This work confirms the value of combining an early determination of maternal serum markers such as PAPP-A with prenatal ultrasound scanning in order to detect fetal aneuploidy [
19‐
21]. Indeed, phenotypic abnormalities exist in both trisomic fetuses and the placenta [
22,
23]. The anatomical differences between the controls and trisomic patients are significant enough to be detected
in vivo using prenatal ultrasound scans. Post-mortem examinations of affected fetuses have confirmed such differences [
24].
As expected, during the first trimester, a common feature of many chromosomal defects is increased nuchal translucency [
25]. However, our work has shown that each chromosomal defect tended to have its own syndromic pattern of abnormalities that affect the skull and brain, the face and neck, the chest, abdomen and extremities [
26].
Although ultrasound scans can demonstrate that major chromosomal defects are often associated with multiple fetal abnormalities, maternal serum markers may provide valuable additional information [
26]. We confirm here in a large cohort that fetal aneuploidies, are generally associated with decreased PAPP-A levels in maternal serum [
27‐
29]. This reduction was limited to the first trimester of pregnancy in trisomy 21 where as it became significative in the second half of pregnancy in case of trisomy 13. We were able to establish that it persists throught the gestation in trisomy 18. These biochemical profiles did not appear to be linked to any specific histological lesions affecting the placenta. The present study has thus confirmed that in a context of aneuploidy, the villi are mainly immature, hydropic and poorly vascularised, with fibrin deposits but with large variability [
30‐
34]. The trophoblastic tissue is poorly developed with a thin syncytiotrophoblast and the persistence of a double layer of villous cytotrophoblasts. The patterns of trisomic placental villi is known to change between the first and second trimesters of pregnancy. During the second trimester, trisomic villi were predominantly large, irregular and hypovascular, while during the third trimester, this type of villus abnormality was only observed in a few villi and was associated with focal hypervascularity.
It is likely that the decrease in PAPP-A levels is not directly related to the chromosomal defect because the PAPP-A gene is located on human chromosome 9 and not on chromosomes 21, 18 or 13. The protein is secreted as an active dPAPP-A homodimer in the form of a metalloproteinase which both interacts with the extracellular matrix and cleaves IGFBP-4 and 5, thus increasing the local bioavailability of IGFs [
2‐
4,
8,
35‐
38]. It has different features that allows PAPP-A to interact with laminin, complement and heparin sulphates on the cell surface and in the extra-cellular matrix. During pregnancy, almost all circulating PAPP-A is bound covalently to a glycoprotein, proMBP (preform of eosinophil major basic protein) to form a hetero-tetrameric complex composed of two PAPP-A and two proMBP subunits [
39]. We were able to establish the maternal profile of htPAPP-A first using antibodies specific to this complex, and second not only during the first trimester but also during the second and third trimesters. We confirmed the sharp increase of PAPP-A during the first half of pregnancy, which has been suggested to reflect the increase in placental volume, and we showed that the slope of this increase rose very slowly during the second half of pregnancy [
40‐
42]. However, very little is known as yet about the individual secretion profiles of dPAPP-A and proMBP [
43]. The latter is believed to occupy the cell-surface binding site of PAPP-A in the circulating complex, so that the tetramer can't bind to the cell surface when it enters the maternal circulation. dPAPP-A and proMBP, and the htPAPPA heterotetrameric complex are expressed physiologically in the villous trophoblast of the first and third trimesters [
4,
44‐
47]. dPAPP-A is weakly expressed in the ST at full-term, whereas htPAPP-A displays the opposite pattern. We had previously explored the pattern of PAPP-A secretion by the villous trophoblast
in vitro, showing that this secretion increased in line with formation of the endocrine syncytiotrophoblast [
48]. During the present study, we investigated the pattern of PAPP-A secretion by the aneuploid villous trophoblast. Our preliminary results suggest that in the case of aneuploidy, the villous trophoblast secretion of PAPP-A was altered. In the case of trisomy 18, we observed an
in vitro decrease in hCG and PAPP-A secretion, and
in vivo a small placental mass and syncytial mass. We also established
in vivo that in trisomy 18, decreased maternal serum PAPP-A levels were not restricted to the first part of pregnancy. Thus, low maternal PAPP-A levels levels are likely to reflect both a reduction in placental volume and lower levels of trophoblastic secretion [
49‐
51]. In trisomy 13, as the placental mass is normal, we can speculate that the decreased maternal serum PAPP-A levels we observed all along the pregnancy result predominantly from a defective trophoblastic production. In trisomy 21, we confirmed our previous
in vitro findings regarding defective differenciation of villous cytotrophoblasts into a syncytiotrophoblast [
52]. This led to the decreased PAPPA secretion we observed. However, we confirmed that
in vivo, maternal serum PAPP-A levels were decreased but only in the first trimester of pregnancy. Thus, the mechanisms involved may be more complex and may differ from one aneuploidy to another [
53].
This PAPP-A decrease seems to be related to a global an impairment of satisfactory differentiation of the villous cytotrophoblast but also of the extravillous cytotrophoblast Indeed, because the decrease in PAPP-A levels is observed early in any pregnancy associated to fetal aneuploidy, the defect may concern the extravillous cytotrophoblast, which is the principal source of PAPP-A at this stage. We had previously demonstrated
in vitro changes to the patterns of PAPP-A secretion, to their regulation during normal gestation and to the trophoblastic phenotype, i.e. villous cytotrophoblast or extravillous cytotrophoblast [
54]. Further studies are now necessary to focus on aneuploid extravillous cytotrophoblasts, but some findings have suggested defective differentiation along the invasive pathway that can affect not only PAPP-A but also other proteases (i.e. MM-9, ADAM12) [
55,
56]. This could explain why these proteases have been proposed as biomarkers of aneuploidy [
57]. It is likely that not only the trophoblastic cells but all cells in the villi could turned over and be differentially modified in the context of aneuploidy [
30,
58,
59].