Prenatal Diagnosis Using Fetal Genetic Material in Maternal Circulation

In the second half of the 20 century, the prenatal diagnosis armamentarium changed dramatically with the introduction of amniocentesis and chorionic villus sampling. Both modalities are, however, invasive techniques and carry a certain risk, albeit low (0.5–1%), of pregnancy loss [1]. Routine noninvasive methods of prenatal diagnosis include firstand second-trimester ultrasonography and maternal serum biochemical screening. When screening women less than 35 years of age, second-trimester measurements of -fetoprotein, human chorionic gonadotropin (hCG), and estriol correctly identify only 60–70% of cases of aneuploidy, with a calculated false-positive rate up to 5% [2]. Prenatal ultrasound examination in the second and third trimesters allows detection of only 17% of fetal anatomic abnormalities [3]. In fact, in the USA, approximately 1 in 1,000 live-born fetuses are postnatally diagnosed with Down syndrome. Most (80%) of these infants are born to women under the age of 35 who have no indications for routine invasive prenatal diagnostic procedures [4]. First-trimester ultrasonographic evaluation of fetal nuchal translucency improves the aneuploidy detection rate up to 82% but requires special sonographic expertise [5]. Recent studies demonstrate that addition of firsttrimester biochemical markers (free -hCG and pregnancy-associated plasma protein-A) can increase sensitivity and improve false-positive rates [6]. Other first-trimester sonographic markers, including the absence of nasal bone and abnormal ductus venosus flow, have potential to improve the positive predictive value of screening, but require further validation [7,8]. Neither of these new techniques are devoid of falsepositive results and both are associated with high health care costs of invasive follow-up studies and patient emotional anxiety [4]. The recovery of fetal genetic material in the form of fetal cells or cell-free fetal DNA from maternal circulation has, therefore, tremendous potential for prenatal diagnosis. Analysis of fetal genetic material acquired by means of routine venipuncture can potentially replace current standard biochemical screening or become an additional noninvasive technique to reduce the falsepositive rates of biochemical and ultrasonographic screening programs.