Homeobox genes in the human placenta: Twists and turns on the path to find novel targets.

Fetal growth restriction (FGR) is a clinically important human pregnancy disorder that is thought to originate early in pregnancy and while its aetiology is not well understood, the disorder is associated with placental insufficiency. Currently treatment for FGR is limited by increased surveillance using ultrasound monitoring and premature delivery, or corticosteroid medication in the third trimester to prolong pregnancy. There is a pressing need for novel strategies to detect and treat FGR at its early stage. Homeobox genes are well established as master regulators of early embryonic development and increasing evidence suggests they are also important in regulating early placental development. Most important is that specific homeobox genes are abnormally expressed in human FGR. This review focusses on identifying the molecular pathways controlled by homeobox genes in the normal and FGR-affected placenta. This information will begin to address the knowledge gap in the molecular aetiology of FGR and lay the foundation for identifying potential diagnostic and therapeutic targets.

Molecular regulators of defective placental and cardiovascular development in fetal growth restriction.

Placental insufficiency is one of the major causes of fetal growth restriction (FGR), a significant pregnancy disorder in which the fetus fails to achieve its full growth potential in utero. As well as the acute consequences of being born too small, affected offspring are at increased risk of cardiovascular disease, diabetes and other chronic diseases in later life. The placenta and heart develop concurrently, therefore placental maldevelopment and function in FGR may have profound effect on the growth and differentiation of many organ systems, including the heart. Hence, understanding the key molecular players that are synergistically linked in the development of the placenta and heart is critical. This review highlights the key growth factors, angiogenic molecules and transcription factors that are common causes of defective placental and cardiovascular development.

Decreased Expression of Placental Proteins in Recurrent Pregnancy Loss: Functional Relevance and Diagnostic Value.

Miscarriages affect 50-70% of all conceptions and 15-20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL, ≥2 miscarriages) affects 1-5% of recognized pregnancies. Nevertheless, our knowledge about the etiologies and pathophysiology of RPL is incomplete, and thus, reliable diagnostic/preventive tools are not yet available. Here, we aimed to define the diagnostic value of three placental proteins for RPL: human chorionic gonadotropin free beta-subunit (free-ß-hCG), pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF). Blood samples were collected from women with RPL (n = 14) and controls undergoing elective termination of pregnancy (n = 30) at the time of surgery. Maternal serum protein concentrations were measured by BRAHMS KRYPTOR Analyzer. Daily multiple of median (dMoM) values were calculated for gestational age-specific normalization. To obtain classifiers, logistic regression analysis was performed, and ROC curves were calculated. There were differences in changes of maternal serum protein concentrations with advancing healthy gestation. Between 6 and 13 weeks, women with RPL had lower concentrations and dMoMs of free ß-hCG, PAPP-A, and PlGF than controls. PAPP-A dMoM had the best discriminative properties (AUC = 0.880). Between 9 and 13 weeks, discriminative properties of all protein dMoMs were excellent (free ß-hCG: AUC = 0.975; PAPP-A: AUC = 0.998; PlGF: AUC = 0.924). In conclusion, free-ß-hCG and PAPP-A are valuable biomarkers for RPL, especially between 9 and 13 weeks. Their decreased concentrations indicate the deterioration of placental functions, while lower PlGF levels indicate problems with placental angiogenesis after 9 weeks.

Liposome-Encapsulated Anti-inflammatory Proteins for Targeted Delivery to the Placenta to Treat Fetal Growth Restriction.

Fetal growth restriction (FGR), the failure of a fetus to reach its genetically determined growth potential, is a serious complication affecting up to 10% of pregnancies. FGR is a major risk factor for stillbirth and, in the survivors, neurodevelopmental disorders. We have recently identified that the anti-inflammatory and pro-resolving molecule, lipoxin A4 (LXA4) and its soluble receptor, formyl-peptide receptor-2 (FPR-2) are significantly decreased in human placentas from FGR pregnancy. The LXA4 synthetic analog Compound 43 (C43) is considered a safe, anti-inflammatory therapy and is being developed as a treatment for disease conditions with an inflammatory basis, for example, asthma in children. Identification of therapies to treat FGR in utero comes with the need to mitigate their potential side effects and the use of nanoparticle-mediated delivery systems could facilitate this. Our current studies are focused on targeting the resolution of inflammation observed in FGR placentas, by synthesizing liposome-encapsulated C43 as a novel therapeutic to improve placental function in FGR. In this chapter, we provide a detailed methodological procedure for the preparation of liposomes and conjugation of the peptide sequences, which selectively bind to the outer placental syncytiotrophoblast layer or the vascular endothelium of the uterine spiral arterioles.

Early screening for preeclampsia / Rastreamento precoce da pré-eclampsia

Preeclampsia, which affects about 3 to 5 percent of pregnant women, is the most frequent medical complication in pregnancy and the most important cause of maternal and perinatal morbidity and mortality. During the past three decades, numerous clinical, biophysical, and biochemical screening tests have been proposed for the early detection of preeclampsia. Literature shows large discrepancies in the sensitivity and predictive value of several of these tests. No single screening test used for preeclampsia prediction has gained widespread acceptance into clinical practice. Instead, its value seems to be in increasing the predictive value of panels of tests, which include other clinical measurements. The aim of this review was to examine the combination of maternal risk factors, mean arterial blood pressure, and uterine artery Doppler, together with biomarkers in the preeclampsia prediction.

A pré-eclâmpsia, que afeta cerca de 3 a 5 por cento das mulheres grávidas, é a mais frequente complicação médica durante a gestação e a mais importante causa de morbidade e mortalidade maternal e perinatal. Durante as últimas três décadas, numerosos testes de rastreamento clínicos, biofísicos e bioquímicos foram propostos para a detecção precoce da pré-eclâmpsia. A literatura mostra grandes discrepâncias na sensibilidade e no valor preditivo de muitos desses testes. Nenhum teste de rastreamento isolado usado para a predição da pré-eclâmpsia tem ganhado ampla aceitação na prática clínica. Ao contrário, parece que o valor preditivo aumenta com a inclusão de um painel de testes, os quais incluem outros parâmetros clínicos. O objetivo desta revisão foi examinar a combinação dos fatores de risco maternos, a pressão arterial média, o Doppler das artérias uterinas com os marcadores séricos, na predição da pré-eclâmpsia.