Dr. Mandakini Pradhan*
Assistant Professor, Dept of Medical Genetics, SGPGIMS, Lucknow, India
Email: firstname.lastname@example.org *
Prenatal diagnosis refers to diagnosis of identifying structural or functional abnormalities in the developing fetus. Many fetal anomalies can be identified prenatally the list of which is ever increasing. Prenatal diagnosis allows consideration of pregnancy termination, antenatal treatment options and optimization of delivery. Steele and Breg did the first prenatal diagnosis in 1966 on amniotic fluid for chromosomal analysis.
Prenatal diagnosis can be performed by one of the following methods:
- Isolation of fetal cells from maternal blood
- Isolation of fetal DNA from maternal plasma
- Chorionic villous biopsy
- Fetal blood sampling (Cordocentesis)
- Fetal tissue biopsy Skin, muscle
- Preimplantation genetic diagnosis
Fetal ultrasonography is an important and easily available method, which provides diagnosis in most of congenital malformations. Structural malformation detected prenatally by USG may be isolated, part of a syndrome or may be an indication of chromosomal or single gene disorder. Detection of isolated structural anomalies warrants a detail examination to look for other anomalies, which may otherwise be overlooked and insignificant. For life threatening or otherwise severe malformations, efforts should be made to complete the evaluation as early in the pregnancy as possible, so that
pregnancy termination can be done safely. The sensitivity and specificity of the antenatal USG varies with different system that is involved. Recently, much interest has been focused on the biology and diagnostic applications of nucleic acids that are present in the plasma of humans. This interest has been stimulated mainly by the finding of tumor derived DNA in the plasma and serum of cancer patients. Lo et al in 1997 showed that cell free fetal DNA has been found to exist in maternal plasma. This discovery has facilitated the development of noninvasive prenatal diagnostic approaches based simply on the analysis of maternal plasma. The non-invasive nature of maternal plasma based approaches represents a major advantage over conventional methods of prenatal diagnosis, such as amniocentesis and chorionic villous sampling which are associated with small but finite risk of spontaneous abortion. However, a technical challenge experienced in this field relates to the ability to discriminate fetal DNA from the coexisting background of maternal DNA in plasma. During pregnancy fetal DNA amounts to 3-6% of the total DNA in maternal plasma. Hence, the diagnostic reliability of fetal DNA analysis in maternal plasma depends on the sensitivity and specificity of fetal specific markers that are used. This has been widely used for X-linked disorder and Rh-negative isoimmunised pregnancy to know the Rh blood group of the fetus.
The invasive fetal prenatal techniques are done to obtain fetal tissue that can be processed for different tests like molecular diagnosis, chromosomal analysis or biochemical tests.
I. Molecular analysis
DNA is extracted from amniotic fluid, chorionic villi or fetal blood and used for diagnosis of numerous monogenic disorders like beta thalassemia, Duchenne muscular dystrophy, spinal muscular atrophy and cystic fibrosis etc. Prior identification of the type of defect or mutation helps in identify the same in the fetal tissue. DNA analysis can be done either by direct mutation detection or by linkage analysis by using closely linked markers. Mutation screening methods can be used when the exact mutation is not known. It provides results with high degree of precision and efficiency.
II. Chromosomal analysis
Chromosomal analysis can be done from amniotic fluid or chorionic villous cells or fetal blood for detection of various structural and numerical chromosomal anomalies. The common indication of doing a invasive prenatal testing for chromosomal abnormalities are advanced maternal age i.e., more than 35 years at the expected date of delivery in singleton pregnancy and 31 years in case of dizygotic twin gestation. The other indications are women who have history of previous pregnancy complicated by autosomal trisomies, women or their partners are balanced translocation carriers, and women or their partners are carriers of chromosomal inversion and a fetus with a major structural defect identified by ultrasound.
III. Biochemical abnormalities
Biochemical tests can be done either to measure level of different enzymes in chorionic villi or by evaluation of various metabolites, which accumulate in amniotic fluid in metabolic disorders.
There are various pitfalls in the methods used for prenatal diagnosis, which need to be kept in mind during counseling.
- False positive or negative results in DNA and biochemical analysis.
- Confined placental mosaicism
- Cell culture failure
- Maternal cell contamination
With availability of prenatal diagnosis for a number of disorders, different ethical issues and dilemmas are encountered during counseling. Some of these issues and dilemmas are discussed here.
- Sex determination for X linked recessive disorders Sex determination and selective termination of all male fetuses may be a method of prevention of X linked recessive disorders especially those disorders where exact mutation is not known. But sex determination is banned by the Prenatal diagnosis Act (1994), and hence cannot be done.
- Unexpected finding in chromosomal analysis There could be other findings other than that for which prenatal diagnosis tests were done. For example, a couple coming for prenatal diagnosis for Down syndrome after a positive triple rest may be shocked to hear that there is a different chromosomal anomaly detected like de novo translocation or marker chromosome for which the prognosis for fetus is not exactly known.
- Termination of pregnancy for minor malformation With advent of newer ultrasound machines with improved resolution, it is possible to detect even minor malformations. But the question arises, whether it is justified to terminate a fetus with minor malformation like isolated cleft lip or polydactyly which can be easily corrected surgically in postnatal period.
- Prenatal diagnosis at late gestation Sometimes the couple may present after 20 weeks for prenatal diagnosis and in such cases, the termination of pregnancy in late gestation may be difficult and is not legally permissible under the MTP act further some diseases can be diagnosed prenatally only in late gestation e.g. Hydrocephalous, Asphyxiating thoracic dysplasias, etc.
Hence, with increasing advance in genetics and its application to diagnose diseases in fetal life, the legal, ethical and social implications need to be looked into before embarking on it.
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