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

Abstract

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 hCGβ, 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.

Relationship between increased maternal serum free human chorionic gonadotropin levels in the second trimester and adverse pregnancy outcomes: a retrospective cohort study

“…Free β-hCG is produced by the trophoblast layer outside the villi, and syncytiotrophoblast cells are the main placental source of free β-hCG. The main function of free β-hCG is to promote the synthesis of progesterone in the corpus luteum, maintain the resting state of the uterine muscle layer and pregnancy, until the placenta itself ensures the production of progesterone [ 23 ]. The exact time and form of free β-hCG secretion peak in early pregnancy are still not reasonably explained.…”

Looking at a baby's heart through the lens of the mother's blood

“…Placental dysfunction is frequently associated with and contributes to morbidity and mortality in CHD. Some of these markers have been already used to monitor the "placental proteomic clock" in at-risk pregnancies and for the screening of diseases such as trisomy 21, which are at risk for CHD (Degnes et al, 2022;Guibourdenche et al, 2023).…”

Placental Related Disorders of Pregnancy 2.0

“…The first two systematic reviews investigate pregnancy latency biomarkers after preterm premature rupture of membranes [ 2 ] and atypical pre-eclampsia before 20 weeks of gestation [ 3 ]. This is followed by detailed reviews of the apelinergic system in pregnancy [ 4 ]; serum screen markers for trisomy 21 and the crucial involvement of the placenta [ 5 ]; how the placenta can provide a protective role in SARS-CoV-2 transplacental transmission [ 6 ]; endoplasmic reticulum aminopeptidase 1 and 2 and their involvement in pregnancy and cancer [ 7 ]; and how rodent and rabbit models can be used in pre-eclampsia research [ 8 ]. Moreover, this Special Issue also contains original articles with novel data covering hypothyroidism [ 9 ] and pre-eclampsia/fetal growth restriction [ 10 , 11 , 12 , 13 ].…”