孕11~13周^+6超声筛查胎儿结构畸形与染色体异常

Chromosomal anomalies in fetuses with structural malformation detected by ultrasonography at 11-13^+6 gestational weeks

目的分析孕11~13周^+6超声筛查发现的胎儿结构畸形,探讨其种类及其与染色体核型及拷贝数变异的关系。方法对2013年1月至2017年12月在中山大学附属第一医院行孕11~13周^+6超声测量颈项透明层的胎儿进行全身结构筛查。发现胎儿结构畸形后行染色体核型或微阵列分析,并在孕16~18周超声复查。随访至分娩。采用Fisher确切概率法进行统计学分析。结果共362例胎儿纳入研究。检出致死性畸形101例(27.9%),严重畸形253例(69.9%),轻微畸形8例(0.2%)。发生较多的前三位系统畸形依次为心脏畸形(32.6%,118/362)、中枢神经系统畸形(24.9%,90/362)及前腹壁畸形(20.9%,76/362)。共107例行染色体核型或染色体微阵列分析,其中致死性畸形25例,严重畸形79例,轻微畸形3例。共检出染色体核型异常30例(28.0%,30/107),其中28例为染色体非整倍体,2例为染色体片段异常。99例CMA检查病例中,25例为染色体核型异常,其余74例中检出拷贝数变异8例,3例(4.05%,3/74)为致病性。严重畸形组中染色体核型异常发生率[32.9%(26/79)]高于致死性畸形组[12.0%(3/25)](P=0.045)。117例中孕期超声复查,16例(13.7%,16/117)未发现异常,19例(16.2%,19/117)心脏畸形修正了主要诊断,5例(4.3%,5/117)新检出其他结构畸形,其余77例的诊断与孕11~13周^+6检查一致。复查后49例引产;39例双胎之一及4例三胎之一畸形减胎;25例继续妊娠,新生儿均存活。孕11~13周^+6超声检查未发现异常的23 699例中,随访到20 182例(85.2%),其中中晚孕超声检查发现胎儿结构异常178例,出生后发现新生儿结构异常31例。结论孕1l^13周^+6超声检查对发现胎儿结构畸形具有重要价值,但尚不能代替中孕期超声检查。早孕期检出的胎儿结构畸形中染色体核型异常的风险高。染色体微阵列分析可进一步检出致病性拷贝数变异,但阳性检出率相对较低。

Objective To investigate the clinical performance of ultrasound screening for fetal structural anomalies at 11-13^+6 weeks of gestation and to evaluate the relation of structural anomalies with karyotypes and copy number variations.Methods A retrospective analysis was conducted on fetuses with structural anomalies detected by ultrasound examination at 11-13^+6 gestational weeks in First Affiliated Hospital of Sun Yat-Sen University from January 2013 to December 2017.Karyotype and chromosomal microarray analysis(CMA) were offered to these fetuses and ultrasound scans were repeated at 16-18 gestational weeks.All fetuses were followed up to termination or birth.Fisher's exact test was used for statistical analysis.Results A total of 362 fetuses with structural anomalies were studied including 101 (27.9%) fatal malformations,253 (69.9%) major malformations and eight (0.2%) minor malformations.Cardiac malformation (32.6%,118/362),central nervous system anomalies (24.9%,90/362) and anterior abdominal wall defects (20.9%,76/362) were the three most common abnormalities.Invasive prenatal test was performed in 107 cases including 25 fatal,79 major and three minor malformations.Thirty (28%) out of the 107 cases had abnormal karyotypes,which were chromosomal aneuploidies (n=28) and chromosomal fragment abnormalities (n=2).Among the 99 cases received CMA,25 had abnormal karyotypes,and copy number variations were identified in eight [three (4.05%) were pathogenic variations] out of the rest 74 with normal karyotypes.The incidence of chromosomal abnormalities in fetuses with major malformations was higher than that of fetuses with fatal malformation [32.9%(26/79) vs 12.0%(3/25),P=0.045].Altogether,117 cases repeated second-trimester ultrasound among which 16 (13.7%) were normal;19 (16.2%) had cardiac defect which was discordant with the first-trimester evaluation and five (4.2%) were found to have additional malformations.Diagnosis of the other 77 cases were consistent with the first-trimester ultrasound findings.After the second-trimester ultrasound scanning,49 pregnancies were terminated;39 twin pregnancies and four triplet pregnancies underwent selective fetal reduction;25 continued to delivery with good neonatal outcomes.Out of the 23 699 cases without abnormal ultrasound findings at 11-13^+6 gestational weeks,20 182 (85.2%) were successfully followed up,among which structural abnormalities were found in 178 during the second trimester and in 31 after birth.Conclusions A detailed ultrasound examination at 11-13^+6 weeks of gestation is important to identify fetal structural defects.However,it could not replace the second-trimester ultrasound.There is a high risk of chromosomal abnormalities in fetuses with early-detected structural defects.CMA is able to identify pathogenic copy number variations with a relatively low detection rate.