Predikční markery preeklampsie a jejich výpovědní hodnota v prvním trimestru gravidity

Preeklampsie je komplexní syndrom, který se může objevit pouze u těhotných pacientek. Vyskytuje se asi ve 2 - 8 % těhotenství v celosvětovém měřítku. Preeklampsie je definována jako proteinurie spolu s novým výskytem hypertenze u jinak normotenzní pacientky. Nejhoršími důsledky preeklampsie jsou eklampsie spojená s tonickými a klonickými křečemi, a eventuálně koma. Mohou nastat i jiné komplikace jako plicní edém, CNS krvácení, anémie, hepatorenální selhání, oběhové selhání a další. Původ preeklampsie není znám stejně jako její příčina, současná zdravotnická péče se tedy soustředí pouze na klinické projevy onemocnění. Včasná predikce preeklampsie by umožnila adekvátní terapeutický zásah a snížilo by se tak riziko ohrožení zdraví matky i plodu. V této studii jsou uvedeny nejdůležitější predikční markery preeklampsie a jejich výpovědní hodnota v prvním trimestru gravidity. Představen je také nejvhodnější prvotrimestrální screening s co nejlepší predikční hodnotou. Powered by TCPDF (www.tcpdf.org)Preelampsia is a clinical syndrome found uniquely in a pregnant patient with an incidence 2 - 8 % of pregnancies worldwide. It is defined as the new onset of hypertension and proteinuria after 20 weeks of gestation, resolving with delivery or soon thereafter. Its worst consequences are eclampsia with tonic and clonic seizures and possibly coma. Also pulmonary edema, CNS hemorrhage, anaemia, hepatorenal failure, circulation failure and other complications can occur. In its most severe form, it affects nearly every organ. Preeclampsia remains a major cause of premature delivery and both maternal and neonatal mortality and morbidity. The origin and the cause of the disease remain unknown and therefore the medical treatment focuses only on clinical manifestations. Timely prediction of preeclampsia would enable accurate therapeutic treatment and a decrease of the threat to maternal and fetal health. In this study, the most important predictive biomarkers of PE and their relevance in the first trimester of gestation are presented. Furthermore, a first trimester screening with the best prediction rates is described. Powered by TCPDF (www.tcpdf.org)Katedra fyziologieDepartment of PhysiologyPřírodovědecká fakultaFaculty of Scienc

Early prediction of preeclampsia

Preeclampsia (PE) is a major cause of perinatal and maternal morbidity and mortality. In the United Kingdom, the National Institute for Clinical Excellence (NICE) has issued guidelines on routine antenatal care recommending that at the booking visit a woman’s level of risk for PE should be determined and the subsequent intensity of antenatal care should be based on this risk assessment. This method relies on a risk scoring system derived from maternal characteristics and medical history; the performance of screening by this method is poor with detection of less than 50% of cases of preterm-PE and term-PE. The objective of this thesis is to develop a method for the estimation of the patient-specific risk for PE by combining the a priori risk based on maternal characteristics and medical history with the results of biophysical and biochemical markers obtained at 11-13 weeks’ gestation. Such early identification of high-risk pregnancies could lead to the use of pharmacological interventions, such as low-dose aspirin, which could prevent the development of the disease. The data for the thesis were derived from two types of studies: First, prospective screening in 65,771 singleton pregnancies, which provided data for maternal factors and serum pregnancy associated plasma protein-A (PAPP-A). In an unselected sequential process we also measured uterine artery pulsatility index (PI) in 45,885 of these pregnancies, mean arterial pressure (MAP) in 35,215 cases and placental growth factor (PLGF) in 14,252 cases. Second, cases-control studies for evaluating the ten most promising biochemical markers identified from search of the literature; for these studies we used stored serum or plasma samples obtained during screening and measured PLGF, Activin-A, Inhibin-A, placental protein-13 (PP13), P-selectin, Pentraxin-3 (PTX-3), soluble Endoglin (sEng), Plasminogen activator inhibitor-2 (PAI-2), Angiopoietin-2 (Ang-2) and soluble fms-like tyrosine kinase-1 (s-Flt-1). A competing risk model was developed which is based on Bayes theorem and combines the prior risk from maternal factors with the distribution of biomarkers to derive patient-specific risk for PE at different stages in pregnancy. The prior risk was derived by multiple regression analysis of maternal factors in the screening study. The distribution of biophysical and biochemical markers was derived from both the screening study and the case-control studies. The prior risk increased with advancing maternal age, increasing weight, was higher in women of Afro-Caribbean and South-Asian racial origin, those with a previous pregnancy with PE, conception by in vitro fertilization and medical history of chronic hypertension, type 1 diabetes mellitus and systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS). The estimated detection rate (DR) of PE requiring delivery at <34, <37 weeks’ gestation and all PE, at false positive rate (FPR) of 10%, in screening by maternal factors were 51, 43 and 40%, respectively. The addition of biochemical markers to maternal factors, including maternal serum PLGF and PAPPA, improved the performance of screening with respective DRs of 74, 56 and 41%. Similarly, addition of biophysical markers to maternal factors, including uterine artery PI and MAP, improved the performance of screening with respective DRs of 90, 72 and 57%. The combination of maternal factors with all the above biophysical and biochemical markers improved the respective DRs to 96, 77 and 54%. The findings of these studies demonstrate that a combination of maternal factors, biophysical and biochemical markers can effectively identify women at high-risk of developing PE

Molecular associations of recurrent spontaneous abortion

Approximately one in four pregnant women experience one or more miscarriages, making spontaneous abortion the most common pregnancy complication, and of public health importance. Recurrent spontaneous abortion (RSA) can be defined as the loss of two or more pregnancies and affects 1% of couples. This prevalence is higher than expected by chance, suggesting some couples have an underlying systemic cause for RSA. We have chosen to study two immunological aspects of pregnancy loss. The first involves maternal defense against infection in terms of predicted mannose binding lectin (MBL) plasma levels. The second approach is to analyze the human leukocyte antigen-G (HLA-G) gene, which is believed to play a role in maternal recognition of paternal antigens at the maternal-fetal interface. The case population included women having two or more clinically recognized spontaneous abortions as well as having unknown etiology for RSA. Controls subjects were selected from healthy primiparous women with no history of miscarriage. Cases and controls were genotyped for five MBL single nucleotide polymorphisms (SNPs). Both populations genotyped were in Hardy-Weinberg equilibrium, at all five sites. Fisher's exact test of cases and controls was not significant at each of the five sites, p-values > 0.05. No association was observed between MBL genotypes or predicted MBL plasma levels and risk of RSA, or presence of live birth and recurrent pregnancy loss, among women with unexplained RSA. Using the same population, the HLA-G promoter region and 3' untranslated region (UTR) was sequenced in cases and controls. Twenty-three SNPs were observed with a minor allele frequency >0.02 in the promoter region. Linkage disequilibrium was detected throughout 1400 base pairs of the promoter region that were sequenced. While SNP data revealed allele frequency differences between cases and controls, haplotype data proved even more beneficial; one haplotype potentially predicting increased risk of RSA, while the other potentially protecting against risk of RSA. Finally, cases had a higher frequency of individuals homozygous for the 14 base pair insertion in the 3' UTR

Evaluation of Maternal Serum sHLA-G Levels for Trisomy 18 Fetuses Screening at Second Trimester

Human leukocyte antigen-G (HLA-G) has been widely acknowledged to play critical roles in fetal-maternal maintenance. However, the significance of using maternal serum sHLA-G to detect prenatal chromosomal abnormality has not been investigated. In China, prenatal screening using maternal α-fetoprotein (AFP), unconjugated estriol (uE3), and free β subunit human chorionic gonadotropin (β-hCG) in the second trimester has been widely applied. In this study, we evaluated the use of sHLA-G as a screening marker, compared with traditional second trimester prenatal screening. Serum samples from 1,019 singleton women in their second trimester were assessed. Among them, 139 infants were confirmed with trisomy 21 (T21) by karyotyping, 83 were confirmed with trisomy 18 (T18), and the remaining 797 infants had no abnormalities. The sHLA-G levels in maternal sera were significantly lower in pregnant women with T18 fetuses (median: 47.8 U/ml, range: 9.8–234.2 U/ml) and significantly higher in those with T21 fetuses (median: 125.7 U/ml, range: 28.7–831.7 U/ml), compared with the normal controls (median: 106.3 U/ml, range: 50.5–1136.4 U/ml) (p &amp;lt; 0.001). The risk values of the screening of T21 or T18 fetuses were assessed using mean and standard deviation log10 analyte multiples of median (MoM) which showed that the predictive values of sHLA-G were the same as free β-hCG, and superior to AFP and uE3 for T18 screening. Logistic regression analysis revealed that sHLA-G MoM was the highest risk factor associated with pregnant women carrying T18 fetuses [Exp(B): 171.26, 95% CI: 36.30–807.97, p &amp;lt; 0.001]. Receiver operating characteristic (ROC) analysis revealed that the area under ROC curve for sHLA-G MoM was 0.915 (95% CI, 0.871–0.959, p &amp;lt; 0.001), for AFP MoM was 0.796 (95% CI, 0.730–0.861, p &amp;lt; 0.001), for free β-hCG MoM was 0.881 (95% CI, 0.829–0.934, p &amp;lt; 0.001), and for uE3 MoM was 0.876 (95% CI, 0.828–0.923, p &amp;lt; 0.001) in the T18 group. sHLA-G MoM demonstrated the best sensitivity and negative predictive value. For the first time, our findings reveal that sHLA-G is a better second trimester screening marker for the detection of T18 fetuses and the combined application of sHLA-G with AFP, free β-hCG, and uE3 could improve clinical screening for T18 fetuses.</jats:p