How Fetal Antigen Tests Can Ease Patient and Provider Anxiety

What Is Alloimmunization?

“Alloimmunized pregnant patients are people who have an antibody against a specific red blood cell antigen. If they have these antibodies and if the fetus has the antigen of interest, it could be dangerous when the blood is mixed. This can happen during pregnancy, either during delivery or even just over the natural process of pregnancy. The mother’s and baby's blood can get mixed,” explained Sharma.

“When the mom has the antibody, and the fetus has the corresponding antigen, it could lead to severe hemolytic disease of the fetus and newborn (HDFN),” she continued. “It can cause anemia, jaundice, heart failure, and sometimes even lead to death.”

In essence, the pregnant parent’s immune system is attacking the antigens of the fetus. According to a 2020 publication in Nature, the prevalence of alloimmunization is between 5.2% and 37%, depending on the source. Of the population in this study, 18% were alloimmunized.

Sharma shared that there are a lot of different red blood cell antigens, but a select few are more likely to lead to HDFN. “The major ones are Big C, Little c, D, Big E, Duffy, also known as FYA, and Kell, also known as K,” she revealed.

Alloimmunization and Pregnancy Protocols

Sharma told LifeScienceIntelligence that alloimmunization is typically detected early in pregnancy through an antibody test. When a pregnant person is deemed alloimmunized, they are monitored by an OB/GYN or a maternal–fetal medicine (MFM) doctor. Most commonly, MFMs monitor alloimmunized patients for the duration of their pregnancy.

“Regardless of who is managing that patient, they can be taking weekly blood draws and getting blood titers to see if it seems like the maternal and the fetal blood is mixing. And then ultimately, if they reach a critical point from the titer level, they'll move on to ultrasounds, which can happen as often as weekly,” she expanded.

Current Alloimmunization Tests

An alloimmunization diagnosis can be debilitating for many people. Upon diagnosis, the pregnant parent may have many anxieties associated with the disease and their child’s risk of HDFN. Some options are currently available to determine whether the baby has the antigen. However, all of these options are imperfect.

Paternal Testing

The first option is to collect a paternal blood test. Despite the small portion of the population that a paternal blood test is helpful for, most patients get little to no benefit from this kind of test.*

“There are many issues in gathering the paternal sample,” shared Sharma. The first issue is parental uncertainty. Providers cannot be 100% certain who the father is without a paternity test.

Additionally, she stated, “it's difficult to get a paternal sample. Providers run into this with carrier screening all the time. That's one barrier today. And even if they can get the sample, you can't necessarily rule out the presence of an antigen.”

There is only one case in which the presence of an antigen can be ruled out if both biological parents have the same blood type. That said, paternal tests are difficult to get and only provide limited information.

Amniocentesis

The other available option for determining alloimmunization is amniocentesis. This procedure allows doctors to extract a sample of amniotic fluid for testing. According to the Mayo Clinic, amniocentesis carries a risk of cramping, bleeding, leaking of amniotic fluid, infection, or preterm labor. Additionally, in 0.1–0.3% of cases, amniocentesis can lead to a miscarriage.

Aside from the risk of the actual procedure, Sharma stated, “the sensitivity of it is about 98.7%, so it's not perfect.”

She also added that “it introduces the risk of the maternal and fetal blood mixing, which is exactly what you want to avoid for these alloimmunized moms whose fetuses potentially are carrying the antigen. So, there's no perfect way to determine fetal antigen status today.”

Often, the risks associated with this test dissuade patients and providers from opting for it. With these risks and the uncertainty of paternity tests, the only standard way to ensure patient safety is to regularly monitor the parent and baby throughout the pregnancy.

Fetal Antigen Blood Test

The company has developed a fetal antigen blood test for certain forms of alloimmunization. Essentially, a fetal antigen blood test will be offered to pregnant individuals who are alloimmunized for specific antigens.

“It can be given as early as ten weeks,” said Sharma. “In theory, if a woman finds out she's pregnant at eight weeks, has her blood work done, and determines that she is alloimmunized, she could take the UNITY test at ten weeks. It doesn't have to be offered at ten weeks; it could be offered at any point during her pregnancy.”

The test can fairly definitively determine whether the fetus is positive for the antigen. This is especially important since Sharma implied that nearly 65% would be negative.

In addition to definitive answers on the presence of antigens, this test can differentiate between maternal and fetal antigens.

“The scientists developing the test could retrospectively look at over 10,000 clinical samples in the lab. And so they were able to incorporate that in the analysis and differentiate between maternal and fetal antigen status,” she said.

“The most important point is that the test is not just detecting if an antigen is present, but it’s able to detect if there's a fetal antigen present in making sure that it's not the maternal antigen that the test is picking up,” emphasized Sharma.

Monitoring Benefits of Fetal Antigen Blood Test

In addition to the test’s ability to determine maternal and fetal antigens, there are several monitoring benefits that this test allows.

“There is not very much data out there because it's difficult to collect ground truths on this testing. It's not currently done today where providers are genotyping the baby after they're born,” she clarified. “However, based on data, it seems like 65% of their pregnant woman’s fetuses will screen negative, which means that this horrible monitoring workflow could be reduced.”

“It’s really up to the provider what they want to do with this information. But what BillionToOne anticipates is, at minimum, there will be reduced monitoring and less anxiety for that patient. So it's game-changing. It'll allow MFMs to focus on management for women who are at high risk. And second, it'll just alleviate a lot of stress and anxiety for those women who are alloimmunized,” added Sharma.

Sensitivity

As previously mentioned, many widely available options for detecting fetal antigens are ineffective as they carry a level of uncertainty. While the certainty of paternal blood tests for antigens is not easily quantifiable, the sensitivity for amniocentesis is 98.7%.

That said, Sharma stated, “UNITY has a sensitivity and specificity of greater than 99.9%.”

Looking Ahead

Although this test has not been widely used and its real-world benefits have not been analyzed, once widely available, clinicians may collect data on how this test improves the quality of life, provider workflow, and patient outcomes. Since the test has been launched, providers caring for alloimmunized patients may consider looking into this diagnostic tool and discussing it as a potential option for patients.

*Editor's Note: This article has been edited to reflect that the company is BillionToOne rather than Billion to One and remove an inaccurate statistic on paternal samples.