gynecology and obstetrics
Noninvasive Prenatal Fetal Screening Tests
First Trimester Screening
First-trimester screening should be offered to all pregnant women. It provides information early so that a definitive diagnosis can be made with CVS. An important advantage of first-trimester screening is that termination of pregnancy is safer during the first rather than the second trimester. One method of screening for fetal Down Syndrome (Trisomy 21) , Cell-free DNA (cfDNA) testing is a type of noninvasive fetal screening that can identify fetal chromosomal abnormalities in singleton pregnancies by analyzing circulating cell-free fetal nucleic acids in a maternal blood sample. This test can be done as early as 10 gestational weeks and has replaced traditional first- and second-trimester noninvasive screening in many medical centers. Cell-free DNA screening is more accurate than Maternal serum screening for chromosomal abnormalities and does not depend on gestational age. CfDNA involves collecting fetal cells, but it is considered a screening test, not a definitive fetal diagnostic test. Cell-free fetal nucleic acids, most commonly DNA fragments, are shed into the maternal circulation during normal breakdown of placental trophoblast cells. Variation in amounts of fragments from particular chromosomes predicts fetal chromosomal abnormalities with higher accuracy than traditional first- and second-trimester combined screening using serum analytes and ultrasonography. Also, sex chromosomal abnormalities (X, XXX, XYY, and XXY) can be identified in singleton pregnancies, although with somewhat lower accuracy. Early validation trials reported > 99% sensitivity and specificity for the identification of Down syndrome (trisomy 21) and Trisomy 18 in high-risk pregnancies. Cell-free DNA (cfDNA) screening was historically recommended only for women with preexisting risk factors for fetal trisomy. However, it is now commonly used in both average-risk and high-risk patients. The American College of Obstetricians and Gynecologists recommends offering cell-free DNA screening to all pregnant women ( First-trimester screening references ). The American College of Medical Genetics and Genomics issued an evidence-based guideline advocating for cell-free DNA screening as the preferred method for all singleton and twin pregnancies ( A meta-analysis of 117 studies found that cfDNA performance for common aneuploidies was ( First-trimester screening references ): Trisomy 21: sensitivity 99%; specificity 100% Trisomy 18: sensitivity 98%; specificity 100% Trisomy 13: sensitivity 91%; specificity 100% Abnormal results from cfDNA screening should be confirmed with diagnostic karyotyping using fetal specimens obtained through invasive techniques. Negative results from cfDNA screening has reduced the use of routine invasive testing. Traditionally, first-trimester combined screening includes measurement of Maternal serum beta-hCG (total or free) Pregnancy-associated plasma protein A (PAPP-A) Sometimes, fetal nuchal translucency (by ultrasonography) Fetal Down syndrome is typically associated with high levels of beta-hCG, low levels of PAPP-A, and enlarged fetal nuchal translucency. Although enlarged nuchal translucency is associated with increased risk of fetal Down Syndrome (Trisomy 21) , no threshold value for nuchal translucency is considered diagnostic. In a large prospective study that included women of various ages, overall sensitivity for detection of Down syndrome was approximately 85%, with a false-positive rate of 5% ( First-trimester screening references ). Specialized ultrasound training and adherence to rigorous quality-assurance monitoring of nuchal translucency measurements are necessary to achieve this level of screening accuracy. 1.Badeau M, Lindsay C, Blais J, Nshimyumukiza L, et al. Genomics-based non-invasive prenatal testing for detection of fetal chromosomal aneuploidy in pregnant women.Cochrane Database Syst Rev11:CD011767, 2017. doi: 10.1002/14651858.CD011767.pub2 2.Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders. Obstet Gynecol. 2016;127(5):e108-e122. doi:10.1097/AOG.0000000000001405 3.Dungan JS, Klugman S, Darilek S, et al: Noninvasive prenatal screening (NIPS) for fetal chromosome abnormalities in a general-risk population: An evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG) [published correction appears inGenet Med2023 Aug;25(8):100874].Genet Med25(2):100336, 2023. doi:10.1016/j.gim.2022.11.004 4.Mackie FL, Hemming K, Allen S, et al: The accuracy of cell-free fetal DNA-based non-invasive prenatal testing in singleton pregnancies: a systematic review and bivariate meta-analysis.BJOG124(1):32-46, 2017. doi:10.1111/1471-0528.14050 5.Malone FD, Canick JA, Ball RH, et al: First-trimester or second-trimester screening, or both, for Down's syndrome.N Engl J Med353(19):2001-2011, 2005. doi:10.1056/NEJMoa043693 