Should All Newborns Be Screened for Congenital Hypothyroidism?

This transcript has been edited for clarity.

Kaniksha Desai, MD: Welcome, everyone, to another episode of the Thyroid Stimulating Podcast, created in conjunction and collaboration with the American Thyroid Association to discuss up-to-date diagnosis and management of thyroid diseases. I'm your host, Dr Kaniksha Desai, and today we're diving into our very first pediatric topic, congenital hypothyroidism.

This condition, if left untreated, can lead to lifelong intellectual disability but is entirely preventable with early detection and treatment. Did you know that congenital hypothyroidism affects about 1 in 2000 to 1 in 4000 newborns worldwide? It's one of the most common preventable causes of intellectual disability. Thanks to newborn screening programs we have, most affected infants are diagnosed and treated early to prevent this disability.

Despite these advancements, challenges remain in awareness, access to care, and long-term management. A missed or delayed diagnosis can have lifelong consequences on brain development, growth, and overall health. While treatment is very effective, there are still gaps in follow-up care and education for parents as well as healthcare providers.

We are honored to have Dr Larry Fox join us today for a great discussion on congenital hypothyroidism. Dr Fox is a professor of pediatrics at Mayo Medical School and is chief of pediatric endocrinology at Nemours Children's Health in Jacksonville, Florida, where he has served for over 25 years.

A dedicated clinician, educator, and researcher, Dr Fox is a recognized expert in pediatric thyroid diseases, including congenital hypothyroidism. As a leading thyroidologist, he has made significant contributions to the understanding and treatment of thyroid diseases in children. Thank you for joining us today.

In today's episode, we will explore the science behind congenital hypothyroidism, the critical role of newborn screening, the impact of delayed or suboptimal treatment for this condition, and lastly, we'll discuss the latest research and expert insights, including why this condition deserves more attention.

Whether you're a clinician, a researcher, or simply passionate about pediatric thyroid health, stay with us while we discuss everything you need to know about congenital hypothyroidism. Thank you, Dr Fox.

Larry A. Fox, MD: Thank you very much. I'm honored to be the first pediatric endocrinologist on this podcast.

Desai: Can you provide us with a brief overview of congenital hypothyroidism and its pathophysiology?

Fox: Obviously, congenital hypothyroidism is something you're born with, and usually it's because the thyroid doesn't develop properly. Sometimes it doesn't develop in the right spot. There are times when it develops, but the mechanisms within the thyroid to make thyroid hormone are faulty. It's either thyroid dysgenesis or thyroid dyshormonogenesis.

The dysgenesis is where the gland doesn't develop properly. Sometimes it can develop in the wrong place. In some cases, the thyroid mechanisms to make thyroid hormone are faulty because you're missing some of the enzymes, missing some of the substrates, or something is going on where you're not making thyroid hormone.

Desai: This condition is actually classified as permanent or transient. How do you differentiate between the two, and are there any clinical implications?

Fox: You may not know if it's permanent or transient until they're 2, usually 3 years of age, when you do a trial off the medicine because brain development is so dependent on thyroid hormone.

We tend to be cautious and leave them on until brain development is not going to be negatively affected, and that's generally after 3 years of age. You don't really know if it's transient until they're taken off the medicine at about 3. If they have to go back on it, then you know it's not transient, and it is permanent.

If they're able to stay off for a while, then it's going to be considered a transient form. You also can know during infancy, if after 9, certainly by 12 months, you have TSH (thyroid-stimulating hormone) levels that are high, especially after 12 months, and you have to go up on the levothyroxine dose, then you know it's going to be a permanent form, because the transient forms generally should resolve by 9 or 12 months of age.

Desai: Can you talk a little bit more about those transient forms? You mentioned that the thyroid gland may not form properly. You should be able to tell that with an ultrasound. When's the earliest you can do the ultrasound in a baby? Do you do ultrasounds on babies? We do them frequently in the adult world.

Fox: We do many thyroid ultrasounds in babies. Actually, the guidelines suggest there should be some imaging done, but you don't want imaging to delay treatment in a baby with congenital hypothyroidism. Two types of imaging are used. One of them, of course, is the thyroid ultrasound, and the other is a technetium or even I-123 scan.

Each has pros and cons. The thyroid ultrasound, of course, is not invasive and there's no radiation involved, but it doesn't give you any functional aspects and really can't pick up easily any ectopic thyroid development.

The scans with usually technetium, you get a little more anatomy. You get to know where the thyroid is located, but it's more expensive. You have to order the technetium and you get an answer of location, but you don't want to delay the treatment by doing a scan. Some people propose doing ultrasound. Some people want to get the technetium and maybe the I-123.

You don't want to delay treatment. I usually do a thyroid ultrasound. Then, if I think it's a permanent form after 3 years, we may do further testing when they're older.

Desai: Can you talk about what causes transient hypothyroidism?

Fox: Often, transient hypothyroidism is caused by something going on in the mom. If mom had thyroid hormone receptor-blocking antibodies, TSH receptor antibodies, then baby’s thyroid may not be functioning properly, but those antibodies go away and that would be causing a transient form.

Other things that can cause transient forms would be iodine exposure. If they're going to surgery and there's a lot of betadine or if the mom has an arrhythmia and is on amiodarone, there's iodine in that. The babies can actually be born with the thyroid not functioning well, but it goes away because whatever's causing it, either with the mom or when the baby was first born, resolves.

Desai: Now we know a little about the background and some of the causes of it. Can you talk about the newborn screening? I think that's something the US does differently than maybe the rest of the world. How does that impact congenital hypothyroidism rates here vs internationally?

Fox: The newborn screen has been around since the mid-70s in the US and Canada and in other developed countries. The problem with newborn screening is that about 70% of babies born worldwide are not undergoing newborn screening. Only about 30% are born in places worldwide that have a newborn screen.

Newborn screens, when they first developed, were T4 based. They measured T4, and if it was low, they measured TSH. As assays improved, the TSH-based screen became more prevalent. In this country and in Canada, most newborn screens are TSH based.

There are still some that do T4 based and there are others that do a combination. They'll do the T4 and the TSH, both at the same time. There are pros and cons for each. With the T4 based and the TSH based, you will maybe pick up things with one and not the other. For example, a TSH-based screen will not pick up central hypothyroidism. There are pros and cons. In Florida, actually, they do a combination of both T4 and TSH.

Desai: Is it more expensive to do both?

Fox: Of course it's more expensive. There are more assays involved. Remember they're on dried blood spots. They're on the heel poke, they do it on the filter paper. It's a dried blood spot, so it's not exactly the same as drawing blood and sending it to the lab to measure T4 and TSH. It does get more expensive the more assays you do.

Desai: Does this test catch everyone, or can you have any false negatives?

Fox: You can have some false negatives. If it's a mild hypothyroidism, if there's mild dyshormonogenesis, if they're able to make some thyroid hormone but not completely, you may miss that if it's done early and not repeated later.

You can also have some false positives, where you have an abnormal newborn screen. Most of the time that has to do with the age at which the newborn screen was done. The newborn screen is really supposed to be done between 48 and 72 hours of age for the baby, but often, babies are going home from the nursery much sooner. They may go home not too long after 24 hours.

If you recall, there's a TSH surge almost immediately after you're born, and that can go up to 80 or even a little higher within the first hour. That TSH rises very, very quickly after birth and then gradually comes down over the next 24 hours. The T4 does the same thing but is a little more delayed. If you do the newborn screen within that first 24 hours, that TSH may be quite high, but it's on its way down. That's why you're supposed to do another screen after 72 hours of age.

Babies are going home between 1 and 2 days, so many times they don't get that repeat newborn screen.

Desai: What happens in that case?

Fox: The process for the newborn screen is pretty similar when there's an abnormal thyroid test on the newborn screen. Actually, with anything abnormal, the newborn screen program calls the specialist.

In this case, they'll call pediatric endocrinologists, and the endocrinologist is going to call the primary care physician, the pediatrician on record, and say the newborn screen was abnormal. The baby needs some thyroid tests.

They'll do regular thyroid blood tests, go to the lab, and then if they're still abnormal, the pediatrician will call us usually.

Desai: This works in North America, but how does it compare to other developed countries like Europe and Asia?

Fox: They're not that dissimilar. Most of the places elsewhere are doing T4- or TSH-based screens. I think the problem we get into is in areas where newborn screening isn't available.

In pretty much all the African countries and Eastern Asia, and some countries like Mongolia, there are no newborn screens being done. Part of that has to do with the fact that, like in Mongolia, which I'm very familiar with, most of the babies aren't even born in a hospital. They're born out in the countryside, so getting a newborn screen is challenging.

I think the problem lies with the countries that aren't able or don't have a newborn screen program set up. It's not just for thyroid; it's for everything else that's checked on the newborn screen.

Desai: Can you talk a little bit about how congenital hypothyroidism is diagnosed in resource-low settings like Mongolia and the consequences?

Fox: Unfortunately, in places where newborn screening is not done, they're not going to diagnose it until they come in for something else, or they notice severe developmental delays and they do thyroid tests, and they have primary hypothyroidism, or central, I guess.

You mentioned in the beginning that congenital hypothyroidism is the leading cause of preventable developmental delays. Unfortunately, if there is no newborn screen, then you're not going to be preventing it, and they're going to be diagnosed because of the developmental delays that are noted later and probably other things. You mentioned the growth — they won't grow well. They'll have severe short stature, they'll have developmental delays, and many other features you wouldn't see in someone who has a congenital hypothyroidism but is treated very, very early.

Desai: Just to clarify, if you do wait and then you do the treatment, this is not reversible. Levothyroxine won't just fix the past years. It just starts wherever you start the treatment?

Fox: What you're probably asking is, if treatment is started early, what is the intellectual outcome, and if treatment is delayed, what is the intellectual outcome? Is that a good way to summarize?

Desai: Can you get some of these things back if you delay the treatment?

Fox: Unfortunately, the intellectual delay, the brain development, like I said, is so dependent on thyroid hormone. You need thyroid hormone for white matter development, and without it, the brain just doesn't develop. You can't reverse that.

If there's a baby who comes in a few months of age or a year of age or whatever that has developmental delays, is really short, and the diagnosis of congenital hypothyroidism is made, the developmental delays you can't reverse. You can help the kid's growth. You can help some of the other usual symptoms of hypothyroidism. The constipation and the puffiness that the kid will have, those can be reversed at any age, but not the intellectual delays.

Desai: That's the importance of early screening and that newborn screening.

Fox: That's why the newborn screen was developed. Remember that newborn screening programs were developed to be able to pick up diagnoses you would otherwise not pick up initially.

Treatment can be either too late, when it is finally diagnosed, or you just have a significant impact on their overall health by diagnosing it early. The very first one, of course, was PKU. It used to be called the PKU screen, but now there are so many other things. At least with congenital hypothyroidism, if you pick it up early, you can have essentially normal intellectual outcomes.

Desai: If you start treatment early, you basically have no growth problems, you'll have completely normal intellectual development, and no delays of anything.

Fox: A variable you may not have an impact on is adherence, but assuming adherence and that they're coming to clinic and adjusting levels, growth can be absolutely normal. In most studies, school performance and IQ can be perfectly normal. There are some kids who have very severe congenital hypothyroidism who will have some more subtle, maybe mild intellectual delays, even if treatment is started early.

The reason people think there is some maternal transfer of thyroid hormone to the fetus: In a baby who's not making any on their own, the maternal transfer will provide some for that baby's brain. If the fetus has severe hypothyroidism, the maternal transfer may not be enough to completely normalize the baby's brain development. By the time the baby is born, the fetus has already had some negative effects from the severe congenital hypothyroidism.

In most cases, the development is normal, but there are some that still have some intellectual delays. School performance, visuospatial abnormalities, and sensory neuromotor function can all be mildly delayed.

Desai: It got me thinking to iodine, right? Iodine deficiency is not a huge problem here in the United States, but this is a worldwide problem. How much does iodine deficiency contribute to the fetal period and then beyond?

Fox: Luckily, I don't have to deal with much iodine deficiency in this country, but I think that might be changing because people are using sea salt or other non-iodized salts. We may see some iodine deficiencies in select populations.

In areas where iodine deficiency is endemic, like Brazil, for example, congenital hypothyroidism is more common, especially if the mom is iodine deficient. If the mom is iodine deficient, then you're going to see more congenital hypothyroidism.

Desai: That’s because you can't transfer over that thyroid hormone, and I guess the baby also can't make enough as well because it's not getting enough.

Fox: That's right, no matter who it is, if the mom is iodine deficient, she can't make enough thyroid hormone, and the baby is subject to the iodine deficiency, too, so he or she can't make enough thyroid hormone. And if she can't make it, but there's not enough maternal placental transfer, then the baby's going to have problems when they're born.

Desai: I deal with a lot of thyroid cancer patients and patients who have thyroidectomies. If they're on thyroid hormone replacement, what are the chances of their children having congenital hypothyroidism problems transiently or permanent?

Fox: You mean if they're on thyroid hormone replacement?

Desai: If they're just on thyroid hormone.

Fox: Then I don't think their baby's chance of having congenital hypothyroidism is any more than the general population. You mentioned the incidence. The incidence is around 1 in 3000. In some studies, it's a little less; some studies, it's a little more.

Just because a mom is on thyroid hormone during pregnancy, that should not cause congenital hypothyroidism. I don't think it's any higher unless mom is well undertreated. There are standards for treatment for pregnant women and those are not data that I follow. That's not literature that I follow, because if any of my patients are pregnant, I will not be seeing them. They do have standards, and you're probably more familiar with those for pregnant women than I am. If they're managed appropriately, it should not increase the risk.

Desai: I always tell my patients, they'll be fine. Just take the extra thyroid hormone, especially in the first half of pregnancy, and it should be fine. But it's always a concern, right? It's always a concern.

Sometimes I also get asked about passing on Hashimoto's or genetic conditions to children. Can you talk a little bit about genetic testing for congenital hypothyroidism?

Fox: That's a very good question. I think genetic testing is becoming more and more popular and more and more useful. There are a couple things to think of when people do genetic testing for congenital hypothyroidism.

You want to be able to improve the diagnosis or make the diagnosis. You want to be able to improve treatment options or establish a prognosis when the genetic testing is done, and there's a number of ways to do that. You could do targeted gene panels. The different genetic labs have certain gene panels that look for a number of genetic causes of congenital hypothyroidism. You could do a chromosomal microarray, but you're going to miss small changes in those, or you could do a whole exome sequencing.

There are limits of these, of course. Limits could include cost. The challenges in getting genetic testing, cost is a big one, because not all insurance companies — and in fact most don't — agree that genetic testing should be done. Cost and insurance approval is a major barrier.

Availability. If you're out in the community, you may not have access to genetic testing. Then there are also problems with interpretation of the results. Sometimes you get these variants of uncertain significance (VUS). A variant doesn't mean it's pathologic, of course. If it says a VUS, it doesn't mean it's not pathologic. Sometimes interpreting the results can be challenging.

I personally think genetic testing should be done in most kids, but there are some instances where genetic testing is most useful. One of them would be familial. If I see a baby whose brother also has congenital hypothyroidism, it's much less likely to be a sporadic form of thyroid dysgenesis, I should say. If they have some other syndrome, because some of the genetic causes of congenital hypothyroidism are monogenic, but some are more associated with other familial syndromes. I think those are the main instances of when genetic testing should be done.

I guess another example is if I see a baby with congenital hypothyroidism and I do an ultrasound, and the ultrasound shows a thyroid in the place that it should be, and this child has a permanent form of congenital hypothyroidism. Then it's most likely dyshormonogenesis, and I think genetic testing should be done in that instance.

That has implications on the kids, it has implications on siblings, and if the mom and dad are going to have other children. Most of these are autosomal recessive, and so there's a 25% chance that another sibling would have that as well. There are specific populations I think genetic testing should be done, but there are some challenges to getting the testing to begin with.

Desai: We talked about the genetic conditions. What do you think is the biggest public health barrier to getting the congenital screening and treatment worldwide? I know we talked about cost. Are there any other health issues or barriers?

Fox: Cost is a big one but also access to the patients when they're born. If they're not born in a public hospital or even a private hospital, then they're born out in the countryside. Again, I can use Mongolia as the example. If they're born out in countryside, like many kids are, they're not seen by a physician right away. If they are seen by a physician, they don't have the ability to do the dried blood spot and send it to a reputable lab that's doing them for the entire country. I think access to patients is a big barrier.

Most kids here in this country are born in the hospital. That's not true for all, of course. Many are born at home. Even the ones born at home should be getting the newborn screen, but that's not the case in some of these underdeveloped countries.

Desai: What do you think the most promising areas of research in congenital hypothyroidism are currently?

Fox: I think one of the biggest areas of research is in genetics, and there has been a large amount learned about the genetics behind congenital hypothyroidism in terms of both thyroid dyshormonogenesis and thyroid dysgenesis. There are, like we said earlier, a number of genes that contribute to both of those categories.

I think the biggest thing that's being addressed now is the genotype-phenotype correlation. Probably one of the things that interests me most in congenital hypothyroidism is the information that's being put out there about the genetics behind it. There are people doing this, actually in many places, not just here, but in Europe as well.

Desai: I know we sort of touched on this. The treatment is levothyroxine. Currently, in the adult world, there's a hot debate about combination therapy. I just wanted to clarify that everybody in the pediatric world just gets levothyroxine. It's never a combination, right?

Fox: Well, never say never, because that's not the case. In most circumstances, it's levothyroxine. In the first couple years of life, we don't allow generic forms because there's too much variability from one generic to the next.

First of all, there's some educated families that read and they come to you and say, I don't want to be on levothyroxine. I want to be on Armour Thyroid, or they want to be on just T3, or they want to be on combination.

There are some kids that have maybe a little bit of T3 or T4 resistance, or they have some problems with their deiodinases, and being on T3 in combination with T4 actually could be beneficial for them. I won't say never, and I do have a handful of kids that are on both T4 and T3.

It's uncommon because most do very well on T4 alone. You're able to normalize their thyroid function and bring down the TSH with just T4 alone, but there are some patients that I've seen where it's a little more challenging. Sometimes we think that they may have a little resistance or deiodinase problems, so we give T3.

Desai: Does genetic testing help with that? Do you guys check for deiodinase polymorphisms?

Fox: You can. I haven't, actually. Honestly, I have not been all that successful in getting the genetic testing that I want. It's an insurance barrier more than anything else, which is unfortunate. I think it can really shed some light on many things going on with congenital hypothyroidism when genetic testing is done.

Desai: How often do you monitor these kids? Do you see them monthly, every couple months, or once a year?

Fox: We start out pretty frequently. Actually, if I'm starting someone on levothyroxine as a newborn, usually in the first week of life, where the TSH is real high and the T4 is low, I'm going to recheck labs within a week, at most two, to make sure there's some improvement.

The TSH does take a little longer to come down than the T4 does to come up. I don't expect normalization in that short timeframe, but I do want to see improvement because I want to make sure they're actually taking it. Every time I see the family, I emphasize how critical the medicine is for brain development and that they can't miss any.

As the kid gets older, you're going to go from every few weeks to every couple months, to every 4 months, to every 6 months, and then, maybe a little more frequently when they're going through puberty because your thyroid hormone needs to go up with puberty.

So pretty frequently in the beginning. Of course, like everybody else, I'm sure if there's a dose change, you're going to check them a little sooner again.

Desai: Do you have any specific instructions for your pediatric patients? In the adult world, we tell patients to wait an hour and they have to take it on an empty stomach. There are these hoops we jump through that might be more challenging with kids.

Fox: There are many hoops that parents have to go through as well. One is there are no liquid solutions readily available.

Desai: Do you use Tirosint-Sol?

Fox: That is the only liquid. What I should have said, I guess, is the tablets are readily available. They're easily crushed, and they're much less expensive. They do dissolve, but we tell them to dissolve it in a tablespoon of water or a tablespoon of breast milk or formula. Don't put it in an entire bottle because if the baby decides not to drink that entire 4-ounce bottle at one sitting, she may not actually consume all the levothyroxine.

If a baby is on soy formula, soy interferes with absorption. We tell them if the baby has to be on a soy formula, that's fine, but we don't want to give the soy formula at the same time as the levothyroxine.

Many times they'll come to me with medicine, and the medicine is a liquid that the pharmacy made. They tried to put it in solution, but they just can't. I show them the bottle and I shake and shake and shake, and then you can easily see really quickly the medicine settling at the bottom. You just can't get it into solution.

There is one brand that's a liquid that's very expensive. I don't think I've ever prescribed that because I just haven't had to. The families have done so well without it for 50 years. They've done well without the liquid and there may be some families that want it. I think that medicine is gluten free, and that's the only version of levothyroxine that might be gluten free. If there's a child who has a gluten allergy, has celiac, then they may want to do that. I don't know exactly how much gluten is in the regular pills, but that's a consideration.

They come with a bottle that's supposed to have been a suspension, but you can't get it into suspension.

Desai: You take the pill, you crush it in the formula. If they're not on formula, in applesauce?

Fox: A tablespoon of applesauce or something else. The most common is they put it in water, or they just swallow it or chew it.

Desai: I've learned some interesting things about the pediatric world. It's just as hard as the adult world, apparently. Given what we know today, what do you think are some critical clinical pearls for pediatricians, neonatologists, or endocrinology fellows managing patients with congenital hypothyroidism?

Fox: You did mention neonatologists, and that's a whole other issue because many times babies are being transferred to the NICU immediately, and many newborn intensive care units will do the newborn screen immediately upon transfer. Like I said earlier, it'll probably be abnormal.

I think they do that in anticipation of the potential for transfusions, which would affect your results. In those babies, they just have to have a repeat done at 72 hours. Premature babies, that's another thing. Levels are very different in premature. That would take the entire podcast to go over as well.

For pediatricians who are listening, I want to make sure that they look at the time that the newborn screen was obtained. I have access to all the newborn screen results in Florida, so I can pull up the report and look at the baby's birth date and time and when the screen was done.

I actually calculate how many hours old the baby was, because that's very important when interpreting the newborn screen results. Probably one of the most important things is making sure that, when you get called about a newborn screen being abnormal, you get repeat tests immediately.

Desai: Do you wait to start the thyroid hormone for the repeat tests, or do you give the patients a prescription and tell them to take it and that you'll get repeat testing?

Fox: I think that depends on the degree of abnormality. If the newborn screen at 23 hours was 15, I am not starting medicine. We're going to recheck it. If at 23 hours, the TSH was 300, we're starting medicine because I pretty much know that's going to be abnormal. That's not going to be because of the timing.

If I'm wrong, for whatever reason, we can stop the medicine. We haven't hurt the child. Delaying treatment can. You're much better off starting treatment and having to stop it than delaying treatment.

If you wait, then they may say, well, we'll just come in and they don't get an appointment or they cancel, and you're delaying that treatment. I don't want that.

Desai: As a summary for our listeners, when you do the newborn screening, it’s so important to look at the time of the test vs the time the baby was born and calculate how old the baby is. Make sure the child gets started on levothyroxine immediately, if possible, and then repeat the testing to confirm, if necessary, if the tests are borderline.

In monitoring long term, there's this relationship with their pediatric endocrinologist, and hopefully the patient can get some genetic testing and a thyroid ultrasound, if needed. Anything else?

Fox: The one thing I would say with that, though, is no matter what the newborn screen showed, if it was abnormal, you're going to get repeat tests at some point.

If the TSH is super high, I'm going to start treatment but still get repeat tests. If it was mildly elevated, like that 15 at 20 hours, I can do a test before I start treatment. You're going to get repeat thyroid function tests, but whether you're starting treatment really depends on the degree of abnormality.

The other thing I would say is my faculty are always available. Pediatricians call us all the time with newborn screen questions and thyroid test questions.

Desai: Thank you. It's so important to get this condition treated because, as you mentioned, it's the number one preventable cause of intellectual disabilities in children.

Thank you for joining us today.

Fox: Thank you for having me. It was an honor, and I appreciate it.

Desai: Thank you. Stay tuned for our next episode.