Center for Fetal Medicine, Pregnancy and Ultrasound, Department of Obstetrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Ultrasound Obstet Gynecol. 2024 Jan;63(1):34-43. doi: 10.1002/uog.27466.
To examine the distribution of nuchal translucency thickness (NT), free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in pregnancies with a fetal 22q11.2 aberration. Furthermore, the performance of combined first-trimester screening (cFTS) and a new risk algorithm targeting 22q11.2 deletions in detecting affected pregnancies was evaluated. Finally, prenatal malformations and pregnancy outcome were assessed.
This was a nationwide registry-based cohort study of all pregnancies that underwent prenatal screening with a due date between January 2008 and December 2018 in Denmark. All cases with a fetal 22q11.2 deletion or duplication (hg19 chr22:18.9mio-25.0mio) diagnosed pre- or postnatally or following pregnancy loss or termination of pregnancy were retrieved from the Danish Cytogenetic Central Register and linked with pregnancy data from the Danish Fetal Medicine Database. Fetal and maternal characteristics, including cFTS results and pregnancy outcome, of pregnancies with any 22q11.2 deletion or duplication (LCR22-A to -H) and pregnancies with a classic deletion or duplication (LCR22-A to -D) diagnosed by chromosomal microarray were compared with those of a chromosomally normal reference group. A risk algorithm was developed for assessing patient-specific risks for classic 22q11.2 deletions based on NT, PAPP-A and β-hCG. Detection rates and false-positive rates at different risk cut-offs were calculated.
We included data on 143 pregnancies with a fetal 22q11.2 aberration, of which 97 were deletions (54 classic) and 46 were duplications (32 classic). NT was significantly increased in fetuses with a classic deletion (mean, 1.89 mm), those with any deletion (mean, 1.78 mm) and those with any duplication (mean, 1.86 mm) compared to the reference group (mean, 1.65 mm). β-hCG multiples of the median (MoM) was decreased in all 22q11.2 subgroups compared with the reference group (mean, 1.02) and reached significance in pregnancies with a classic deletion and those with any deletion (mean, 0.77 and 0.71, respectively). PAPP-A MoM was significantly decreased in pregnancies with a classic duplication and those with any duplication (mean, 0.57 and 0.63, respectively), and was significantly increased in pregnancies with a classic deletion and those with any deletion (mean, 1.34 and 1.16, respectively), compared to reference pregnancies (mean, 1.01). The screen-positive rate by cFTS was significantly increased in pregnancies with a classic deletion (13.7%), any deletion (12.5%), a classic duplication (46.9%) or any duplication (37.8%) compared to the reference group (4.5%). A risk algorithm targeting classic 22q11.2 deletions more than doubled the prenatal detection rate of classic 22q11.2 deletions, but with a substantial increase in the false-positive rate. Structural malformations were detected in 41%, 35%, 17% and 25% of the pregnancies with a classic deletion, any deletion, classic duplication or any duplication, respectively. Pregnancy loss occurred in 40% of pregnancies with a classic deletion and 5% of those with a classic duplication diagnosed prenatally or following pregnancy loss.
The distribution of cFTS markers in pregnancies with a classic 22q11.2 duplication resembles that of the common trisomies, with decreased levels of PAPP-A. However, classic 22q11.2 deletions are associated with increased levels of PAPP-A, which likely limits early prenatal detection using the current cFTS risk algorithm. The scope for improving early detection of classic 22q11.2 deletions using targeted risk algorithms based on NT, PAPP-A and β-hCG is limited. This demonstrates the capability, but also the limitations, of cFTS markers in detecting atypical chromosomal anomalies, which is important knowledge when designing new prenatal screening programs. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
研究具有胎儿 22q11.2 异常的妊娠中颈项透明层厚度（NT）、游离β-人绒毛膜促性腺激素（β-hCG）和妊娠相关血浆蛋白-A（PAPP-A）的分布情况。此外，评估联合早孕期筛查（cFTS）和针对 22q11.2 缺失的新风险算法在检测受影响妊娠中的表现。最后，评估产前畸形和妊娠结局。
这是一项基于全国的注册队列研究，纳入了 2008 年 1 月至 2018 年 12 月期间在丹麦接受产前筛查的所有妊娠。所有产前或产后诊断的胎儿 22q11.2 缺失或重复（hg19 chr22：18.9mio-25.0mio），或因妊娠丢失或终止妊娠后诊断的病例，均从丹麦细胞遗传学中央登记处检索，并与丹麦胎儿医学数据库中的妊娠数据相关联。将任何 22q11.2 缺失或重复（LCR22-A 至 -H）的妊娠和经典缺失或重复（LCR22-A 至 -D）的妊娠的胎儿和母体特征，包括 cFTS 结果和妊娠结局，与染色体正常的参考组进行比较。根据 NT、PAPP-A 和 β-hCG，开发了一种用于评估经典 22q11.2 缺失患者特定风险的风险算法。计算了不同风险截止值的检出率和假阳性率。
我们纳入了 143 例胎儿 22q11.2 异常的妊娠数据，其中 97 例为缺失（54 例经典缺失），46 例为重复（32 例经典重复）。与参考组（平均 1.65mm）相比，经典缺失的胎儿（平均 1.89mm）、任何缺失的胎儿（平均 1.78mm）和任何重复的胎儿（平均 1.86mm）的 NT 值显著增加。与参考组相比（平均 1.02），所有 22q11.2 亚组的β-hCG 中位数倍数（MoM）均降低，经典缺失和任何缺失组的差异均有统计学意义（平均 0.77 和 0.71）。经典重复和任何重复组的 PAPP-A MoM 均显著降低（平均 0.57 和 0.63），经典缺失和任何缺失组的 PAPP-A MoM 均显著升高（平均 1.34 和 1.16），与参考妊娠相比（平均 1.01）。与参考组（4.5%）相比，经典缺失（13.7%）、任何缺失（12.5%）、经典重复（46.9%）或任何重复（37.8%）的妊娠 cFTS 阳性率显著增加。针对经典 22q11.2 缺失的风险算法将经典 22q11.2 缺失的产前检出率提高了一倍以上，但假阳性率显著增加。分别有 41%、35%、17%和 25%的经典缺失、任何缺失、经典重复和任何重复的妊娠中发现结构畸形。产前或妊娠丢失后诊断的经典缺失妊娠中 40%发生妊娠丢失，而经典重复妊娠中仅 5%发生妊娠丢失。
经典 22q11.2 重复妊娠的 cFTS 标志物分布类似于常见三体，PAPP-A 水平降低。然而，经典 22q11.2 缺失与 PAPP-A 水平升高相关，这可能限制了使用当前 cFTS 风险算法进行早期产前检测。基于 NT、PAPP-A 和 β-hCG 的针对经典 22q11.2 缺失的靶向风险算法提高早期检测的范围有限。这证明了 cFTS 标志物在检测非典型染色体异常方面的能力，但也显示了其局限性，这在设计新的产前筛查计划时很重要。
