Biochemical Screening for Fetal Trisomy 21: Pathophysiology of Maternal Serum Markers and Involvement of the Placenta

It is now well established that maternal serum markers are often abnormal in fetal trisomy 21. Their determination is recommended for prenatal screening and pregnancy follow-up. However, mechanisms leading to abnormal maternal serum levels of such markers are still debated. Our objective was to help clinicians and scientists unravel the pathophysiology of these markers via a review of the main studies published in this field, both in vivo and in vitro, focusing on the six most widely used markers (hCG, its free subunit hCG beta, PAPP-A, AFP, uE3, and inhibin A) as well as cell-free feto-placental DNA. Analysis of the literature shows that mechanisms underlying each marker's regulation are multiple and not necessarily directly linked with the supernumerary chromosome 21. The crucial involvement of the placenta is also highlighted, which could be defective in one or several of its functions (turnover and apoptosis, endocrine production, and feto-maternal exchanges and transfer). These defects were neither constant nor specific for trisomy 21, and might be more or less pronounced, reflecting a high variability in placental immaturity and alteration. This explains why maternal serum markers can lack both specificity and sensitivity, and are thus restricted to screening.

Automated summary

It is well established that maternal serum markers can be abnormal in fetal trisomy 21, and their determination is recommended for prenatal screening and pregnancy follow-up. However, the mechanisms leading to abnormal levels of these markers are still debated. This review of published studies aims to unravel the pathophysiology of these markers, with a focus on the six most widely used markers and cell-free feto-placental DNA.