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.

Keywords: PAPP-A; cell free fetal DNA; fetal aneuploidy; hCG; hCG free β subunit; inhibin A; maternal blood; placenta; prenatal screening; unconjugated estriol.

Figure 1

Structure and secretion of hCG in vivo (A) and in vitro (B). hCG is a dimeric glycoprotein composed of a common α subunit (hCGα), and a specific ß subunit (hCGβ). The secretion of hCG and its free ß subunit in maternal blood increase during the first trimester of gestation, and decrease thereafter; the secretion of its free α subunit increases all through pregnancy in line with placental mass (A). In vitro and vivo, the morphological differentiation of the villous cytotrophoblasts (VCT) into a syncytiotrophoblast (ST) is mainly associated with functional differentiation, as assessed by the increasing production of hCG and its subunits (B).

Figure 2

Human placental definitive villi and trophoblastic tissue. From the end of the first trimester of gestation, the human placenta is composed of two types of villi: the anchoring villi with extravillous cytotrophoblasts (EVCT) that proliferate, migrate, and invade the maternal uterine wall to reach the spiral artery; the floating villi composed of villous cytotrophoblasts (VCT), aggregating and fusing to form the syncytiotrophoblast (ST) on the borders of floating villi in contact with maternal blood as from 10 to 12 WG. EVCT is likely to be the major source of maternal serum markers in early pregnancy, whereas ST becomes the major source at the end of the first trimester of gestation.

Figure 3

Structure and main functions of pregnancy-associated plasmatic protein A (PAPP-A).

Figure 4

Synthesis and secretion of alpha feto protein (AFP) during pregnancy. AFP is mainly synthetized by the fetal liver and secreted in fetal blood. It is then excreted by the immature fetal kidneys via urine in amniotic fluid, peaking at around 14 WG. Thereafter, renal AFP filtration decreases with kidney maturation and therefore its amniotic levels fall until the end of pregnancy. AFP reaches the maternal circulation through the membranes and placenta. This transfer, which may involve lectins, is very low and reaches a plateau at about 32 WG.

Figure 5

Synthesis and secretion of estriol during pregnancy. The human placenta lacks cytochrome P450 17alpha-hydroxylase-17:20 lyase, which is required to convert progestins into androgens (a). Thus, the placenta participates in the enzymatic conversion of fetal 16α-OH-DHEA-S, DHEA-S (b), and the maternal DHEA-S (b’) into E3, by sulfatase (STS), and aromatase activities (c). Estrogens diffuse into both the fetal and maternal compartments (d). estriol (E3), estradiol (E2), estrone (E1), dehydroepiandrostenedione (DHEA), sulfate of dehydroepiandrostenedione (SDHEA), delta 4 androstenedione (Δ4A).

Figure 6

Physiopathology of maternal serum markers in trisomy 21-affected pregnancies. The human placenta releases soluble markers into the maternal blood as well as cells and cell-free DNA. Soluble markers can be of fetal origin, such as the alpha feto protein (AFP), of feto–placental origin, such as the unconjugated estriol (uE3), or of placental origin, such as the human chorionic gonadotropin (hCG) and its free beta subunit (hCGβ), the pregnancy-associated plasmatic protein A (PAPP-A), and the inhibin A (inhibin A). In trisomy 21-affected pregnancies, both placental and fetal functions are disrupted, leading to the decrease (↓) or the increase (↑) of their concentrations in maternal blood.