![]() The cumulative false positive rate was less than 0.4%. 4,13 In a pooled meta-analysis, the detection rate across different NIPT methods was just over 99% for trisomy 21, 96% for trisomy 18 and 91% for trisomy 13. Using the cFTS, a detection rate of approximately 85–90% can be achieved for trisomy 21, 18 and 13, at a false positive rate of 4–5%. NIPT typically requires a specific request form, and can be requested by a medical practitioner (general practitioner or obstetrician) who is involved in the patient’s antenatal care. NIPT can be carried out at any point in the pregnancy from 10 weeks of gestation onwards to increase the likelihood of sufficient fetal fraction. Many NIPT assays therefore have a fetal fraction cut-off level, and samples with fetal fraction below the defined cut-off do not produce a result. 9,10 As the majority of cfDNA is maternal, the ability to detect an abnormality of a given fetal chromosome requires sufficient fetal fraction. Fetal aneuploidy can cause these proportions to deviate from expected values, and statistical tests are applied to determine whether such deviations are significant. In general, NIPT assays examine the proportion of cfDNA derived from specific chromosomes. Non-invasive prenatal testing (NIPT) tests differ in their exact methodology and there are several different assays available in Australia a detailed comparison is beyond the scope of this review. The median value at 10 weeks of gestation is approximately 10%. There is a wide normal range of fetal fraction. 7 The percentage of cfDNA derived from the trophoblast is termed the ‘fetal fraction’. However, a proportion is derived from the outer trophoblast cell layer of the placenta, which typically reflects the fetal genotype. In a woman who is pregnant, most of the cfDNA is derived from turnover of maternal cells. ‘Cell-free’ DNA (cfDNA) consists of short DNA fragments, which are released into plasma from normal cellular turnover and are rapidly cleared from circulation. 2 Non-invasive prenatal testing – Cell-free DNA 6 Chromosomal abnormalities can be diagnosed in cells derived from the invasive procedure by karyotyping or at higher resolution by microarray analysis. The degree of risk is commonly quoted as 0.5–1%, although recent meta-analyses suggest that the true procedure-related risk may be much lower. 5 Both procedures carry a small risk of provoking spontaneous miscarriage. Alternatively, after 15 weeks of gestation, fetal amniocytes can be sampled by amniocentesis. This can be carried out between 11 and 14 weeks of gestation by chorionic villous sampling (CVS) of placental tissue. 1,4 If the risk score is higher than a given cut-off value, it is considered a ‘screen-positive’ or ‘high-risk’ result, indicating that diagnostic testing should be considered.ĭiagnostic testing requires an invasive procedure. 1 This is carried out between 11+0 and 13+6 weeks of gestation, and combines ultrasound measurements, including nuchal translucency, maternal serum analytes (human chorionic gonadotropin, oestradiol, pregnancy-associated plasma protein A ) and maternal age to produce a risk score. ![]() In Australia, the most common screening modality for fetal chromosomal abnormalities is the combined first-trimester screen (cFTS). The likelihood of each of these three aneuploidies increases with maternal age. Most cases of trisomy 21, 18 and 13 arise de novo (as a spontaneous event), although in rare cases there may be a predisposing parental chromosomal rearrangement, such as a translocation. Other fetal aneuploidies are generally associated with spontaneous pregnancy loss, but some, particularly trisomy 18 and 13, can result in live births. The most common chromosomal abnormality is trisomy 21 (ie presence of an additional copy of chromosome 21), which causes Down syndrome. ![]() These can range in size from small segments of chromosomes (termed ‘microduplications’ or ‘microdeletions’) to entire chromosomes (ie aneuploidy). 1 Clinically significant fetal chromosomal abnormalities generally involve gains or losses of genetic material. It also enables them to make informed decisions about whether to proceed to diagnostic testing. Prenatal screening for fetal chromosomal abnormalities is carried out to identify women who are at higher risk of having an affected fetus. Articles in this series aim to provide information about emerging laboratory tests that general practitioners may encounter. This article is the first in a series on pathology testing. ![]()
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