We discuss the history, methods, management, and future directions of the newborn metabolic screening program. We are joined by Joe Schneider, MD, MBA, Assistant Professor of Neonatal-Perinatal Medicine at the University of Texas Southwestern Medical Center.
Dr. Neeta Goli:
Welcome to Newborn News, a podcast where we discuss educational topics for medical professionals who care for newborns. I'm your host, Dr. Neeta Goli, a pediatrician in the UT Southwestern Newborn Nursery.
Dr. Neeta Goli:
Welcome back to the podcast. Today, we'll be discussing the newborn metabolic screen. Due to the COVID pandemic, this will be another social distancing episode. We are joined remotely today by Dr. Joe Schneider, Assistant Professor in the UT Southwestern Division of Neonatal-Perinatal Medicine.
Dr. Joe Schneider:
Hello?
Dr. Neeta Goli:
Joe, how are you doing today?
Dr. Joe Schneider:
Doing, let's see Wednesday. I'm wonderful today.
Dr. Neeta Goli:
Wonderful. I love it. Dr. Schneider, thanks for joining us today.
Dr. Joe Schneider:
It's great to be doing this with you. I'm really looking forward to it.
Dr. Neeta Goli:
All right. To start off with, can you tell us a little bit about what the metabolic screen is and the history behind why we do it?
Dr. Joe Schneider:
Sure. It's actually a very interesting story. Before 1963, it was known that the intelligence of children with an elevated level of substance called phenylalanine could be dramatically improved if they had a diet low in protein, and you caught them early enough before damage was done. In 1963, Dr. Robert Guthrie, he demonstrated that the elevated phenylalanine in the blood of these infants inhibited the bacterial growth around their blood spots when you put it into what's called an agar plate and that newborn screen, that's the very first one. It caught on rapidly, as parents with intellectual disabilities throughout the country began to advocate for state laws to test all the newborns in the United States. By 1965, which is a short two years later, 32 states had what were called PKU screening laws. By the mid-1970s, it was routine in nearly every industrialized nation and in most states.
Dr. Joe Schneider:
Now, today, we don't use agar plates and bacterial growth. We use what's called tandem mass spectrometry, but the concept of taking blood spots, putting them on filter paper, it remains the primary approach for metabolic screening almost 60 years later. Just to bring us up to date, additional diseases were added to newborn screening, starting the 1970s, all with the little blood spots. They do vary by state. By the late 1980s, Texas was screening for five metabolic diseases.
Dr. Neeta Goli:
That is really incredible that they were able to generate such an impressive public health response so quickly. You said from 1963 to 1965, they were able to get this going.
Dr. Joe Schneider:
Yes, yes.
Dr. Neeta Goli:
How did they decide in subsequent years which disorders to add to the newborn screen?
Dr. Joe Schneider:
Well, that really varies by state. Right now, all states require screening for about 29 conditions. In Texas, we screen for 31, what are called core conditions and 22 secondary conditions, a total of 53, and the secondary conditions are detected as you look for what are called the core conditions. Now how did we get from 5 to 53? New tests are added periodically to what's called the United States Recommended Uniform Screening Panel, or RUSP. That's after a national review by the advisory committee and then also state review by the Texas Advisory Committee on Newborn Screening. In order to get on to the RUSP, you have to have enough prevalence of the disease, and there has to be proof of effectiveness of the testing and effectiveness of the treatment. At this point, Texas screens for almost all of the diseases on the RUSP. There's three that are not included at the moment.
Dr. Joe Schneider:
One of those, spinal muscular atrophy screening will be added in 2021. The other two one's Pompe disease, and the other is MPS, mucopolysaccharidosis type 1, that'll be added probably in the next couple of years as funds become available. Now, I can go in to the types of screening that is done, because that fits under this question. Bloodspot screening, there's really four different categories of diseases that are tested for. One is metabolic disorders that arise from processing amino acids, fatty acids, and organic acids. The infant either has a genetic defect that they either can't make or break down certain key substances and treatment for these is a special diet or medical formulas or medication.
Dr. Joe Schneider:
The second category is endocrine disorders, such as hypothyroidism, or congenital adrenal hyperplasia, where the infant lacks certain hormones that are important. In those cases, if you give the child those hormones such as thyroid supplementation, for example, they essentially lead a pretty normal life. The third category is hemoglobin disorders, such as various forms of sickle cell disease and thalassemia. Then there's a fourth category, which includes cystic fibrosis, severe combined immunodeficiency, and a bunch of others that really don't fit well into the other categories. All told, it's an amazing amount for a relatively small price.
Dr. Neeta Goli:
Since you mentioned funding and low price, what is the cost that's involved and who pays for it?
Dr. Joe Schneider:
Well, yes. That is indeed also interesting. It really varies by state. The fees can be no charge in some states or up to $150, depending upon how the state has decided to fund the newborn screening program. Now, no matter what, the newborn screening is performed on every infant and the parents don't pay anything. In Texas, the cost of the blood spot card to do these 50 some tests is $60.58 cents per card currently, which is a good deal. If the child's on Medicaid or CHIP, or is in essence, can't pay, doesn't have any insurance, then the state provides the card to the hospital or physician's office for free. You can get reimbursed from insurance companies for the cost of this card, as the cost goes up, as it almost certainly will, that will become more important. Currently, most physicians don't file with insurance to get reimbursed for this.
Dr. Neeta Goli:
Okay. That's good to know. What happens when you get the test results? If it comes back and the screen is negative, everything is normal?
Dr. Joe Schneider:
My recommendation is that the baby's physician needs to communicate this to the parents and tell them that the screen came back negative. Some will have forgotten about the tests, but others can be very concerned, and so it's important to close the loop. A very critical thing is it's important also to let them know that this is a screening test. It's not true to say your baby doesn't have whatever the disease ... Cystic fibrosis or the disease, because screening tests aren't always perfect. While it's unlikely that a baby might be a false negative, it's always possible. If the child is having symptoms of a disease that is part of the screen, don't just say that the screen was negative, so it can't possibly be that. Retest them to be certain.
Dr. Neeta Goli:
Okay. Then on the flip side of that, what happens if it comes back positive?
Dr. Joe Schneider:
Well, this is a complex answer. It really varies by disease, the degree of urgency and whether it's the first or second screen and even more things, but here's some recommendations. First, contact the parents, as in most cases, further testing is usually required. Your state newborn screening service will probably contact you or may contact you depending upon the urgency of the situation and your state has information usually on the web, that can be helpful in explaining the findings to the parents. If they don't, or if you find that that's not adequate, the American College of Medical Genetics has what are called ACT, A-C-T, short for action sheets, and they're available on the internet. If you just put in American College of Medical Genetics, ACT sheets into Google, you'll get them. They contain helpful algorithms and information. So talking to the parents and is important. The what to do next is also important.
Dr. Joe Schneider:
The state might be just asking you to get a second screen. If that's the case, get that arranged with the parents. In some cases, there are a few disease where immediate diagnosis and treatment is needed. That's where you have to convey to the parents the importance of this and Make sure that they get the follow up as quickly as possible. Now I mentioned before, when I was talking about negatives that the parents might've forgotten about this. You have to remember that for the most, usually these babies look very healthy to the parents. We'll talk about false positives in a moment, but the convincing, if there is a positive and the state coordinator says the baby needs to get immediate testing and diagnosis, then it's important to convey that to the parents, so that they actually do that. Then I also, which we'll talk about a little later, I recommend recording the information in your electronic medical record, because there's lots of steps and it's important to track the steps that are taken to make sure that everything gets done.
Dr. Neeta Goli:
Before we get to that, you mentioned that there are some diseases that have more of a sense of urgency. Are there any certain categories that would fall under the increased urgency or some that would be more routine, I suppose?
Dr. Joe Schneider:
Yeah. An example of a urgent one. At least one example. Hypothyroidism, it's important to get it diagnosed extremely quickly and to get the baby on thyroid supplementation. They need to get in there quickly. Similarly congenital adrenal hyperplasia, and some of the metabolic disorders, can manifest themselves with severe consequences very quickly. Other sorts of diseases on the other side, sickle cell disease. It's important to get the baby to be seen by a hematologist and to get them treated, but it is not quite as urgent as some of the others. Similarly with cystic fibrosis, these are diseases that manifest more slowly. Important to act on them, but not in quite as rapid a mode.
Dr. Neeta Goli:
Okay. Then we can get back to what you were addressing earlier in terms of documenting in the medical record.
Dr. Joe Schneider:
Yes. This is an area that needs some development. Newborn screening, it's often a multi-visit process and EMRs generally aren't particularly good at doing things over multiple visits. Also each EMR is different and how it's used is different, but I've got some suggestions. First, I recommend that you record the abnormal newborn screen in the child's problem list. The ICD-10 code is P as in Paul, 09, abnormal newborn screen and put in the specific, in the description of that, put in the particular thing that is abnormal. Now, if you already know the answer. For example, if the child has been diagnosed with sickle cell disease on the newborn screening, it's one of the few cases where newborn screening is actually diagnostic. You don't have to put an abnormal newborn screen. You could immediately go to sickle cell disease.
Dr. Joe Schneider:
Now, ideally, that problem list is going to be connected to the patient portal and any interoperability functions so that the child's information is visible to the parents through the portal and other clinicians through say a health information exchange because the child might wind up someplace else. Also, hopefully if you're using the problem list with each visit, the recording the condition on the problem list will make sure that you follow it in each visit. Now, some people also use a reminder system to make sure that they are tracking things between visits and different EMRs have different ways of supporting those, but if you use those, that's also a handy way to make sure that the parents did what they were supposed to do in terms of getting to the right place for example. Now, when the diagnosis is confirmed, I recommend replacing the newborn screen problem with the actual disease.
Dr. Joe Schneider:
In some EMRs, there's a replacement function where you can simply replace one problem with another, and it allows the reviewer to see how a problem resolved. In other EMRs, you have to resolve the newborn screen problem and then set up a new problem for the disease. Two other places where EMRs need this information. One would be depending upon the EMR and how it's used would be the patient's medical history. Since typically these conditions are lifelong. Then finally, the newborn screening report from the state with all the things that are negative, needs to go into the results section of the EMR. Eventually, I hope that all this is electronic and that you don't have to go through all these steps, but at the moment, it's the best way to keep track of these kids to make sure that they've got the right things going on.
Dr. Neeta Goli:
I think you brought up a really good point, too, that it's sometimes difficult to make sure that the clinicians who are going to be caring for these babies have the information as well, because if we're responding to newborn screens from the nursery, we need to make sure that the PCP knows that as well. Sometimes getting that information and contacting them, tracking them down can be challenging.
Dr. Joe Schneider:
Yes.
Dr. Neeta Goli:
In an ideal world, all EMRs connect and-
Dr. Joe Schneider:
Indeed.
Dr. Neeta Goli:
One day. So to get back to test results, how common are false positives?
Dr. Joe Schneider:
More common than we would like, but that's the point of screening tests is that they're rapid and you get results. With that comes false positives and false negatives. The frequencies of these, they really vary by state and by test. I did some research on this and it was reported in Ohio that for every 10 positive screening tests for cystic fibrosis, only one child actually had the disease. Because of different state methodologies, the parents in one state might have false positives as low as 0.1% of all newborn tests, while a few states over because they use different methodologies and approaches, it might be as many as 1.5% of the tests are false alarms. That's a significant difference. Unfortunately, because of the lack of follow-up in most states at the state level, it's difficult for state newborn screening programs to know their true false positive and false negative rates.
Dr. Joe Schneider:
I do recommend if you have a case of false positive or false negative, it is helpful to report it to your newborn screening service. Now, one other quick thing about false positives, they're not benign. The impact on families can be huge. Imagine getting told that your child who you think is essentially a perfectly normal child potentially has this awful sounding disease. They need to wait to for confirmatory tests in most cases. During that time, there's an incredible amount of worry that has been studied. Some studies have found that for parents who have received false positives, even after they've gotten the answer, they seek more healthcare services for their children, just because of lingering concerns related to the false positive result. It is the sort of thing that we want to try to minimize false positives, but worse than a false positive is missing a disease, which is a false negative.
Dr. Neeta Goli:
Agreed. Then you mentioned that the false positive rates might vary due to a difference in methodology or testing. For those core conditions that are screened for nationally, is it the same? You mentioned mass spec. Is it the same techniques that are used, or what do you think is the difference there?
Dr. Joe Schneider:
Well, for the most part as best I understand, the mass spectrometry techniques are the same, but reagents might be different. Also cutoff levels are different. You're going to ask me in a moment about single screen versus multiple screen states and so your cutoff level actually is a function, partly of whether you do a single screen, because if you only do one, you want to capture more possible cases than if you do two screens. But we'll cover that in a moment, but it turns out that there are a broad number of different ways of doing newborn screening. Different manufacturers, for example, of the machines. Sadly, each state is not the same.
Dr. Neeta Goli:
That's a shame. I wonder, do you know where Texas falls along that spectrum?
Dr. Joe Schneider:
Texas is a two screen state and they do two screenings. I'll cover that now. They do two screens, partly because it's just an easier process to do two screens from their perspective. If you're a single screen state, what you're relying on. For example, if you've picked up a child that has potential cystic fibrosis, you've got to actually find that parent and get them back for a second screen, which is not a normal thing in the medical care of children in that state. In a two screen state, if you've got a positive result in your first screen, again, now using cystic fibrosis as an example, you can be pretty sure that they're coming back for a second screen at some point. Your follow-up efforts relative to that first screen don't have to be anywhere near as extensive as they do in a single screen state.
Dr. Joe Schneider:
Another factor about one screen versus two screenings is in a one screen state, the longer you wait after a child is born, the better the result is. Whereas in a two screen state, that gives states like Texas the advantage of being able to do newborn screens as early as 24 hours. They will get false negatives at that point, on some things that are picked up in the second screening. Now two screens come at a huge cost. Because you're doing two screens on everybody. The other thing is that with all those screens, you've got to match the first and the second screen. Texas does a remarkably good job of that. About 80 to 90% of second screenings are matched to the initial screen. It's very, very interesting how the different states approach this thing. Again, it goes to each one is doing their own thing because newborn screening is a state-level program, as opposed to a federal program.
Dr. Neeta Goli:
What is the timing of the second screen in Texas?
Dr. Joe Schneider:
It's generally, it should be one to two weeks of age. In reviewing the clinics that I am able to see into in the Parkland system, they actually, if a baby is six days old, they won't do a second screen and they probably could, but the recommendation is one to two weeks of age. Minimum of seven days.
Dr. Neeta Goli:
Okay. You mentioned that in some states where just a single screen is performed, there might be some babies who are lost to follow-up. Has there been any data to show that Texas has a different loss to follow-up rate due to the second screening?
Dr. Joe Schneider:
Not that I know of. I'm on the advisory committee and we've probed the reason as to why two screens are necessary. Certainly the state doesn't do second testing on things that don't need a second test. For example, if the child was diagnosed with sickle cell on the first test, they're going to be sickle cell on the second test. Those sorts of things don't change. There is a lost to follow-up amount. It's a couple of percent. I mean, it's certainly something that the state does everything possible to find the kids and make sure that they get their second screens. If you're relying upon that second screen to cover your false negatives, one of the disadvantages of doing that is that if a child just simply doesn't show up, and so they're one screen versus two screens, there are massive debates about that at a national level. There's really not any good ... There are pros and cons on each side and nothing so far has come forward that would drive everybody one way or the other.
Dr. Neeta Goli:
Okay. Since we discussed earlier that this was started as a public health intervention in the '60s, what have the outcomes shown for the past sixty years?
Dr. Joe Schneider:
Fascinating benefits. Collectively, about 1 in every 600 children in the United States is picked up through newborn screen ... Blood spot newborn screening with one of these diseases. A disease of some sort. The most common of those are congenital hypothyroidism, cystic fibrosis, sickle cell disease, and medium-chain acyl-CoA dehydrogenase deficiency. Just as an example, every year about one in 2,000 infants is diagnosed with congenital hypothyroidism. If you catch these children early enough, in particular, in hypothyroidism as we had mentioned before, and you get them the right treatment, it's the difference between an essentially normal IQ and profound intellectual disability. Screening for congenital hypothyroidism reportedly saves about $400 million a year. PKU, the net benefits are somewhere greater than a billion dollars a year. At each test, before it's added to the recommended panel, the RUSP, it goes through a cost-benefit analysis to make sure that there's a positive return to society versus the cost of the program.
Dr. Neeta Goli:
Okay. Then since you mentioned SMA, and some other disorders are going to be added soon, what are some other future directions?
Dr. Joe Schneider:
Well, this is where newborn screening gets even more fascinating. Genomic screening is coming rapidly. Already some newborn screening tests rely upon genetic testing, and we can only expect this to increase. In addition to that, the whole genome sequencing in neonatal ICUs is now becoming talked about as a potential standard of care, because they're diagnosing up to about a third of patients with genetic conditions. These are NICU graduates who otherwise would have just, we would have said, we don't know what's going on with them. Now, so genetic testing is occurring. Treatments are also advancing. One of the preconditions of getting on the recommended panel is that there's a treatment for the disease. Well, as we get better at identifying drugs that can treat genetic disease, there's going to be more and more pressure to add tests to the newborn screening.
Dr. Joe Schneider:
Using spinal muscular atrophy as an example, there's drugs that stimulate the genome to produce the right proteins, to take a child who would be essentially unable to move and make them essentially normal. Then finally, we're near the beginning. We're still at the beginning, but we're getting there, of genetic surgery where an infant's genome might be manipulated in some ways to correct the disorder. In all of these cases, the sooner the diagnosis is made, the better. The thinking back to Dr. Guthrie and PKU, he had no clue as to how this was all going to unfold. I would venture that with whole genome sequencing in the NICU, for example, we're discovering incidences of diseases that we didn't even know existed, and somebody is going to come along and soon enough afterwards and come up with a treatment for it. I wouldn't be surprised in short order, if there are hundreds, if not more of tests that are candidates for newborn screening, and that's going to provide quite a bit of a challenge for the way that we do new newborn screenings through 50 individual states at this point.
Dr. Neeta Goli:
In terms of needing something more centralized, do you mean?
Dr. Joe Schneider:
Well, it's the ... Right now, for example, when I say 50, it's actually a few states pool their resources, but a small state like Delaware, for example. They do about 40,000 tests a year, a big state like Texas, 400,000 births. It's a two screen state. They do about 800,000 tests. Delaware can't possibly be anywhere near as efficient as Texas. Moving to the concept of regionalized newborn screening is something that's talked about, but there's a lot of politics because it means giving up a chunk of your lab at a state level. That lab is used for other sorts of things. It also means you have to go through the legislature for funding and Delaware, for example, would have to ship funds to Pennsylvania to do their tests. There's all sorts of things that make the newborn screening process resistant to change. My argument then is that it's going to have to change because of all these pressures that are coming along through genetic testing and genetic treatments.
Dr. Neeta Goli:
Then a quick question about the whole genome sequencing you mentioned in the NICU. Are they whole genome sequencing or whole exome sequencing, or both?
Dr. Joe Schneider:
No. Whole genome. Yeah.
Dr. Neeta Goli:
Are there certain indications for that? Or how often is that occurring?
Dr. Joe Schneider:
If I've got this right, so San Diego, the University of California San Diego, they're doing whole genome sequencing on all their NICU patients. There actually was a conference last year where ... When we could still get together, where we all talked about whether this should be expanded. At Intermountain Healthcare, they are starting to pick this up and a number of other NICUs are doing this and the results have been published. I haven't looked at them recently, but it was reported at the conference that roughly a third of children that you'd say, "I just don't know what's going on." That there actually was a genetic reason for "This is what's causing this child's problem,” that they found by looking at the whole genome. That they could understand or explain.
Dr. Neeta Goli:
Do you know what the cost is with exome sequencing or whole genome sequencing?
Dr. Joe Schneider:
It was in the thousands. At the conference, the number that was bandied about was closer to $500.
Dr. Neeta Goli:
Oh. That's much less than I had thought it was going to be. Do you think this is something that could be taken as a more widespread approach?
Dr. Joe Schneider:
I'm a fan of it. I happen to have a niece who has selective aphasia. Meaning she can hear, everything's fine, but she can't speak. And or she has difficulty in speaking. Nemours is, as we speak is doing whole genome sequencing on her to be looking for, in essence a genetic problem that caused her problem. It's the sort of thing that I think there's a whole lot more that we don't know. The only way we'll know is to actually go looking for it. Now, while we're diagnosing in one third, that means in two thirds, we're not diagnosing. I mean, it becomes expensive to do those sorts of things, but imagine if Dr. Guthrie had ... It was probably not cost-effective for Dr. Guthrie to do his first newborn screens, but if you discover that there's a particular genetic condition that's out there and we can do something about it, that's pretty important.
Dr. Neeta Goli:
Agreed. The future holds many exciting things, I think, for this program.
Dr. Joe Schneider:
I would say indeed yes, it does.
Dr. Neeta Goli:
Okay. Well, thanks so much for having this discussion with us today. I really appreciate your expertise. To end the episode today, do you have any advice for our listeners while they're taking care of newborns?
Dr. Joe Schneider:
I do. Newborn screening's an extremely successful public health program. But as I mentioned with the advent of all the new genetic testing methods, medications, and treatments, and so on, we have the opportunity to expand on that success, but like all public health programs, it's really dependent upon the confidence and support of the public, which stems from vigorous support from the pediatric community. My pitch to everyone who's listening to this is please be supportive of newborn screening, get involved if you can. It's a fascinating world and work together with us to make sure that the new processes that we need to come up with support the gains that we've had in the past and extend them into the future.
Dr. Neeta Goli:
Okay. Thanks so much for joining us today, Dr. Schneider.
Dr. Joe Schneider:
Well, it was my pleasure and thank you very much. I appreciate it.
Dr. Neeta Goli:
Thanks for listening to Newborn News. We hope you join us next time. If you like what you hear, make sure to subscribe and leave us a review. If you have questions, comments, feedback, or suggestions for future episodes, please email me at NewbornNews@utsouthwestern.edu. As a reminder, this content is educational and is not meant to be used as medical advice. Views or opinions expressed in this podcast are those of myself and my guests and do not necessarily reflect the views of the university.