The cell-free foetal DNA based maternal blood test could aid obstetricians to prevent the birth of an affected child
In India, an increased prevalence of genetic disorders parallels with the increased population, birth rate and consanguineous marriage preferred by several communities. It is estimated that about 21,400 are born each year with Down syndrome. An increased burden of genetic disorders in India, as compared with the Western countries, is owing to the inadequate diagnostic and management services available in the country. To reduce the burden of genetic diseases, screening for foetal anomalies during pregnancy is essential, as recommended by the global obstetric societies.
Awareness is increasing among obstetricians and primary care physicians about the essentials of the screening and prenatal diagnosis for the genetic disorders. However, their knowledge about the appropriate test and proficiency in counselling for pre-test and post-test is constantly lacking. With the availability of varied screening tests with different detection rates and costs, an inconsistency in counselling for the specific screening test exists. Moreover, in India, a population-based government programme for antenatal screening is still lacking. Consequently, there is a need for an appropriate, evidence-based screening to assist obstetricians and primary care physicians to prevent the birth of an affected child.
Conventional tests, including screening and diagnostic techniques, are typically used to identify foetuses with Down syndrome. Screening tests, usually based on serum biochemical tests and ultrasound scans, are non-invasive and cheaper. However, they are less accurate, have low detection rate and high false positive rate. Diagnostic tests, which encompass chorionic villus sampling (CVS)/amniocentesis followed by karyotyping, are highly accurate with high detection rate and low false positive rate. However, these diagnostic tests are invasive and expensive.
Noninvasive Prenatal Test (NIPT)
NIPT, which comprises the combined features of both screening and diagnostic tests, has emerged, based on the discovery of the cell-free foetal DNA (cff-DNA) present in maternal blood. cff-DNA is released as small DNA fragments (150–200 bp) into the maternal blood through the apoptosis of cytotrophoblastic cells of placenta. Maternal blood consists of a mixture of both maternal and foetal cff-DNA, and foetal DNA accounts for only 5–10% of it. Foetal DNA, which is usually detected after 7 weeks of gestation, is not detectable within hours after the birth.
As a result, NIPT test is considerably effective from early to late pregnancy. Moreover, the DNA fragment present in the maternal blood is indicative of existing pregnancy only. NIPT, that involves cff-DNA analysis, a non-invasive option, is currently available for women at increased risk of foetal aneuploidy to evade the risk of spontaneous abortion associated with the invasive tests. As per the American College of Obstetricians and Gynecologists (ACOG) recommendations, either screening or invasive prenatal diagnosis can be offered to women, irrespective of their maternal age, for the prenatal assessment for aneuploidy. Moreover, any woman may choose cff DNA analysis as a screening strategy for common aneuploidies irrespective of her risk status. However, the patient who opts for this test should understand the benefits and limitations of the test in the context of the availability of alternative screening and diagnostic options. In India, NIPT was introduced in 2013. However, it is still not well recognized in clinical practice.
NIPT is associated with a considerable improvement as compared with the conventional testing, and provides a detection rate of over 99% and a false positive rate of less than 0.1%. Moreover, wherever NIPT has been implemented in clinical setups, it is associated with a significant reduction (50–70%) of invasive procedures.
Although the cost of NIPT is slightly more than amniocentesis and is significantly more expensive than biochemical and ultrasound screening, using NIPT as a second level test would reduce the use of invasive procedures and the risk of test-related miscarriage by 72% and 66% respectively.
A study by Verma IC et al 2018 assessed the performance of single nucleotide polymorphism-based NIPT among 516 pregnant women with intermediate-to-high risk on conventional first and second trimester screening for trisomies 21, 18, 13; sex chromosome abnormalities and triploidy. The results were confirmed by invasive test or clinical assessment following the birth. Amongst 511 samples analysed, results were obtained from 499. Among these, 480 were at low risk and 19 at high risk. A sensitivity of 100% was obtained for detection of trisomies 21, 18, 13 and sex chromosomal abnormalities, and specificity ranged from 99.3 to 100% for the anomalies studied.
The good outcome associated with NIPT as demonstrated in the study by Verma IC et al 2018 is in line with the overall performance of NIPT. Moreover, the positive predictive values (PPV) ranged from 80–85.7% as observed in this study, and is considerably greater than the conventional tests. A vast number of women (96.6%), who were at intermediate-to-high risk based on conventional screening, were found to be at low risk on NIPT, and invasive procedures were avoided in these women for the confirmation of aneuploidies. Again the high negative predictive value is a reassurance to pregnant women with important benefits. Moreover, the advantages of SNP based technology used to analyse cff DNA include the ability to work without reference chromosome, the ability to detect a vanishing twin, triploidy, maternal mosaicism as well as increased accuracy.
Indian Council of Medical Research endorses genetic screening to all pregnant women under the National Family Welfare Programme. With its good performance among the Indian women population, NIPT would be a useful add-on diagnostic tool to the prenatal screening programme when available at a low cost. NIPT can be used in women with high-risk for aneuploidies on conventional screening to evade invasive tests that are not required. To conclude, the reduction in cost of NIPT and increased awareness among patients and physicians would enable the Indian population to achieve greater benefit from this emerging technology.