenatal management and outcomes in mirror syndrome associated with twin-twin transfusion syndrome.

The aim of this article is to investigate the prevalence, clinical presentation, prenatal management, and prognosis of mirror syndrome associated with twin-twin transfusion syndrome (TTTS) treated by amnioreduction or selective fetocide. A retrospective study of twin pregnancies with TTTS was conducted. The prevalence of mirror syndrome, defined as severe maternal edema related to fetal hydrops and placental edema, was calculated for TTTS, and data on clinical characteristics, treatment, and outcomes of the patients were reviewed. We observed mirror syndrome in 4.85% (5/103) of pregnancies with TTTS and 26.32% (5/19) of pregnancies with TTTS Stage IV. Most cases (4/5) of mirror syndrome associated with TTTS were diagnosed before 24 weeks of gestation. The patients manifested edema, anemia, hemodilution, and hypoproteinemia (5/5); proteinuria (4/5); complicated postpartum hemorrhage (4/5); and pulmonary edema and congestive heart failure (2/5). Maternal hemoglobin, hematocrit, and plasma protein dropped after amnioreduction. The perinatal survival rate at 28 days was 28.57% (2/7), and only one infant born after selective feticide survived beyond 18 months. TTTS carries a high risk of mirror syndrome, a disease with significant materno-fetal mortality and morbidity. Amnioreduction alone or with selective feticide in mirror syndrome may transiently aggravate anemia and hemodilution and lead to severe maternal complications. © 2014 John Wiley & Sons, Ltd.

Microarray Screening for Novel Preeclampsia Biomarker Candidates

Introduction: Our aim was to identify novel biomarker candidates for the near-term prediction of preeclampsia in a homogenous collective. In this study, we screened at the genome-wide level for gene expression in placental villous tissue from patients with severe preeclampsia in comparison to normal healthy pregnancies. Material and Methods: Total RNA was extracted from placental villous tissue from 9 preeclamptic patients and 7 normotensive controls after scheduled cesarean sections. After sample pooling, gene expression analysis was performed using six Affymetrix Human Gene 1.0 ST arrays, followed by quantitative RT-PCR and validation of selected markers in the serum of patients at the protein level. Results: In total, 896 significantly differentially expressed genes were identified (p ≤ 0.05). After restricting these to molecules present in the circulation, 9 upregulated and 5 downregulated genes were selected. Four of them (β-hCG, HTRA4, LHB1, all upregulated; and NOX4, downregulated) were validated by quantitative real-time RT-PCR. Finally, the maternal plasma protein levels of 2 of these genes (LHB and β-hCG) were confirmed to be significantly different between preeclampsia cases and controls. Discussion: We identified 14 potential new biomarker candidates for preeclampsia and validated 4 of them by quantitative RT-PCR and 2 of them with subsequent serum protein analyses. Further studies will assess the optimal marker combination for the imminent prediction of impending preeclampsia.

Pharmacokinetics of Flunitrazepam Transfer Across the Rat Term Placenta

The aim of the present study was to describe the pharmacokinetics of transplacental passage of flunitrazepam compared with antipyrine as a marker. Placental transfer of both drugs was studied using the rat term placental perfusion system. Flunitrazepam showed considerably rapid passage across the placenta. Both the first-order transfer constant (ktr = 0·171 min−1) and the first-order equilibration constant (keq = 0·061 min−1) tended to be higher than those of antipyrine (ktr = 0·046 min−1, keq = 0·020 min−1). On the other hand, there was a significant difference between flunitrazepam and antipyrine in the foetal concentrations reached at equilibrium (Ceqm = 640·113 and 1541·136 ng mL−1, respectively) and in the foetomaternal concentration ratio at equilibrium (FMCReq = 0·324 and 0·991, respectively). This indicates that flunitrazepam reaches lower concentrations in the foetal compartment and therefore it might be a relatively safe drug when used during pregnancy. Maternal plasma protein binding of both compounds was evaluated by equilibrium dialysis (flunitrazepam = 75·5%, antipyrine = 1·4%). The plasma protein binding could possibly be one of the most important factors in establishing FMCReq.

772: Glycosylation of maternal plasma proteins attenuates monocyte chemotaxis in the first trimester

The connection between dyslipidemia and inflammation is well established in the pathogenesis of preeclampsia. Lipid laden macrophages are found in decidual spiral arteries of preeclamptic placentas. Serum from preeclamptic patients readily promotes monocyte recruitment to dysfunctional endothelial cells, implicating serum-borne proteins in the chemotaxis and extravasation of immunocytes. A potential mechanism of action for the aberrant regulation of proteins is a change in glycosylation status of plasma proteins in early pregnancy.