Placental mosaicism for autosomal trisomies: comprehensive follow-up of 528 Danish cases (1983-2021)

Background: Mosaicism, characterized by the presence of two or more chromosomally distinct cell lines, is detected in 2% to 4% of chorionic villus samples (CVSs). In these cases, the aberration may be confined to the placenta or additionally present in the fetus. Fetal involvement may manifest as fetal malformations, while confined placental mosaicism (CPM) poses risks such as preterm birth and low birth weight. Differentiating between true fetal mosaicism and CPM at the time of the chorionic villus sampling is challenging and requires follow-up by an amniocentesis and ultrasonography.

Objective: To estimate the risk of fetal involvement or adverse pregnancy outcomes for specific chromosomes after detecting mosaicism for an autosomal trisomy in a CVS and identify high (red), intermediate (yellow), and low (green) risk chromosomes. Further, to explore possible associations with level of mosaicism and screening parameters.

Study design: A retrospective descriptive study of all singleton pregnancies with mosaicism detected in CVSs from 1983 to 2021 identified in the Danish Cytogenetic Central Registry and the Danish Fetal Medicine Database.

Results: Of 90,973 CVSs, 528 cases had mosaicism involving an autosomal trisomy and where genetic follow-up had been performed. The overall risk of fetal involvement was 13% (69/528) with extensive variations depending on which chromosome was involved (eg, trisomy 7: 0% [0/55] or trisomy 21: 46% [19/41]). Higher levels of mosaicism in the CVS suggested fetal involvement as mean mosaic level was 55% in true fetal mosaics vs 28% in cases confined to the placenta (P=.0002). In cases with CPM (459/528), the risk of delivering small-for-gestational-age neonates was 14% (48/341). The risk of preterm birth (before 37 weeks) was 15% (51/343). The collective risk of adverse outcome was 22% (76/343) in pregnancies that continued and where information on birth weight and gestational age at birth was available. Adverse outcomes varied substantially between chromosomes. Also, multiple-of-the-median (MoM) values of pregnancy-associated plasma protein A was predictive of these issues as it was significantly lower in cases with adverse outcome compared to cases with a normal outcome (small for gestational age: 0.23 MoM vs 0.47 MoM, P<.0001) or preterm birth: 0.25 MoM vs 0.47 MoM, P<.0001). After the introduction of combined first-trimester screening (cFTS) in 2004, the detection of cases with fetal involvement seemed to increase as the risk before 2004 was 9% (16/174) compared to 15% (53/354) after 2004 (risk ratio: 1.7 [95% CI: 1.0; 2.8]). The risk of adverse outcome in CPM pregnancies increased from 16% (22/139) before 2004 to 27% (55/204) after 2004 (risk ratio 1.7 [95% CI: 1.1; 2.7]).

Conclusion: Introducing cFTS increased the detection of placental mosaicism with fetal involvement and CPM with adverse outcome. In cases of mosaicism in CVSs, the risk of fetal involvement and adverse outcomes varied considerably between chromosomes. Importantly, adverse outcomes were seen in CPM for many trisomies besides trisomy 16.