Selected from: Chinese Journal of Obstetrics and Gynecology, vol.55, No.2, February 2020
Author: Hu Yali 1, Yang Huixia 2
1. Department of gynecology and obstetrics, Gulou Hospital Affiliated to Nanjing University Medical College 210008;
2 Department of Obstetrics and Gynecology, the first hospital of Peking University 100034
Correspondence Author: Hu Yali, email: yalihu@nju.edu.cn
Abstract: noninvasive prenatal test (NIPT) is a kind of prenatal screening technology which has no risk of puncture related abortion, infection and other risks compared with invasive prenatal diagnosis. Many scholars and professional magazines call for the use of CF DNA test to describe the detection of common chromosomal aneuploidy of fetus by CF DNA sequencing in maternal serum or comparative genomic hybridization. It should be emphasized that on the premise of the pregnant women's full informed consent, it can be pointed out that CF? DNA testing can be selected for prenatal screening in land acquisition; before the reasonable cost-benefit ratio is clear, it is not recommended to carry out CF? DNA testing in low-risk pregnant women, and standardize the clinical service process of CF? DNA testing.
Noninvasive prenatal testing (NIPT) is a kind of prenatal screening technology which has no risk of puncture related abortion, infection and other risks compared with invasive prenatal diagnosis. Therefore, NIPT actually includes at least the detection of fetal chromosomal aneuploidy by maternal serum (or plasma) screening and fetal structural ultrasound based on imaging technology. In order to avoid misunderstanding of the term "NIPT", many scholars and professional magazines call for the use of free DNA (CF? DNA) test to describe the detection of common chromosomal aneuploidy of fetus by CF? DNA sequencing in maternal serum or comparative genomic hybridization. NIPT is not recommended as a synonym for CF? DNA detection.
1、 CF? DNA detection ≠ NIPT with the discovery of maternal serum CF? DNA and the rapid progress of genetic detection technology, since lo and Chiu [3] first published the study of detecting fetal chromosomal aneuploidy through maternal serum CF? DNA in 2008, prenatal screening of fetal trisomy 21 and trisomy 18 based on CF? DNA The method of trisomy and trisomy 13 syndrome has been popularized rapidly, which is called NIPT for short. Therefore, NIPT has become the synonym of CF? DNA detection for a long time. The detection rate of fetuses with trisomy 21, trisomy 18 and trisomy 13 syndrome is high and the false positive rate is low. More than 40000 cases of fetal chromosome aneuploidy were screened based on CF? DNA test reported by Liang Dong et al. [4] in this period. The results showed that although there was a gap with the results reported by related meta-analysis [5], it was significantly better than the detection rate and false-positive rate of prenatal screening using maternal serological and biochemical indicators [6].
However, from the point of view of the target diseases screened by CF DNA testing, CF DNA testing is only a part of NIPT screening content, and the two cannot be equated. In order to correctly guide the development of CF DNA detection technology and avoid commercial driving, the National Health Authority issued the "trial specification for high-throughput gene sequencing prenatal screening technology" in 2015, emphasizing that on the premise of the pregnant women's full informed consent, it is possible to select CF DNA detection for prenatal screening on land acquisition, and not recommended in low-risk pregnant women until the reasonable cost-benefit ratio is clear Routine CF DNA testing was carried out, and the clinical service process and quality management of CF DNA testing were standardized. It should be said that this "trial specification" has played a very important role in guiding the rational clinical application of CF? DNA detection technology in China.
2、 CF? DNA testing alone could not meet the purpose of prenatal screening. In the 1970s, at the beginning of the concept of prenatal screening, the target birth defects of prenatal screening were trisomy 21 syndrome and open neural tube defects. After nearly 40 years of rapid development, the current prenatal screening has developed from a single detection of maternal serological and biochemical indicators to a relatively perfect multi technology fusion system. The clinical evidence-based research also further defines the practical scope and screening efficiency of each technology. On this basis, the purpose of prenatal screening has been sublimated, which is no longer limited to the screening of trisomy 21 syndrome, but to improve the health quality of the birth population for the purpose of expanding to the screening of fetuses who may have serious birth defects. Therefore, from the current purpose of prenatal screening, the task of prenatal screening is not only to screen out the common chromosomal aneuploidy abnormalities of the fetus, but also to screen out the fatal or severely disabled fetal structural abnormalities. According to the 2012 National Health Department birth defects monitoring report, trisomy 21, trisomy 18 and trisomy 13 syndrome only accounts for nearly 4% of the total birth defects, and more birth defects are fetal structural abnormalities. Therefore, the two major parts of NIPT, namely, the high-quality implementation of fetal chromosome aneuploidy screening and fetal major structural abnormality screening, are the guarantee to improve the efficiency of prenatal screening. The current prenatal screening strategy recommended by the professional committees of the International Association for prenatal diagnosis, Europe and the United States and other developed countries, the first-line screening program is the ultrasound examination in the early stage of pregnancy (11-13 weeks + 6 weeks of pregnancy) and the measurement of the thickness of the fetal neck hyaline layer combined with the detection of the maternal serum hCG and pregnancy related glycoprotein A, and the fetal structure ultrasound screening in the middle stage of pregnancy. The international society of Obstetrics and Gynecology has also issued guidelines for the screening of fetal structures in early pregnancy. The cohort study on the prognosis of fetus with thickened cervical hyaline layer in early pregnancy reported by Tang Huirong et al. [9] shows the importance of prenatal ultrasound. The Chinese government attaches great importance to the comprehensive prevention and control of birth defects. During the 12th Five Year Plan and the 13th five year plan, it has continuously deployed key issues of prevention and control of birth defects, and has made unremitting efforts in the training of the backbone team for ultrasonic screening of fetal structural abnormalities. In recent years, it has set up training bases nationwide. It is expected that in the near future, the majority of pregnant women at the grass-roots level will not only get fetal chromosome aneuploidy In addition, we can get a high quality ultrasound screen of fetal structure.
3、 The problems worthy of attention in the current clinical application of CF DNA detection prenatal screening in China's "trial specification for high-throughput gene sequencing prenatal screening technology" [7] clearly pointed out that currently, CF DNA detection is only used to screen high-risk single pregnant women with trisomy 21, trisomy 18 and trisomy 13 syndrome. Although the whole genome sequencing using CF? DNA detection technology can also find other chromosomal aneuploidies or structural abnormalities in the ultrasound part, but it will increase the cost of detection, and with the increase of chromosomal detection content, the false-positive rate will continue to rise, and because the incidence of other chromosomal abnormalities is low, the positive predictive value of detection is also very low [10]. Chang Jiazhen et al [11] reported that in the prenatal diagnosis of pregnant women suspected of X-chromosome abnormality by CF? DNA detection, the accuracy of fetal sex chromosome screening is not high, and it is easy to be affected by the mother's X-chromosome abnormality. At present, there is no evidence-based recommendation for clinical application of CF? DNA detection to screen chromosomal aneuploidy and chromosomal structural abnormalities other than trisomy 21, trisomy 18 and trisomy 13 syndrome.
Most of the studies on the clinical application of CF? DNA detection are to use it as a second-line screening method for high-risk pregnant women. The British foundation for fetal medicine (FMF) reported that in 6 In more than 10000 cases of high-risk pregnant women screened in the early stage of pregnancy, CF? DNA detection was used as the second-line screening, which reduced 30% of the early pregnancy villocentesis sampling, and the detection rate was not affected [13]; a clinical trial in the Netherlands showed that using CF? DNA detection as the second-line screening of high-risk pregnant women in the early stage of pregnancy, it is expected to reduce 62% of invasive prenatal diagnosis [14]. The risk of this screening strategy is that children with chromosomal abnormalities and phenotypes that are not trisomy 21, trisomy 18, trisomy 13 syndromes may be missed. Based on the population data of more than 190000 pregnant women in Denmark, 262 (23.4%) of the 1122 fetuses with abnormal chromosome karyotypes are non-21, 18, 13 and phenotypic. If they are screened by CF? DNA test, they will be missed. Duan Honglei et al. [16] analyzed the distribution of chromosomal karyotype abnormalities in 4915 fetuses with invasive prenatal diagnosis indications, evaluated the detection rate and missed diagnosis risk of chromosomal abnormalities in fetuses with different prenatal diagnosis indications, and found that those with structural abnormalities in fetuses found by ultrasound, such as CF DNA detection as the second-line screening, missed diagnosis was the most.
Based on the results of the first-line screening program of ultrasound examination in early pregnancy combined with maternal serological and biochemical indicators, it is recommended to use CF? DNA detection as the second-line screening strategy in a certain interval. For example, FMF in the United Kingdom defines the high risk of the first-line screening program in early pregnancy. For example, if the incidence rate is ≥ 1 / 10, the villus sampling should be performed directly, and the incidence rate is ≤ 1 / 1 000 patients were followed up, and those with the risk of disease between them were tested with CF? DNA. This is a strategy that not only wants to ensure the detection rate, but also does not want to increase the cost. However, there are many factors that affect the determination of high-risk and medium risk thresholds, which not only depends on the quality of first-line screening in early pregnancy, but also on the price of CF? DNA testing.
In the clinical service process of CF? DNA testing, we should emphasize informed consent, explain to pregnant women that CF? DNA testing is a screening test, and its target birth defects and significance, risk and limitations of testing failure, etc.; we should emphasize that when clinical samples are sent for testing, we must provide necessary clinical information, such as the age of pregnant women, gestational age, singleton pregnancy, body mass index, previous allogeneic acceptance Because of the history of cell or organ transplantation, the results of CF? DNA test must be explained to pregnant women face to face by clinicians. High risk only means that the risk of fetal suffering from trisomy 21, trisomy 18 and trisomy 13 syndrome is increased, and further prenatal diagnosis should be carried out. If the result is low risk, it must be explained in combination with the results of fetal ultrasound, because even if the result of CF? DNA test is low risk However, invasive prenatal diagnosis should be highly recommended if the fetal neck transparent layer & gt; 3.5mm is detected by ultrasonography in early pregnancy, or obvious structural abnormality is found. Therefore, in order to avoid pregnant women misunderstanding the results of CF? DNA testing, practitioners should follow the clinical service process.
References: omitted
Editor: Jiang Qiqi