孕晚期介入性产前诊断的指征和妊娠结局

Indications of invasive prenatal diagnosis in third trimester and pregnancy outcome

目的探讨孕晚期介入性产前诊断的指征及妊娠结局。方法回顾性分析2016年1月至2020年12月于解放军总医院第一医学中心行孕晚期介入性产前诊断的共121例病例的临床资料。根据产前诊断指征的不同采用不同遗传学诊断方法。对孕晚期介入性产前诊断的指征、结果、术后2周内并发症发生情况、妊娠结局以及新生儿随访情况进行描述性统计分析。结果121例于孕晚期行介入性产前诊断的病例中,行羊膜腔穿刺107例,脐血穿刺7例,同时行羊膜腔穿刺及脐血穿刺7例(其中1例同时行胎儿胸腔穿刺)。孕中晚期新发的超声异常为主要产前诊断指征,占99.2%(120/121),其中四肢长骨短小和胎儿生长受限分别占超声指标异常病例的25.0%(30/120)和20.0%(24/120)。通过介入性产前诊断明确胎儿患有遗传性或先天性疾病20例,检出率为16.5%(20/121),其中9例软骨发育不全,5例致病性拷贝数变异,1例软骨发育不全合并致病性拷贝数变异,1例18-三体,1例47,XXX,1例12p四体嵌合体,1例WTX基因c.1072(exon2)C>T p.R358X新发杂合变异,1例胎儿低蛋白血症。另检出临床意义未明的拷贝数变异6例,检出率为5.0%(6/121)。20例介入性产前诊断明确患遗传性或先天性疾病的病例中,15例引产终止妊娠,2例于产前诊断结果回报前早产,1例于产前诊断结果回报前足月剖宫产分娩,2例继续妊娠。6例存在临床意义未明的拷贝数变异病例中1例引产终止妊娠,5例继续妊娠。121例病例中,仅1例(0.8%)于羊膜腔穿刺术后2 d发生未足月胎膜早破。对105例新生儿进行随访,发现2例孕晚期介入性产前诊断未见异常的病例生后全外显子组测序提示为单基因遗传病;12p四体嵌合体患儿发育迟缓;WTX基因变异患儿出生当日死亡;其余新生儿目前均发育正常。结论孕晚期介入性产前诊断有助于严重遗传病和出生缺陷胎儿的产前检出,具有较高安全性;产前全外显子组测序的合理应用有望进一步降低孕期单基因遗传病的漏诊率。

Objective To analyze the indications for invasive prenatal diagnosis in the third trimester and summarize the pregnant outcome.Methods Clinical data of 121 women who underwent invasive prenatal diagnosis in the third trimester in the prenatal diagnostic center of the First Medical Center of Chinese PLA General Hospital from January 2016 to December 2020 was retrospectively analyzed.Different genetic diagnostic methods were used according to different indications.Indications and results of prenatal diagnosis,as well as the complications within two weeks after the invasive procedure,pregnancy outcome,and neonatal follow-up of all the participants were described.Results Among the 121 cases,107 cases underwent amniocentesis,seven underwent percutaneous umbilical blood sampling,and seven had both procedures performed at the same time(one underwent thoracocentesis at the same time).Newly identified ultrasound abnormalities in the second and third trimesters were the main indications for prenatal diagnosis,accounting for 99.2%(120/121),of which short limbs and fetal growth restriction accounted for 25.0%(30/120)and 20.0%(24/120),respectively.Genetic abnormalities and congenital diseases were detected in 20 cases with a detection rate of 16.5%(20/121).Among them,there were nine cases of achondroplasia,five cases of pathogenic copy number variations,one case of achondroplasia with pathogenic copy number variation,one trisomy 18,one 47,XXX,one tetrasome mosaicism of 12p,one de novo WTX c.1072(Exon2)C>Tp.R358X heterozygous mutation,and one fetal hypoproteinemia.In addition,six cases with copy number variation of unknown significance(VUS)were detected,noting for a detection rate of 5.0%(6/121).Among the 20 cases with abnormal detection,15 were terminated,two delivered prematurely before obtaining the prenatal diagnosis results,one underwent cesarean section before obtaining prenatal diagnostic results and two continued the pregnancies.In the six cases with VUS,one was terminated and the other five continued the pregnancy.Only one case had preterm premature rupture of membranes 2 d after amniocentesis and the incidence rate of complications after all kinds of invasive procedures was 0.8%(1/121).During the neonatal follow-up,postnatal whole exome sequencing revealed monogenetic disorder in two cases with normal prenatal diagnostic results;the patient with 12p chimerism had developmental delay;the one with WTX mutation deceased on the day of born;the rest newborns developed normally.Conclusions As a relatively safe method,invasive prenatal diagnosis in the third trimester is of great importance and value in reducing the miss diagnostic rate of fetuses with severe genetic diseases and birth defects.The appropriate application of prenatal whole exome sequencing could further help to decrease the miss diagnostic rate of monogenetic disorder.