Introduction
Population control and improving the quality of the population is a basic national policy of China. China has a high incidence of birth defects. Compared with a relatively lower rate of infectious disease and perinatal mortality, birth defects and genetic diseases have become threats to children’s health and are becoming main issues affecting the quality of the population. Genetic counseling and prenatal diagnosis are major methods to reduce the incidence of birth defects. Based on clinical medicine, prenatal diagnosis is closely connected with cytogenetics, molecular genetics, biochemistry, medical image, immunology, obstetrics, etc. Prenatal diagnostic techniques, nowadays, are of “three high” characteristics: (1) high-tech in nature, (2) high uncertainty, and (3) high risk. The level of perinatal care in China is advanced; however, prenatal diagnosis is relatively backward on a weak basis. Therefore, it is of great importance to actively promote prenatal diagnosis and reduce the incidence of birth defects in China so as to improve the quality of the population.
Prenatal screening and prenatal diagnosis of fetal chromosome abnormalities
Chromosomal diseases are causes of major birth defects. Down syndrome is the most common chromosomal disease (an incidence rate of 1 per 800-1000 live births, or 1/150 pregnancies). Since the late 90s of the last century, China has conducted serological screening to mothers under 35 years old with singleton pregnancy during 15-21 weeks of gestation. Amniocentesis is performed on high-risk mothers for amniotic fluid cell culture and karyotype analysis, which has played an important role in reducing the birth rate of Down syndrome
Currently, there are three kinds of screening methods applied in China: time-resolved fluorescence method, enzyme-linked immunosorbent assay and chemical luminescence. All these methods use data from Caucasian populations as normal ranges. Using foreign standards in screening pregnant women in China leads to a low accuracy, high false positive rate, and following high rate of invasive prenatal diagnosis. For this reason, the Research on the Application of New Technology in Prenatal Screening and Diagnosis of Fetal Congenital Disease, one of the 10th Five-year Plans and the National Program for Key Science and Technology Project, was carried out in the period of 2004-2006. A prospective study of a large sample of Chinese women during pregnancy using a time-resolved fluorescence method for the double-marker screening test (alphafetoprotein (AFP) + free β-human chorionic gonadotrophin (β-HCG)) was carried out and acquired the normal range of the Chinese population. It is a good impetus to prenatal screening work in China and the standardization of related work in future, and also provides a scientific basis to establish the corresponding technical standards [
1]. It is gratifying that most provinces have set up their own prenatal diagnosis center and started to cover the corresponding area in prenatal screening network, and the coverage of prenatal screening is expanding. According to statistics, the false-positive rate of serum screening is 5%-8%, while the detection rate is above 60%, which is relatively satisfactory.
Currently, the major problem is lack of technical standardization and quality control, and following prenatal diagnostic techniques are not strong enough. Although the invasive prenatal diagnostic techniques, such as amniocentesis, chorion biopsy and percutaneous umbilical cord puncture, have a high success rate and safety, they are hardly fully carried out in small clinics due to a low cytogenetic technical level. For that reason, a large number of screening-positive cases may miss the follow-up diagnosis. Screening and diagnosis cannot form a complete system, which makes screening of less significance. Lack of the support of cytogenetic diagnosis has become a bottleneck for the development of prenatal screening and diagnostic work. Therefore, to standardize the management of prenatal screening and promote invasive prenatal diagnosis and prenatal cytogenetic techniques, standardize clinical and laboratory operations, put more focus on the training of technical personnel, as well as to gradually develop rapid prenatal diagnostic techniques will be the focus of our work in future.
Since 1992, the first trimester prenatal screening has developed progressively. Ultrasound measurement of fetal Nuchal Translucency (NT) combined with serum pregnancy-associated plasma protein-A (PAPP-A) and free β-HCG triple screening program has become the most mature test. However, the early pregnancy screening is only carried out in a few centers; its screening efficiency, technical standards and quality control need further evaluation and specification. All the screening parameters of these techniques for Chinese people are also required to be determined.
On the other hand, there are some new markers that have been noticed for prenatal screening of fetal chromosome abnormalities [
2]. Some multi-center studies like Serum Urine and Ultrasound Screening Study (SURUSS) [
3] and First- and Second-Trimester Evaluation of Risk (FASTER) [
4] also promoted some new screen models, hoping to reach a highest detective rate (95%) out of low false-positive rate. These new models are notable for their high detective rate, but with problems of complicated process, long cycle and high costs.
Non-invasive prenatal diagnostic techniques
Prenatal diagnosis methods are invasive examination. It is hard to avoid the risk of miscarriage in screening false-positive healthy fetus. Therefore, non-invasive prenatal diagnostic techniques attract more and more attention. Detection of fetal cells obtained in maternal blood for prenatal diagnosis is the primary research direction; however, the difficulties of cell separation, purification and identification techniques have not been resolved, nor do the complexity of operation and finance problems. The techniques still remain at the laboratory research stage and are only applied in the field of diagnosing fetal gender. Therefore, the clinical value is very limited. Recently, free fetal DNA and RNA were found in peripheral blood of pregnant women, which provides a new way of non-invasive prenatal diagnosis. Free fetal DNA and RNA have the advantages of high concentration, fast removal after delivery and high sensitivity to analysis. It can be applied mainly in the following areas as a prenatal diagnosis method: (1) screening of sex chromosome-linked genetic disease; (2) screening of RhD hemolytic disease; and (3) fetal aneuploidy. Non-invasive prenatal diagnosis of Down syndrome pregnancy has high potential in application [
5]. There are still some issues to be resolved in this field, such as the source of free fetal DNA and RNA and its clearance mechanisms, and how free fetal RNA keeps its stability in maternal blood is not very clear. More fetal-derived DNA and RNA markers are required to be discovered to diagnose clinical genetic diseases and pregnancy-related diseases.
Prenatal diagnosis of monogenic diseases and congenital metabolic diseases
Other common birth defects, including thalassemia, progressive pseudohypertrophic muscular dystrophy, nerve deafness, spinal muscular atrophy, phenylketonuria, mucopolysaccharidosis and Kinnier-Wilson syndrome, mainly are monogenic diseases or congenital metabolic diseases. Prenatal diagnosis of these diseases requires high technology and strong professional background. After 20 years of research, we have achieved a number of research results in the field of molecular basis and genetic diagnosis of common monogenic diseases and established suitable targets for clinical application [
6,
7]. However, most work is in the stage of laboratory testing, as it has not been well studied for the conversion from basic science to clinical applications. It has not been integrated into a mature technology system to apply in clinic, and the diagnosis process or quality control is not compatible with clinical work, which restricts application of clinical genetics and its development in clinic. The urgent need in practice is high-flux mutation detection method, which is simple, rapid, automated, and low cost, as well as of high sensitivity and specificity. Some new technologies, such as array-comparative genomic hybridization (Array CGH), microarray-based-comparative genomic hybridization [
8], multiplex ligation-dependent probe amplification, multiplex ligation-dependent probe amplification (MLPA-chip technology), and matrix-assisted laser desorption/ionization time-of-flight mass spectrometric based on matrix-assisted laser desorption time-of-flight mass spectrum (MALDI-TOF-MS), can improve the accuracy of prenatal diagnosis. At the same time, prenatal diagnosis of genetic disease needs strict quality control to ensure the consistency and accuracy of diagnosis. Disease-specific prenatal diagnosis and standardized techniques need to be established, which is the basis of future development of clinical genetics.
Prenatal diagnosis of polygenic diseases
Congenital neural tube defect (NTD) is the major polygenic birth defect in China. In 1996, its incidence was the second highest among all birth defect diseases. In the past decade, the incidence of NTD has had a clear decline through effective primary and secondary preventive measures. According to the statistics of 2002, its incidence dropped to No. 4. Among the primary prevention measures, the measure that has been most studied and based on most adequate evidence is the addition of folic acid in early pregnancy. The Sino-US cooperation project on preventing neural tube defects in China has been carried out in a massive crowd of 24 thousand people as an interventional trial and has confirmed that a daily dose of 0.4 mg of folic acid may be effective in preventing neural tube defects; in the Northern area, it can reduce the incidence by 85%, and 40% in the Southern low-incidence area. Now, pre- and early pregnancy folic acid supplements have been vigorously promoted; however, issues like the specific addition dosage, the related safety evaluation, as well as monitoring indicators of blood folic acid level still need further refinement. Secondary prevention measures, including the second trimester (15-22 weeks) maternal serum AFP screening and ultrasound screening, have been carried out throughout the country. Increasing screening coverage, raising the detection rate, and continuing improving related technology trainings and its quality control are future targets.
Incidence rate of congenital heart disease (CHD) is 8‰-10‰, as the second highest incidence rate of human birth defects. Data from the Chinese birth defects monitoring network show that incidence of CHD continues to rise, especially in developed regions and cities. The annual births of CHD in China are about 220 000. The etiology and pathogenesis are extremely complex, and there are about 8% with chromosome aberrations, 1% with monogenic defect diseases, and more than 90% with a number of genetic abnormalities. Diagnosis is primarily dependent on fetal echocardiography which is only carried out on high-risk mothers due to the higher cost, longer time requirement and high technical demand. The high-risk population includes one parent with CHD, former birth of CHD child, diabetic mothers and so on. As most parents do not have the risk factors, the high-risk population screening strategy is a cost-efficient program because it can reduce not only the number of inspections and costs but also misdiagnosis. It is now gradually getting international recognition. Recent research shows that 22q11 microdeletion is closely related to CHD, and it distributes in almost all types of CHD, mostly seen in five types as ventricular septal defect, Fallot’s tetralogy, persistent truncus arteriosus, interrupted aortic arch, and pulmonary artery disorders. This provides a very useful clue and platform to study the genetics of CHD. To systematically study the relationship between CHD and the 22q11 microdeletion and to explore a feasible method of genetic diagnosis suitable for our populations will deepen the understanding of CHD and improve the level of clinical diagnosis and treatment. The establishment of genetic prenatal diagnosis can reduce many uncertain factors of fetal echocardiography for CHD diagnosis and also provide more information and better consultation to pregnant women for reproductive choices; meanwhile, early diagnosis with early treatment will improve patients’ survival rate and quality of life. This is undoubtedly of great theoretical significance and clinical value.
Imaging in the prenatal diagnosis
Chromosomal diseases are closely related to some ultrasound markers, such as NT, choroidal cysts, echogenic bowel, severe fetal growth restriction (FGR),
etc. Therefore, it is necessary to introduce the “genetic ultrasound” concept. Combination of our existing system in ultrasound screening in the 2nd trimester and gradual improvement of 1st trimester fetal structural screening makes the serum screening test more effective and improves the detection rate. The screening of serious fetal malformation should still focus on ultrasound images, which take two-dimensional ultrasound as a primary screening tool. In addition, based on ultrasound screening, three-dimensional ultrasound and other new methods are welcomed; combination with magnetic resonance imaging (MRI), if allowed, would lead to further research on some special diseases. Compared to ultrasound, MRI is superior in brain imaging and part of pathological pregnancy screening, such as oligohydramnios [
9].
Epidemiology of birth defects and genetic diseases
Epidemiological investigation of birth defects and genetic disease aims to develop strategies to improve the quality of births and direct our practice. In China, the basic situations, such as national incidence rate or prevalence rate, characteristics of distribution, type of disease, etc, of most birth defects and genetic diseases are not clear; investigation on the prognosis and outcome of birth defects and genetic diseases is far from enough; a systematic and comprehensive economic evaluation is needed in consumption of public health resource and finance burden to patients and families for birth defects and genetic diseases. Time consumption of health service, utilization and service delivery capacity to these patients need to be studied systemically. Therefore, the urgent need is to carry out a national epidemiological investigation of birth defects and genetic diseases in order to get a good grasp of basic information and to make improvements of the quality of the population.
Emphasis on ethical issues of prenatal diagnosis
With the development of modern medicine and evidence-based medicine, the mother and the fetus are seen as two closely related but different living organisms, which is a very particular ethical issue we must cope with in prenatal counseling, prenatal diagnosis and fetal therapy. Prenatal diagnosis institutions should establish ethics committees in order to practice safe, effective and rational implementation of prenatal diagnosis and to respect and ensure the rights of all parties. It should be guided by the following ethical principles: (1) respect for the autonomy and informed consent; (2) avoid disadvantages, favor mother and children; (3) confidentiality, respect patients’ privacy; (4) obey laws and regulations, social welfare; and (5) ethical oversight, rights and interests protection.
In conclusion, prenatal diagnosis is an effective means to improve the quality of the newborn population in China and to reduce the rate of birth defects. With the continuous progress of science and technology, prenatal diagnosis is facing huge opportunities and challenges. Improving the construction of epidemiology data, standardizing prenatal screening and prenatal diagnosis techniques, strengthening quality control, following the ethical principles, and enhancing the training of employees to form a multi-disciplinary team of experts are our goals, so as to promote the development of prenatal diagnosis in China.
Higher Education Press and Springer-Verlag Berlin Heidelberg
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