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Prenatal Testing

Goals and Practices for Next-Generation Prenatal Testing

  • PRENATAL TESTING ARTICLE

Evolution of Prenatal Testing

Over the past half century, medicine has gained new and improved tools and methods for assessing whether a fetus is likely to have—or has—a range of genetic and congenital conditions. These advances are the result of new or improved methods for acquiring data about the fetus, and new or improved abilities to interpret that data. These advances mean that more information about the fetus’s anatomy, genetic make-up, and health can be available today than ever before, often earlier in pregnancy. Despite these significant technological advances, the quality of the information that data yields can vary greatly. Sometimes a definite diagnosis can be provided, but even in those cases, the phenotypic presentation (how the condition would affect a child) can vary greatly. Some results will indicate only an increased risk of a condition. Other kinds of results are so rare or poorly understood that it is difficult to be sure what if any impact the genetic difference would have on a child. In response to these technological advances and the diverse nature of the information that can be returned to patients, policies and practices are being revised and, in some cases new policies are being developed.

Data Acquisition: There are three main methods for acquiring data about the fetus: ultrasound/sonogram, maternal blood tests, and direct sampling of placental or fetal cells (CVS, amniocentesis and umbilical blood sampling).

Data Interpretation:  Current genetic technologies can read at the chromosomal (karyotyping and fluorescent in situ hybridization), sub-chromosomal (chromosomal microarray analysis) and nucleotide base pair (sequencing) levels.

Policy and Law: Policies and laws impacting prenatal screening and diagnostic include guidance specific to prenatal testing (e.g. guidelines from the American College of Obstetrics and Gynecology) and policies shaping the broader landscape (e.g. laws regarding access to health insurance such as the Affordable Care Act).

Timeline of Technology Development

Data Acquisition Data Interpretation Policy and Law
1956: Amniocentesis first used to identify genetic disorders    
Late 1960s and early 1970s: Ultrasound first used clinically to detect and assess the fetus 1959: Karyotyping first used to identify trisomy 21 as cause of Down syndrome  
Early 1970s: Amniocentesis first in use in the US    
1980s: Ultrasounds routinely used in early pregnancy for dating, identification of multiples, and identification of major malformation 1980: Fluorescent in situ hybridization (FISH) developed  
1980s: Second trimester (15-20 weeks) multiple marker maternal blood screen first used to measure likelihood of that fetus has Trisomy 18 and 21, as well as neural tube defects such as spina bifida and anencephaly.    
1983: Chorionic villus sampling (CVS) first performed    
1983: Percutaneous Umbilical Blood Sampling first performed    
Early 1990s: Detailed fetal scan at 20 weeks gestation became part of routine prenatal care in developed nations 1990s: Chromosomal Microarray Analysis developed  
Early 1990s: CVS in use in US (10-12 weeks)    
Early 2000s: First trimester (11-14 weeks) maternal blood tests first used in combination with ultrasounds to assess likelihood that the fetus has Trisomy 13, 18, and 21. Nuchal translucency result could also indicate increased likelihood of a heart defect or rare genetic condition. 2003: Human Genome Project completed in the United States, developing sequencing technologies advanced enough for a human genome 2007: American College of Obstetrics and Gynecology recommend that all women should be offered prenatal screening or diagnostic testing before 20 weeks gestation.  (Before this, the recommendation was to offer invasive prenatal testing to women over 35 or otherwise at high risk.)
2011: Cell free DNA screening tests (also known as “non-invasive prenatal testing or sequencing”) first clinically available, performed between 8-12 weeks.  The tests isolate and analyze fragments of placental and fetal DNA circulating in pregnant woman’s blood to assess fetal sex and the likelihood of Trisomy 13, 18 or 21. 2010: First use of Chromosomal Microarray Analysis by some clinical laboratories for analysis of samples obtained from amniocentesis or CVS 2007: American College of Obstetrics and Gynecology recommend that all women should be offered prenatal screening or diagnostic testing before 20 weeks gestation.  (Before this, the recommendation was to offer invasive prenatal testing to women over 35 or otherwise at high risk.)
2013: Testing companies begin marketing versions of cfDNA tests that assess likelihood that the fetus has other chromosomal conditions, including sex chromosome aneuploidy, rare trisomy (such as Trisomy 16 or 22), as well as microdeletions and microduplications.   2015: ACOG Committee on Genetics releases opinion on cell-free DNA, recommending that “a discussion of the risks, benefits, and alternatives of various methods of prenatal screening and diagnostic testing, including the option of no testing, should occur with all patients.”
2017 and beyond: Ultrasound is still used from the earliest stages of pregnancy to confirm pregnancy, check dates, measure development, and detect structural abnormalities.  It can be used in combination with other methods for enhanced information, such as a blood test with cfDNA, to calculate the likelihood that the fetus has certain chromosomal conditions, particularly Trisomy 21. Direct sampling methods are still available, but many opt for the “non-invasive” blood tests instead as a secondary screen. 2017 and beyond: Noninvasive whole genome sequencing is technically possible but is not yet commercially available in the prenatal context. 2016: ACOG Practice Bulletin addressing prenatal diagnostic testing for genetic disorders recommends that chromosomal microarray analysis replace karyotyping as the primary test for diagnostic testing of fetal structural abnormalities detected by ultrasound.
Screening for some single gene disorders is possible (provided the disorder is not carried by the mother and is either inherited from the father or occurs de novo, e.g. achondroplasia, thanatophoric dysplasia and Apert syndrome).  Detection of elevated risk for cancer in the pregnant woman is also possible.