Department of Clinical Medicine, Center for Fetal Diagnostics, Aarhus University, Aarhus, Denmark (Thomsen Becher, and Vogel); Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark (Thomsen, Lund, and Becher); Center for Fetal Diagnostics, Aarhus University, Aarhus, Denmark (Thomsen, Lund, Becher and Vogel).
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark (Thomsen, Lund, and Becher); Department of Biomedicine, Center for Fetal Diagnostics, Aarhus University, Aarhus, Denmark (Lund); Center for Fetal Diagnostics, Aarhus University, Aarhus, Denmark (Thomsen, Lund, Becher and Vogel).
Am J Obstet Gynecol MFM. 2024 Nov;6(11):101497. doi: 10.1016/j.ajogmf.2024.101497. Epub 2024 Sep 19.
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.
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.
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.
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]).
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.
在 2%至 4%的绒毛膜绒毛样本（CVS）中检测到嵌合体，其特征是存在两个或多个染色体明显不同的细胞系。在这些情况下，异常可能局限于胎盘，或者另外存在于胎儿中。胎儿受累可能表现为胎儿畸形，而局限性胎盘嵌合体（CPM）则存在早产和低出生体重等风险。在绒毛膜绒毛取样时，区分真正的胎儿嵌合体和 CPM 具有挑战性，需要通过羊膜穿刺术和超声检查进行随访。
估计在 CVS 中检测到常染色体三体嵌合体后，特定染色体发生胎儿受累或不良妊娠结局的风险，并确定高（红色）、中（黄色）、低（绿色）风险染色体。此外，还探讨了与嵌合体水平和筛查参数的可能关联。
对 1983 年至 2021 年丹麦细胞遗传学中央登记处和丹麦胎儿医学数据库中发现的 CVS 中检测到常染色体三体嵌合体的所有单胎妊娠进行回顾性描述性研究。
在 90973 例 CVS 中，528 例存在涉及常染色体三体的嵌合体，且已进行了遗传随访。胎儿受累的总体风险为 13%（69/528），具体取决于涉及的染色体而异（例如，三体 7：0%[0/55]或三体 21：46%[19/41]）。CVS 中嵌合体水平较高提示胎儿受累，因为真正的胎儿嵌合体的平均嵌合体水平为 55%，而局限于胎盘的病例为 28%（P=.0002）。在 CPM 病例（459/528）中，小于胎龄儿的分娩风险为 14%（48/341）。早产（37 周前）的风险为 15%（51/343）。在继续妊娠且有出生体重和胎龄信息的 343 例妊娠中，不良结局的总风险为 22%（76/343）。不良结局在不同染色体之间存在显著差异。此外，妊娠相关血浆蛋白 A 的倍数中位数（MoM）值可预测这些问题，因为与正常结局（小于胎龄儿：0.23 MoM 与 0.47 MoM，P<.0001）或早产（0.25 MoM 与 0.47 MoM，P<.0001）相比，不良结局病例的 MoM 值明显较低。在 2004 年联合早孕期筛查（cFTS）引入后，胎儿受累病例的检出似乎有所增加，因为 2004 年之前的风险为 9%（16/174），而 2004 年之后的风险为 15%（53/354）（风险比：1.7[95%CI：1.0；2.8]）。CPM 妊娠的不良结局风险从 2004 年之前的 16%（22/139）增加到 2004 年之后的 27%（55/204）（风险比 1.7[95%CI：1.1；2.7]）。
引入 cFTS 增加了胎盘嵌合体伴胎儿受累和 CPM 伴不良结局的检出率。在 CVS 中存在嵌合体的情况下，胎儿受累和不良结局的风险在不同染色体之间存在显著差异。重要的是，CPM 中除了三体 16 之外，还存在许多其他三体的不良结局。
