What is cell-free DNA? 

Cell-free DNA describes DNA (genetic material) that is not held or enclosed within a cell. Whereas most human DNA is typically stored along structures called chromosomes located within the nucleus (control center) of a cell, cell-free DNA pieces are no longer confined within the cell’s nucleus. Human bodies are made up of trillions of cells, and almost every cell contains a nucleus with chromosomes and the DNA they hold. When these cells naturally break down and die through a process called apoptosis, tiny chromosome fragments are released into the bloodstream, and the DNA they previously held becomes “cell-free DNA.” 

During pregnancy, a person’s blood contains a mix of cell-free DNA from their own biological tissues as well as cell-free DNA from the placenta of the pregnancy. This placental cell-free DNA is often called cell-free fetal DNA (cffDNA) because it comes from the placenta of the fetus. What’s more, fetal and placental DNA are usually (but not always) identical since the placenta and fetus both develop from the same embryo. 

Cell-free fetal DNA can typically be detected in a pregnant person’s bloodstream starting around 6-7 weeks gestation, and over the course of pregnancy, the amount of cell-free fetal DNA increases. After delivery, cell-free fetal DNA quickly clears from the maternal bloodstream and is often undetectable even just a few hours after giving birth.

What is “fetal fraction”? 

“Fetal fraction” refers to the percentage of cell-free DNA in a pregnant person’s blood that comes from the fetus/placenta rather than from the pregnant person’s own biological tissues. Fetal fraction often ranges between 2-20%1,2, meaning that about 2-20% of the cell-free DNA in a pregnant person’s bloodstream comes from the fetus/placenta. Since the amount of cell-free fetal DNA increases over time, the fetal fraction tends to be lowest in the first trimester and higher in the second and third trimesters. 

In addition to varying with gestational age, fetal fraction can be influenced by other factors related to the pregnant person or the fetus. For example, fetal fraction tends to be lower when a pregnant person has a higher body mass index (BMI), has certain autoimmune disorders, or uses certain medications. In addition, some studies have suggested that fetal fraction can be lower in pregnancies conceived through assisted reproductive technology such as in vitro fertilization (IVF). Pregnancies that have chromosomal aneuploidy (extra or missing chromosomes) may have a lower fetal fraction, although this isn’t a guarantee.3

If the fetal fraction is extremely low (e.g., less than 2%), it can be difficult to accurately screen a pregnancy for chromosome conditions such as Down syndrome, trisomy 18, and trisomy 13. However, it’s important to note that the reported fetal fraction of a pregnancy often differs depending which lab did the testing and how the fetal fraction calculations were performed. 

How is cell-free DNA used for non-invasive prenatal screening (NIPS)?

In 1997, the discovery that cell-free fetal DNA circulates in a pregnant person’s bloodstream4 opened the door for new possibilities in prenatal genetic testing. Once scientists realized that cell-free fetal DNA is present in a pregnant person’s blood, they were able to develop non-invasive prenatal screening (NIPS) tests to screen pregnancies for chromosomal conditions using a simple blood sample collected from the person carrying the pregnancy, rather than invasive procedures such as chorionic villus sampling (CVS) and amniocentesis.

cell-free DNA, second trimester of the pregnancy

Non-invasive prenatal screening (NIPS) works by analyzing millions of cell-free DNA pieces found in a pregnant person’s bloodstream. As mentioned earlier, many of the cell-free DNA pieces in a pregnant person’s blood come from the pregnant person themself, but others are cell-free fetal DNA (cffDNA) fragments that come from the placenta, and analyzing these cffDNA fragments can give us insight into a pregnancy’s chance for certain chromosomal conditions like Down syndrome, trisomy 18, and trisomy 13. To learn more about how NIPS works, check out our blog post here.  

Learn more about the Juno Hazel™ prenatal screening tests, and the genetic counseling resources available to our patients.

- Authored by Kelly Miller, MS, LCGC | Genetic Counselor 


Sources: 

  1. Barrett, A, Zimmerman BG, Wang D, Holloway A, Chitty L. Implementing prenatal diagnosis based on cell-free fetal DNA: Accurate identification of factors affecting fetal DNA yield. PLoS One. 2011;6(10):e25202.
  2. Nigam A, Saxena P, Prakash A, Acharya A.Detection of fetal nucleic acid in maternal plasma: A novel noninvasive prenatal diagnostic technique. J Interntl Med Sci Acad. 2012; 25(3): 119-120.
  3. Deng C, Liu S. Factors Affecting the Fetal Fraction in Noninvasive Prenatal Screening: A Review. Front Pediatr. 2022 Jan 27;10:812781. doi: 10.3389/fped.2022.812781. PMID: 35155308; PMCID: PMC8829468.
  4. Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, Wainscoat JS. Presence of fetal DNA in maternal plasma and serum. Lancet. 1997 Aug 16;350(9076):485-7. doi: 10.1016/S0140-6736(97)02174-0. PMID: 9274585.

 

JunoDx.com and the materials and information it contains are not intended to be and do not constitute medical advice, other health advice, or diagnosis.  Do not use JunoDx.com or the materials and information published at JunoDx.com as a substitute for medical care and treatment. You should always consult with a qualified physician or healthcare provider about your specific circumstances. 

January 10, 2023 — Stephanie McClintock