Newborn Screening and Congenital CMV

Newborn Screening and Congenital CMV

Author: Patrick Fleming, M.D. Candidate

Newborn Screening and Congenital CMV

Early detection of congenital CMV (cCMV) infection in newborns is essential to providing the best possible care. Unfortunately, cCMV is not yet included in universal newborn screening (NBS) programs in the United States. Like many other conditions that are currently included in NBS, cCMV has a unique set of challenges regarding its characteristics, diagnosis, and treatment. As experts and advocates in the field of cCMV continue to make progress in addressing these unique challenges, its path towards inclusion in NBS resembles the path taken by the conditions that precede it. Understanding the history and principles behind current newborn screening programs is an important part of expanding impactful legislation that addresses cCMV.

In general, NBS programs seek to screen all newborns for a panel of accepted conditions, allowing for early interventions that improve medical outcomes. Many congenital diseases are initially asymptomatic, or at least difficult to detect. By the time symptoms arise, there are fewer opportunities to intervene effectively as the disease has progressed. Ideally, a screening test is very sensitive, meaning that it can correctly identify positive cases, with very few false negatives. This helps minimize missed opportunities for intervention. Positive screening test cases can then be referred for additional tests to confirm the result and for further workup.

Early NBS History

One of the earliest established universally screened conditions in newborns is Phenylketonuria (PKU). It is a rare metabolic disease first described by a Norwegian physician, Ivar Asbjørn Følling, in 1934. He worked with parents Borgny and Harry Egeland, who had young children with progressive developmental delay and a strange odor in their urine.1 Dr. Følling determined that these children had elevated levels of an essential amino acid in their body, suggesting a metabolic defect. This link was then explored in a larger population. When testing the urine of other developmentally delayed children for the same defect, Dr. Følling identified additional cases.2 This was a monumental discovery, in part, because of subsequent developments in screening and treatment.

A key feature of PKU is that the signs or symptoms are not often present at birth. It can take months for the elevated amino acid and its metabolic products to accumulate and cause the neurological damage. While Følling’s discovery paved the way for detection of the disease, it was not a cure. In the 1950’s, a group of researchers pioneered dietary therapy that improved developmental outcomes in children with PKU.3 A combination of selective food restriction and supplementation of others prevented the damaging amino acid accumulation. This approach was the first time a dietary therapy was found to help treat a metabolic disease, serving as a model for other conditions. However, early detection and widespread screening were needed to reduce the burden of PKU more widely.

Many physicians and scientists worked on early detection techniques. Dr. Robert Guthrie, a microbiologist at the University of Buffalo, helped to develop a diagnostic test for PKU that used whole blood on filter paper. This “Guthrie Card” or “Dried Blood Spot” could be collected within the first few days of life, before the critical period when dietary intervention is necessary. It allowed for widespread testing for PKU, and even additional diseases with the same original blood sample. Massachusetts was the first state to use the dried blood spot to screen all infants for PKU in 1962 and many states adopted similar strategies over the following years.4

With PKU as a template, additional conditions were added to state newborn screening panels, such as classic galactosemia and congenital hypothyroidism. NBS policies were expanded, state by state, after consideration by expert advisory committees.5 New conditions were added based on classic screening principles, such as those from Wilson and Jungner’s Principles and Practice of Screening for Disease presented in 1968. To justify screening, a condition should have an adequately sensitive test, an available and effective treatment, and involve a disease that is medically well understood.6

Despite the ongoing success of these programs through the 1970’s and 1980’s, the variable approach taken by multiple states created a complicated landscape of legislation. Details of which conditions were tested, how they were tested, what supportive services were provided, and other important aspects of newborn screening were not standard. As testing technology improved, more conditions could be tested from one sample of blood, further widening disparities from one state to the next. This led to growing concerns regarding medical ethics and justice, presenting an opportunity for federal-level intervention aimed at creating a fairer NBS system.7

Recommended Uniform Screening Panel

In 2002, the American College of Medical Genetics (ACGM) selected 29 core conditions to make up the original Recommended Universal Screening Panel (RUSP).8 The RUSP is supported by the Secretary of the Department of Health and Human Services (HHS) to provide states with recommendations regarding NBS to keep policies more consistent across the country. The recommendations are not required in each state, but they lower the threshold to begin screening new conditions and provide additional expertise. Formed in in 2003, the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) advises the HHS secretary on newborn screening, including on the process of adding additional conditions.8 In 2003, most states only screened for 6 conditions, but by April 2011, all states were screening for at least 26.8

Nominating a condition for the RUSP is a helpful step in expanding newborn screening programs nationally. Pompe disease, a rare metabolic disorder, was added to the RUSP in 2015. It had previously been rejected for inclusion after a submission in 2008, but stakeholders across the country continued to facilitate progress in the field. Regardless of the RUSP, some states already included it in NBS programs. A pilot program in Missouri, for example, helped to fill in knowledge gaps and demonstrated feasibility. 9 These state efforts influence the recommendations of the ACHDNC.
cCMV was nominated for addition to the RUSP in 2018. While efforts are ongoing, details of this process can be seen in previous blog posts from the National CMV Foundation.
More information about conditions included in the RUSP and the process of nominating a condition can be found here:

How is Congenital CMV Unique

While many experts feel that cCMV is worth including in NBS programs, its unique characteristics have created challenges in achieving this goal.

Most of the conditions in the RUSP are rare metabolic disorders with a genetic component. For example, PKU is inherited in an autosomal recessive pattern that only appears when both parents pass on a copy of the affected gene. Because 2 abnormal copies of the gene are needed for serious symptoms, autosomal recessive diseases are often quite rare. PKU is reported in 1 in 23,930 newborns globally.10 CMV, by contrast, is a common viral infection, with congenital infections in the U.S. closer to 1 in 200 infants. People can get the infection multiple times and can even have an existing infection reactivate, including during pregnancy.11 This is one of the reasons why understanding the burden of cCMV is complicated.

Next, many of the genetic RUSP disorders are screened using streamlined tandem mass spectrometry. This allows for the metabolites of interest to be tested all at once, from the same dried blood spot sample. Congenital CMV testing is commonly performed using saliva or urine samples, and with a real-time PCR test, which is often labor intensive and costly. However, ongoing efforts to expand use of dried blood spots for cCMV are promising.12 This strategy, using the same dried blood spot that is already sampled, has the potential to make screening easier and more cost effective. Other additions to the RUSP, such as Severe Combined Immune Deficiencies (SCID) in 2010, use a similar strategy that combines a molecular assay with a a dried blood spot sample.13 This is a valuable precedent that shows how NBS programs have evolved to accommodate an ever-expanding scope.

Finally, many of the newborns infected with congenital CMV never develop symptoms. This differs from some other conditions in the RUSP where almost all positive cases will be symptomatic. Therefore, when it comes to cCMV, experts usually only support treating moderate to severely symptomatic newborns with antiviral therapy.14 While this strategy does provide an intervention for the newborns initially impacted, it raises questions about how to address the asymptomatic newborns, many who will still develop symptoms as they get older. At the very least, these patients may benefit from pediatric follow-up.

Consistent progress in cCMV research is being made across the United States, all of which moves cCMV closer to being accepted as a screening target. Earlier this year, the Minnesota Commissioner of Health, Jan Malcolm, added cCMV to their state’s newborn screening panel. The decision was supported by the research performed involving the cCMV dried blood spot screening strategy cited above. This is the first state-specific universal screening policy of its kind and can serve as a template for the aspirations of other state screening programs.

Regardless of the nuances of cCMV, many of the same historical lessons from other NBS programs can be applied. Medical and technological advances create opportunities for expansion of screening policy. State supported legislation and pilot programs demonstrate feasibility and generate data. Federal support further enhances impact and lasting changes are made in public health. cCMV will continue to follow its own path to prevention, identification, and cure.

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-- Authored by Patrick Fleming; Frank H. Netter MD School of Medicine, North Haven, CT, Doctor of Medicine Candidate, anticipated graduation 2023, Northeastern University, Boston, MA.