Invasive or non-invasive prenatal genetic diagnosis?

About 40 years ago, invasive prenatal diagnosis techniques were introduced in obstetrics. Initially, amniocentesis was performed followed by placentacentesis, fetoscopy, fetal blood sampling (FBS), and chorionic villus sampling (CVS). These procedures, while invading the uterine environment, have made it possible to proceed with the retrieval of biological tissue of fetal origin for analysis and definitive diagnosis [6, 20, 21, 27]. The development of such techniques was facilitated by improvements in instrumentation and technology, and was further propelled by the advancement of cytogenetics and molecular genetic techniques [3, 13, 14, 22]. However, invasive prenatal diagnosis carries the inherent risk of fetal loss, which is low, but not negligible (amniocentesis and CVS approximately 0.3%–0.5% and FBS 1%–2%). In addition, there is a significant economic burden from the costs associated with laboratory techniques. Public health programs of nations interested in the utilization of invasive procedures have generally limited their use to high-risk cases, where the risk of procedure related loss is comparable to the risk of an affected fetus for a given condition [25, 26]. As a result, in the 1980s amniocentesis was offered to women at higher risk of trisomy 21 based on maternal age alone, if there was an increased risk due to prior complications or pre-existing conditions (i.e., chromosomal alterations in the parents or in prior offspring), or because of prenatal detection of fetal malformations or other abnormal ultrasound findings. The initial policies led to an offering of invasive prenatal diagnosis to 5% of all pregnant women (positive screen rate), with a 40% detection rate for trisomy 21. With the advent of biochemical screening tests using maternal serum in the second trimester, the “triple” and “quadruple screen”, the detection rate of trisomy 21 increased to 60% [28]. Meanwhile, with advancements in ultrasound, numerous reports were published that identified sonographic “markers” for trisomy 21, leading to additional screening with a “genetic ultrasound” in the second trimester [1]. However, second trimester ultrasound for the purposes of screening an unselected population never gained universal acceptance, and was primarily used in higher-risk populations (i.e., a woman with advanced maternal age that wished to avoid invasive testing). At this time, second trimester amniocentesis was the primary invasive diagnostic test practiced, while fetal blood sampling by cordocentesis was utilized when a diagnostic test was desired later in the second trimester, often in the setting of identification of a fetal anomaly in the second trimester ultrasound. As mean maternal age at childbirth continued to increase, especially in Western countries, alongside increasing scientific advancements, the number of indications for prenatal diagnosis rose. This trend led to an increased rate of invasive prenatal diagnosis, based on maternal age alone up to 15–20% in some nations, and spurred a search for new solutions. In the mid-1990s, an important turning point was the use of ultrasound to measure fetal nuchal translucency at 11–14 weeks [17], along with maternal serum biochemical screening, pregnancy associated plasma protein-A (PAPP-A), and free beta subunits of human chorionic gonadotropin (free beta-hCG), for the screening of trisomy 21 [24]. With a similar invasive testing rate as maternal age alone of 5%, the combined test led to a detection rate of approximately 90% for trisomy 21 (in the setting of a positive test, the odds of an affected fetus were 1:24). The introduction of the nuchal translucency measurement raised the issue of certification, reproducibility, and reliability of *Corresponding author: Giovanni Monni, Department of Obstetrics and Gynecology, Microcitemico Hospital, Prenatal and Preimplantation Genetic Diagnosis, Cagliari, via Edward Jenner SNC, Sardinia, Italy, Tel.: +39-706095546, Fax: +39-706095514, E-mail: [email protected] Maria Angelica Zoppi, Ambra Iuculano, Alessandra Piras and Maurizio Arras: Department of Obstetrics and Gynecology, Microcitemico Hospital, Prenatal and Preimplantation Genetic Diagnosis, Cagliari, via Edward Jenner SNC, Sardinia, Italy