基于前瞻性队列研究建立高龄孕妇产前筛查与诊断方案

With the two-child policy in full operation, the prevention for birth defects caused by an increasing number of elderly parturient women might be quite tough. Prenatal screening and diagnosis is an important prevention to control birth defects. However, there were no effective schemes for prenatal screening and diagnosis for advanced maternal age (AMA) women. According to our previous studies, the main problem of prenatal screening and diagnosis for AMA as below: (1) 98% of the elderly parturient women accepted unnecessary invasive prenatal diagnosis by current program. We are likely to adjust age cutoff of judgment of invasive prenatal diagnosis. (2) It was unnecessary for AMA pregnant women whose age over 38 to receive serological prenatal screening, because they are almost as high risk or critical risk. (3) If the risk value of prenatal screening is over 1/150, it indicates a high possibility for serious fetal malformations. (4) NIPT is quite effective when applied to elderly parturient women for prenatal screening, whose efficacy has a positive correlation with age. .Therefore, our research team propose that we should have risk stratification management on AMA pregnant women and design appropriate schemes for their prenatal screening and diagnosis in accordance with their age and screening risk value. Firstly, our research reviews sex cohort study, further analyzes the serological effectiveness of prenatal screening and diagnosis and then design proper schemes for prenatal screening and diagnosis. Secondly, based on prospective cohort study which assisted by Changzhou Center of national birth cohort, we explore the relationship between the risk factors for AMA pregnant women and the clinical effects of prenatal screening and diagnosis. Combine with the analysis of cost effectiveness, our research team plans to establish a proper scheme for prenatal screening and diagnosis for elderly parturient women. Thirdly, based on the diagnosis scheme established, we conduct risk stratification for AMA pregnant women, provide suitable technique of screening and diagnosis for them, and assess the effectiveness of the scheme according to randomized and comparative clinical study. This research will provide new ideas for prenatal screening and diagnosis technique for AMA pregnant women, which will improve their risk management, provide them with proper and personalized technique, thus decreasing birth defects.

随着二孩政策的全面实施，日益增多的高龄孕妇人群所带来的出生缺陷防治新形势将极为严峻。迄今为止尚缺乏针对高龄孕妇有效的产前筛查与诊断方案。项目组前期研究发现：单纯以年龄作为介入性产前诊断的指征并不合理，年龄及筛查风险值与胎儿染色体异常检出率显著正相关。因此，项目组提出以年龄与筛查风险值作为主要危险因素，对高龄孕妇进行风险分层管理，建立产前筛查与诊断方案。本研究通过回顾性队列研究设计产前筛查与诊断的适宜路径；依托于国家出生队列常州中心，结合前瞻性队列研究和成本效益分析，建立“高龄孕妇产前筛查诊断方案”，通过临床随机对照研究评估该方案的效果。本研究将为高龄孕妇选择产前筛查与诊断技术提供新的思路，将有助于该人群的风险管理，提供个性化的适宜技术，以降低出生缺陷出生。

我国高龄孕妇数量呈逐年上升趋势，由此带来的出生缺陷高发已成为重大的公共卫生问题和科学问题。课题组采用回顾性队列开展了高龄孕妇产前筛查与诊断的系列研究，建立了适合国情的方案，通过前瞻性队列评估了临床应用效果，主要取得研究结果：（1）经问卷调查，32.8%的高龄孕妇因为安全因素不愿意接受有创性的产前诊断，而78.8%的愿意接受NIPS。（2）高龄孕妇应用NIPS：T21/T18/T13敏感性、特异性、PPV和NPV分别为100%、99.88%、92.55%、100%；胎儿SCAs PPV为66.67%；胎儿致病性CNVs PPV为15.1%。然而，如果NIPS完全取代产前诊断，12.4%的胎儿染色体异常将被漏诊。（3）高龄孕妇胎儿染色体异常率为5.13%，40岁以上将高达7.07%，直接接受产前诊断极为必要。CMA的应用可提高异常检出率1.4%。（4）利用Treeag构建决策树模型发现，“产前诊断策略”与“NIPS筛查策略”的成本效益最佳，是高龄孕妇产前筛查与诊断较适宜的技术。（5）依据高龄孕妇出生队列发现，高龄孕妇不良妊娠发生率高达72.3%，以早产、胎儿生长受限、妊娠期高血压疾病、GDM为主要特征。据此，得出主要研究结论：（1）越来越多的高龄孕妇愿意接受NIPS，而非有创性产前诊断，充分知情同意和遗传咨询至关重要。（2）高龄孕妇不适合传统的血清学筛查，NIPS是较好的产前筛查方法，进一步按年龄分层管理有助于提高其筛查与诊断效果，并且避免漏诊风险。（3）高龄孕妇是胎儿染色体异常的高危人群，尤其是40岁以上的高龄孕妇，直接接受产前诊断更为适宜，染色体核型分析+CMA联合检测是合适的技术方案。（4）高龄孕妇数量急剧增加，由此带来的妊娠风险（出生缺陷、不良妊娠等）值得高度关注。.通过研究，课题组获得了一定研究成果，共发表学术论文8篇，其中SCI收录6篇，出版专著1部，获得中国妇幼健康科学技术奖自然科学二等奖1项。面对高龄孕妇数量急剧增加的新形势，本研究为我国高龄孕妇选择最优化的产前筛查与诊断技术提供新的思路，对提升高龄孕妇出生缺陷防治、提高出生人口素质具有重要意义。