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-β-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 β-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 β-hCG: AUC = 0.975; PAPP-A: AUC = 0.998; PlGF: AUC = 0.924). In conclusion, free-β-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.

The prevention of pre-eclampsia is difficult due to the syndromic nature and multiple underlying mechanisms of this severe complication of pregnancy. The current clinical distinction between early- and late-onset disease, although clinically useful, does not reflect the true nature and complexity of the pathologic processes leading to pre-eclampsia. The current gaps in knowledge on the heterogeneous molecular pathways of this syndrome and the lack of adequate, specific diagnostic methods are major obstacles to early screening and tailored preventive strategies. The development of novel diagnostic tools for detecting the activation of the identified disease pathways would enable early, accurate screening and personalized preventive therapies. We implemented a holistic approach that includes the utilization of different proteomic profiling methods of maternal plasma samples collected from various ethnic populations and the application of systems biology analysis to plasma proteomic, maternal demographic, clinical characteristic, and placental histopathologic data. This approach enabled the identification of four molecular subclasses of pre-eclampsia in which distinct and shared disease mechanisms are activated. The current review summarizes the results and conclusions from these studies and the research and clinical implications of our findings.

AbstractThe concept of the Great Obstetrical Syndromes was introduced to explain the unique nature of obstetrical disease, which differs fundamentally from disorders in other areas of medicine. These syndromes, including preeclampsia, fetal growth restriction, fetal death, and spontaneous preterm birth, represent clinical endpoints rather than single diseases and share defining characteristics: they arise from multiple etiologies, have a prolonged subclinical phase, involve the fetus as an active participant, are adaptive in nature, and result from complex genetic and environmental interactions between the mother and fetus. Among the diverse mechanisms leading to these syndromes, abnormalities of the maternal supply line to the placenta constitute one major etiology and are often caused by vascular disorders affecting the maternal cardiovascular system and uterine spiral arteries, resulting in placental lesions of maternal vascular malperfusion. The most severe spiral artery lesion is atherosis, which closely resembles atherosclerosis and links obstetrical syndromes to maternal vascular disease. Disorders of deep placentation associated with maternal vascular malperfusion are accompanied by characteristic alterations in angiogenic balance, and the ratio of placental growth factor to soluble fms-like tyrosine kinase-1 in the maternal circulation serves as a biomarker of this pathophysiologic process. Importantly, each obstetrical syndrome is associated with a stereotypic temporal pattern of angiogenic imbalance that reflects differences in disease burden, timing, and clinical expression. While substantial progress has been made in the prediction and prevention of preeclampsia, these concepts extend to other obstetrical syndromes, including fetal growth restriction, fetal death, and spontaneous preterm labor, supporting a unified biologic framework for early risk assessment and personalized prevention.