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Newborn screening

Learn about a newborn's first test and how it is used to flag babies who may have severe combined immune deficiency (SCID) or other disorders affecting T cells.

What is newborn screening?

Newborn screening is an important part of a baby’s care. It is a state-based public health service that ensures all babies are screened for certain conditions that can cause serious health problems. 

While originally intended to screen infants for common conditions, newborn screening tests are also performed for rare conditions that result in significant disease or carry a high risk of death early in life. Many babies born with these conditions do not show any signs at birth, appear healthy, and have no family history of the condition.

Over 60 different conditions, including some PIs that affect white bood cells called T cells, can be detected through newborn screening. For babies born with these serious, but treatable conditions, newborn screening allows them to receive a diagnosis and treatment as early as possible. Newborn screening can change a baby’s life by helping health professionals make a diagnosis and begin treatment before serious problems develop.

  • Nearly 4 million babies born in the U.S. receive newborn screening each year.
  • Almost 1 in 300 babies has a condition that can be detected through newborn screening.
  • In the United States, all states require newborn screening, but not every state screens for the same conditions. 

Through the Recommended Uniform Screening Panel (RUSP), the Secretary of the Department of Health and Human Services (HHS) recommends states test for 37 core conditions and 26 secondary conditions.

How is newborn screening done?

Newborn screening has three different parts: the blood test or heel stick; the hearing screen; and the pulse oximetry test. These tests all happen within 24-48 hours after birth. The newborn screening hearing and pulse oximetry results are ready immediately, and the blood screening results are available within a week.

The blood test or heel stick determines if a newborn might have one of many serious health conditions, including severe combined immunodeficiency (SCID). A small blood sample is taken from a baby’s heel, or sometimes through a vein, and placed on a newborn screening card. The newborn screening card with the dried blood spot (DBS) is then sent to a state laboratory for analysis.

The hearing screening determines if a newborn might have hearing loss. Two different tests can be done to screen for hearing loss. Both tests involve earphones or earbuds to check the baby’s hearing, usually while the baby is asleep.

The pulse oximetry test determines if a newborn might have certain heart conditions. A painless sensor is placed on the baby’s skin to monitor the amount of oxygen in their blood.

How does the screening test for SCID work?

Beginning in December 2018, after 10 years of advocacy work by IDF, every state in the U.S., as well as Washington, D.C., Puerto Rico, Guam, and the Navajo Nation, now screens every newborn for SCID as part of the baby’s blood screening. 

To screen for SCID, the public health laboratory measures the number of T cell receptor excision circles (TRECs) in the baby’s blood. TRECs are created when a type of white blood cell called a T cell matures in the thymus. As T cells develop, they excise, or cut out, a small piece of DNA that forms a circle inside the developing cell—this is the TREC. Since TRECs are small pieces of DNA, they can be detected reliably even on dried blood samples using a method called polymerase chain reaction (PCR)

The number of TRECs detected indicates how many T cells a baby has. The TREC screening results are either normal or abnormal.

  • A normal TREC result, also called negative, in-range, or low-risk, means that it is unlikely that a baby has a health condition affecting their T cells.
  • An abnormal TREC result, also called positive, out-of-range, or high-risk, means that a baby needs more testing to see if they have a health condition affecting their T cells.

If the results are normal, families are often not notified, but it is always important to confirm the newborn screening results with the baby’s primary healthcare provider.

If the results are abnormal, the provider will contact the family. An abnormal TREC test raises concern that the baby might have no or very low T cells. T cells are vital components of the immune system that prevent life-threatening infections. Low or no T cells means the baby’s immune system is not functioning properly. 

The family should follow the provider’s directions about what to do next, which may include:

  • Isolating the baby to protect the infant from developing infections. 
  • Starting immunoglobulin (Ig) replacement therapy and/or prophylactic antibiotics, antiviral, and antifungal medications. 
  • Avoiding live vaccines, such as the rotavirus (oral) vaccine, and using blood that is depleted of white blood cells (or irradiated) and does not contain any cytomegalovirus (CMV) if the infant requires a blood transfusion. 
  • Using commercial infant formula or pasteurized breast milk to feed the baby in order to avoid exposing them to CMV through their mother’s milk.

What does an abnormal TREC result mean?

Abnormal TREC results could mean a child has no or low numbers of T cells, which is a condition called T cell lymphopenia or T cell deficiency. T cell deficiency can be caused by SCID, commonly known as the bubble boy disease, or it could mean a child has another disorder. In some cases, the initial abnormal TREC result cannot be confirmed and the baby likely does not have a disorder affecting their T cells. 

It is important to remember that TREC testing is very useful for screening for low T cells, but it doesn’t confirm a diagnosis—it only identifies that something may be abnormal. Additional testing and evaluation by healthcare providers determine if the child does in fact have low or no T cells and why.

About 40-50% of babies with abnormal TREC results are confirmed through follow-up testing to have a T cell deficiency. Some states perform another TREC test with a different blood sample to confirm the initial abnormal results, while others proceed directly to the next tier of testing described below.

To determine if the number of T cells in the baby’s blood is actually low, a follow-up test, called immunophenotyping, is performed on another blood sample from the baby. In this test, T cells and other types of lymphocytes, including B cells and natural killer cells, are counted directly. Experts recommend also measuring the proportion naïve to memory T cells during this test to determine if any residual T cells could be from the baby’s mother (T cells from the baby should be mostly naïve T cells). If the baby has no or low numbers of T cells by immunophenotyping, or the T cells they do have are likely from their mother, they are confirmed to have T cell deficiency. Again, further testing and evaluation are needed to determine why the baby has a T cell deficiency.

In about one-third of cases, the T cell deficiency is ultimately determined to be caused by a type of SCID. 

However, in most cases, the T cell deficiency is caused by another condition. Other conditions that may cause low T cell numbers include:

Other conditions that can cause abnormal TREC results are often not as severe as SCID, but it's important to find out about them and test for them. If your child is diagnosed with low T cells and it’s not SCID, continue to pursue testing and medical intervention. Keep in mind that some of the medical steps taken overlap those of SCID, at least in the beginning. 

Infants definitively diagnosed with SCID are immediately sent for treatment appropriate for their diagnosis. Children without a definitive diagnosis also require ongoing evaluation and follow-up with a specialist to ensure the reason for their low T cells is understood and appropriately treated.

Babies with confirmed T cell deficiency—both those with SCID and those with non-SCID T cell deficiency—need to be evaluated by a clinical immunologist. Clinical immunologists have undergone specialty training in recognizing, diagnosing, and treating disorders associated with low T cells. The clinical immunologist can determine if the baby’s low T cell count requires further evaluation and treatment.

It is also important to note that some infants who have abnormal TREC results and confirmed low T cells at birth eventually normalize over time, without suffering from serious infections or poor health outcomes. However, all babies with T cell deficiency should be evaluated by a clinical immunologist to help families and pediatricians decide the best treatment and monitoring plan for each baby’s individual needs.

SCID and non-SCID conditions associated with low T cells may require continued care by a clinical immunologist who has the knowledge and experience to recognize which treatments are most likely to address each patient’s unique needs. 

The most important thing to remember is that if your baby has a low T cell count, you should always follow up with a skilled clinical immunologist. For help finding a clinical immunologist, use IDF’s Clinician Finder or the Primary Immune Deficiency Treatment Consortium (PIDTC) website.

If a baby has a confirmed T cell deficiency, additional, more definitive testing will be done to establish a diagnosis. These tests can include measures of T cell function, determining whether any T cells seen in the baby’s blood are from the mother, and genetic tests.

If the TREC test shows low T cells instead of no T cells at all, a test of T cell function may be done to determine how well the baby’s T cells work. The most common type of T cell function test is called lymphocyte proliferation to mitogens. Mitogens are plant-derived chemicals that stimulate healthy, functional T cells to divide and multiply. Most laboratories will check at least two of the three following mitogens – phytohemagglutinin, pokeweed, or concanavalin A. By measuring the T cells’ ability to divide when mixed with the mitogen, the test helps determine if the baby’s T cells are functioning normally.

Since low T cells can arise from chromosomal problems (such as Down syndrome or 22q11.2 deletion syndrome), doctors may order blood tests to evaluate the size, shape, and number of the baby’s chromosomes. Tests that can identify chromosomal problems include karyotype, fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray. 

Genetic testing may also be done, especially if there is a high suspicion of SCID. Most genetic testing laboratories offer a SCID panel that analyzes the baby’s DNA for variants in a number of genes known to cause SCID. However, these panels are not standardized and include different numbers of genes and/or variants depending on the laboratory, so they may not test for all known SCID-causing genetic variants. Healthcare providers usually have to get prior authorization from the baby’s insurance provider before ordering any genetic testing.

Sometimes, no disease-causing variants are identified through these panels. The baby’s doctor may recommend more extensive genetic testing, such as whole exome or whole genome sequencing, which looks for variants in a larger number of genes (whole exome sequencing) or in all of the baby’s DNA (whole genome sequencing).

This page contains general medical and/or legal information that cannot be applied safely to any individual case. Medical and/or legal knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical and/or legal advice.

Adapted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases, Sixth Edition 
Copyright ©2019 by Immune Deficiency Foundation, USA