Single cell-free DNA test accurately detects fetal antigen status in alloimmunized women
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Key takeaways:
- Cell-free fetal antigen analyses had 100% consistency for 465 calls on antigens in which women were alloimmunized or genotype negative.
- Cell-free DNA analyses had a sensitivity, specificity and accuracy of 100%.
Cell-free DNA analyses were accurate in detecting fetal antigen status as early as 10 weeks’ gestation in women with alloimmunized pregnancies, according to results of a large, diverse U.S. cohort study published in Obstetrics & Gynecology.
In European countries, cell-free DNA has already been used as a standard of care to determine fetal antigen status and guide pregnancy management.
“We recognize that less than 1% of pregnancies are alloimmunized, but those of you taking care of these patients also recognize that there is a significant opportunity to improve care for those families, and we can drastically simplify management for over 50% of alloimmunized patients simply by knowing the fetal status,” Jen Hoskovec, MS, CGC, vice president of medical affairs at BillionToOne, a molecular diagnostics company, said during a related webinar. “In this particular paper, as well as in previous studies and our clinical experience, over 50% of samples that come in for fetal antigen status are released as not detected or fetus is negative, indicating that those pregnancies do not need the extensive follow up and management that they would have had otherwise. And we wanted to ensure that this test was accessible to all patients, which is why it was designed and currently is offered as an addon to a routine screen, allowing us to do it quickly with a rapid turnaround time of about 4 to 6 days, at no additional cost or resource to the to the family.”
Researchers conducted a prospective, multicenter cohort study with data from 156 alloimmunized pregnant women from 10 to 37 weeks’ gestation who received clinically ordered BillionToOne’s UNITY Fetal Antigen cell-free DNA testing from 120 U.S. practices in 37 states. Median gestational age at the time of fetal antigen testing was 16.4 weeks with a median fetal fraction of 11.1%. After delivery, all women submitted neonatal buccal swabs for antigen genotyping when their infants were aged 0 to 270 days.
Overall, 15.4% of women were Hispanic, 9% were Black, 65.4% were white, 4.5% were Asian, 1.3% were multiple races/ethnicities and 4.5% were of unknown race/ethnicity. The cohort was alloimmunized to 191 antigens. The most common alloimmunized antigen was E in 53 women and 34 women were alloimmunized to multiple antigens.
Researchers observed 100% consistency between cell-free DNA analyses and neonatal genotype for 465 antigen calls. This included 190 antigen calls wherein the mother was alloimmunized and 275 wherein the mother was not alloimmunized but was genotype negative and able to become alloimmunized. The antigen calls were for K1 (n = 143), E (n = 124), C (n = 60), Fya (n = 50), c (n = 47 )and RhD (n = 41 ) antigens. Of these, 145 calls had antigen-positive fetuses.
Prenatal fetal antigen cell-free DNA analyses had a sensitivity, specificity and accuracy of 100%.
“This particular paper really was focused on the alloimmunized patients, but then continued on, just to show that for patients who are negative for particular red blood cell antigens, we can accurately call the fetal status,” Hoskovec said. “This is important, obviously for alloimmunized patients, but it's also quite important currently in the conversation of patients who are RH negative given that we know that across the country there are many centers that are dealing with a shortage of RhoGAM.”
References:
- Panel Discussion: UNITY Fetal Antigen. unityscreen.com/unityfetalantigenwebinar/. Accessed Aug. 15, 2024
Perspective
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Alloimmunization to red blood cell antigens is rare but can lead to complications when the alloimmunized individual becomes pregnant with a fetus expressing the concerning antigen. The mismatch may cause the pregnant person to reactivate antibodies against the red blood cells of the fetus, leading to a spectrum of harm to the fetus that ranges from asymptomatic to fetal hydrops and death. Although this most catastrophic outcome is rare, it is clearly devastating for all involved.
What is common is the need for increased monitoring of all pregnancies in alloimmunized individuals. In the current clinical paradigm, surveillance begins with simple blood tests, but additional ultrasounds are also indicated throughout pregnancy. These tests add cost to the health care system, complexity to care and anxiety for patients. Although many patients may be carrying pregnancies that are negative for the concerning antigen and ultimately not at risk of any fetal harm, they are still subject to the surveillance and its attendant consequences.
This study by Rego et al shows with 100% positive predicative value that we can determine whether or not the fetus is carrying the concerning antigen. This will allow a clinical paradigm shift away from surveillance throughout pregnancy and toward the use of a single cell-free DNA test in early pregnancy for those patients carrying a fetus without the concerning antigen. As the authors point out, this strategy saves about $8,000 per pregnancy. It also decreases the cost to the patient for time off work, travel for surveillance and the anxiety of worrying that their pregnancy may develop signs of harm secondary to alloimmunization. For those patients carrying a fetus with the concerning antigen, cell-free DNA testing will allow earlier referral to care, the potential to end the pregnancy via induced abortion when desired and allowed by law and the potential to enter phase 3 trials, as indicated by the authors.
This paper provides an important scientific rationale for the clinical use of cell-free DNA testing in patients alloimmunized to the included red blood cell antigens. We can reduce cost, complexity and anxiety by adopting this practice.
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