We discuss the pathophysiology, presentation, and management of congenital hypothyroidism. We are joined by Soumya Adhikari, MD, Associate Professor of Pediatric Endocrinology 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. Welcome back to the podcast. In today's episode, we'll be discussing congenital hypothyroidism. We're recording remotely due to the ongoing COVID pandemic. We're joined today by Dr. Soumya Adhikari, associate professor of pediatric endocrinology at UT Southwestern and Medical Director of the endocrinology clinic.
Dr. Soumya Adhikari:
Hello?
Dr. Neeta Goli:
Hi, Dr. Adhikari. This is Neeta. Thank you for joining us today.
Dr. Soumya Adhikari:
Yeah. How are you?
Dr. Neeta Goli:
Good. Thank you. We can go ahead and get started. Congenital hypothyroidism is the most common congenital endocrine disorder and the most common preventable cause of intellectual disability. To start off with, can you remind us of the functions of the thyroid gland and the physiology and pathophysiology of congenital hypothyroidism?
Dr. Soumya Adhikari:
Yeah. The thyroid gland is a small butterfly-shaped gland that sits in the front of your neck. Really, its main function is that it takes up iodine from the things that we eat and it uses that iodine together with a handful of other things in our body to make thyroid hormone, which we also call thyroxine or T4. Thyroid hormone plays for babies and for children, a really important role in normal growth and development. If your thyroid gland hasn't developed properly, then it doesn't produce enough T4 for the body to grow and develop normally. Like many other glands in the body, your thyroid gland is under the control of another gland that sits at the base of our brain called our pituitary gland. Many people refer to the pituitary as your "master gland", because of the level of influence it exerts over many other glands in your body.
Dr. Soumya Adhikari:
In the case of the thyroid gland, if the amount of T4 in your body is too low, your pituitary has an ability to sense that and release a signal, in this case, thyroid stimulating hormone, to stimulate a normal thyroid gland to produce more T4. When those levels get high enough, when the pituitary senses that your T4 levels are in target ranges, then your TSH production drops off and both TSH and T4 levels hover within “normal” ranges. In most hypothyroid babies, your thyroid gland has just not properly developed and can't make appropriate levels of T4. As a result, your pituitary gland has to work extra hard to stimulate your thyroid gland by producing more and more TSH, but often with no benefit of that, because there's not enough functional tissue to respond to those high levels of TSH to produce what your brain is trying to get the gland to produce.
Dr. Neeta Goli:
Okay. There are several potential etiologies of congenital hypothyroidism, including thyroid agenesis, like you mentioned, hormone synthesis defects, and receptor defects. Can you walk us through some of the most common causes we might see?
Dr. Soumya Adhikari:
Yeah. I mean worldwide, so in the US, I think you mentioned two or three of the more common ones that anyone is most likely to run into. Worldwide, I think it's worthwhile to at least mention that iodine deficiency remains a common cause of neonatal hypothyroidism. Thankfully, we don't see that near as much in the US anymore. The most common cause that we run into is, as I alluded to, underdevelopment of the thyroid gland, if not frank agenesis of the thyroid gland. Early in pregnancy, your thyroid gland really forms actually at the base of your brain. Then it migrates to come to rest in its final position in the lower part of your neck, where it finishes growing after it's migrated there. Sometimes that process is interrupted, leaving either a small piece of the thyroid gland in its normal location, but not fully developed. Sometimes there's a remnant of thyroid tissue that is not even in its normal bed. It's just somewhere along that migratory pathway, but it hasn't made it all the way down to the lower neck. If it's out of position, it almost invariably doesn't form and doesn't function as it normally would be expected to do, or on occasion, we run into less common, but important to recognize causes of hypothyroidism, which can include no true thyroid pathology, if the cause is secondary, meaning TSH deficiency or pituitary pathology can cause hypothyroidism as well. They can present in the neonatal period or even less commonly any of a number of enzyme deficiencies that are involved in normal thyroid hormone production. If you're deficient in any of those enzymes, then you might apparently have normal anatomy, but still low levels of the end product, which is the actual thyroid hormone.
Dr. Neeta Goli:
Okay. Since you mentioned this, I am curious, I just have a quick question about the iodine deficiency. When in the US did we start supplementing salt and other foods with iodine?
Dr. Soumya Adhikari:
Well, that's a good question. I don't know that timeline and history off the top of my head. That sounds like a great thing for me to know, but I don't know.
Dr. Neeta Goli:
Okay. I was just curious because I wasn't sure how the rates of hypothyroidism were affected by that, like you mentioned.
Dr. Soumya Adhikari:
Yeah, absolutely. For better or for worse, a lot of my experience with understanding the history of hypothyroidism is kind of starting in the 90s and later when Texas newborn screening program started and everything about our approach has been very consistent since then, but some of the longer term history and when things changed, I'm not as familiar with.
Dr. Neeta Goli:
Okay. Then since you mentioned it, so with newborn screening, now we can diagnose early and for the most part treat most cases early, which can lead to better outcomes. How common is congenital hypothyroidism now? Then how common is it for it to be diagnosed on newborn screening versus later, or potentially missed on newborn screening, conversely?
Dr. Soumya Adhikari:
Yeah. First off in the state of Texas, newborn screening for hypothyroidism has been around since the early 1990s. We have done screening in the state of Texas in one of really three commonly accepted ways that are practiced by different states across the US. We do a primary T4 screen, meaning every baby that's born gets a T4 level, measured on a spot of dried whole blood. Then every day, the lowest 10% of the batch of T4 levels gets a double check of the T4 in addition to a TSH measured. We do a dual screen only on the worst, if you will, 10% of each day's batch. That's one way of doing the screening. Another way of doing a screening is to check a T4 and TSH on every sample. Then yet a third way of doing the screening is to do a primary TSH screen where every sample gets a TSH drawn. There's advantages and disadvantages to all of those, whether it be from a cost or a sensitivity or specificity perspective. The commonly cited numbers are for congenital hypothyroidism that it's has a worldwide prevalence depending on the region. Depending on the population of about one in 2,000 to one in 4,000 in Texas, we're probably on the higher side of that, about one in 2,000. In some datasets that's even cited as one in 1,500 prevalence in newborns, born in the state of Texas. Lately, within the last several years, the thresholds for detection getting more and more sensitive, we have picked up on somewhere between 200 to 300 cases of hypothyroidism by newborn screening every year. Not all of those are true, permanent, durable, congenital hypothyroidism, but 200 to 300 cases per year. Some of which might later be weaned off thyroid supplements.
Dr. Neeta Goli:
How would we expect a baby with congenital hypothyroidism to present?
Dr. Soumya Adhikari:
The irony of it is that the thing we stress to trainees who come to our clinic is, most babies with congenital hypothyroidism look like perfectly healthy babies. That's the reason that we have newborn screening to begin with. I guess you could argue is that the physical symptoms, when present can certainly be helpful and can help to raise your index of suspicion about maybe a preliminary positive or preliminarily concerning newborn screening results, that you don't have confirmatory testing on yet. Mother's placenta actively transports T4 to the fetus. Babies with true significant hypothyroidism, even thyroid agenesis can still be born looking fairly healthy because of their ability to rely on the mother all throughout gestation.
Dr. Soumya Adhikari:
When babies do have symptoms, the classically cited symptoms tend to be, I mean, amongst other things, these are parents who will walk in at two or three weeks of life, especially mothers who've had children previously and say, "He or she is such a good baby that she's sleeps all the time, not very fussy. If anything, I have to wake him up to nurse him a little bit. He doesn't really ask for much. He's the easiest baby I've ever had." Then we put them on treatment and they are telling us a few weeks later that the baby's crying more and doing all the things you'd expect a healthy term baby to do, but it was a little bit masked by the presence of the hypothyroidism previous to that. Other symptoms, a hoarse cry, some feeding problems, some constipation, some degree of puffiness around the face.
Dr. Soumya Adhikari:
Sometimes you'll hear a baby's having a bigger tongue than one would expect to see. The fontanelles can be pretty patent in a baby with significant hypothyroidism. Some can even be a little bit hypotonic and then they can have a little bit of prolonged jaundice. Just jaundice does that persists beyond the age at which you would expect it to resolve in an otherwise healthy baby with no cause for elevated bilirubin levels.
Dr. Neeta Goli:
Okay. That gives us an idea of what to watch out for it, but it sounds again, like you mentioned, sometimes we might not see that except for the newborn screen. Then if we do get an abnormal newborn screen, what would our next steps be for these babies?
Dr. Soumya Adhikari:
Yeah. Obviously, taking a second to think through who is this that I'm getting this result on and did they in fact have anything on history that... Were they in fact a little bit jaundiced and we went through all the precautions and normal advice for a baby who's dealing with that or were they gaining weight a little bit slowly? We talked about all the things that we should keep an eye on over the course of the next few weeks, meaning taking 30 seconds to think about, were there any clinical signs or symptoms present, just to flavor your pre-test probability a little bit of what's the likelihood that this is a false positive screen versus a true significant signal of concern on the newborn screen.
Dr. Soumya Adhikari:
Then all babies with an abnormal newborn screen for congenital hypothyroidism deserve a T4 and TSH, and really in 2020, in most places that most clinicians will practice, it's probably worth doing a TSH and a free T4 so as to eliminate those somewhat rare, but still occasionally problematic binding globulin deficiencies that will lead to lab abnormalities, but really no significant clinical concern that you can essentially rule out by measuring the free hormone levels instead of the total hormone level. At TSH and free T4 for all babies with an abnormal newborn screen for CH.
Dr. Neeta Goli:
Okay. Then would you recommend that the primary care pediatrician or the person seeing this baby start treatment immediately as well or wait until they see endocrinology?
Dr. Soumya Adhikari:
That's a great question. I think for the majority of babies, because treatment is fairly simple and because there is a sense of urgency to the need to treat from a timing perspective, and frankly, because we as pediatric endocrinologists are so rare. If you're a pediatrician in the DFW area, maybe your patient that you're seeing in your office can get into our office the next day. If you're out in the middle of nowhere and your nearest pediatric endocrinologist is 300 miles away, then all those things need to be factored into the equation as well.
Dr. Soumya Adhikari:
For the most part, if a pediatrician calls us with a clear-cut diagnosis of congenital hypothyroidism in an infant, then we will encourage them to get the baby started on treatment with every intent to hopefully see the family as soon after in our office, as we can, to make sure that the family has their questions about the condition answered, to make sure that they get to hear about all the nuances of managing the condition from us in terms of how is the medication stored? How is the medication administered? What can they expect in terms of prognosis and to just hear from us something that they hopefully have already heard from their pediatrician about just what is the condition? What's the importance of treatment? What are the possible risks of under-treatment and all of that?
Dr. Neeta Goli:
Well, so to kind of get into that, how do you usually counsel families during that first visit in terms of risk of under treatment, appropriate treatment? Then earlier you had mentioned that not all babies have the permanent durable congenital hypothyroidism, so some might be able to be weaned off treatment. Could you speak to that as well?
Dr. Soumya Adhikari:
Yeah. It's a little bit of a catch 22, because on the one hand it's, "so simple to treat", and yet the consequences of non-treatment or significant under-treatment can be so significant because you're talking about some potentially durable, permanent neurologic deficits if the under-treatment is really lengthy, or if a child goes untreated completely for any significant length of time. We're not talking typically about, "Hey, it's important whether you get a baby started on treatment at day eight of life versus day 10 of life." That order of magnitude of difference probably doesn't make much of a difference, but we aim to start everybody on treatment within two weeks of life. Ideally, certainly within three weeks of life, if we can't do within two weeks of life. Those are the orders of magnitude that we're talking about in terms of really making a difference in terms of neurologic outcome downstream.
Dr. Soumya Adhikari:
If you start a child on treatment at two or three weeks of life, then you have in all likelihood, the data suggests given that child with significant congenital hypothyroidism, every opportunity to grow up, to be a normally grown and normally developed young child with little, if any, noticeable deficits of growth or development. That's the biggest piece of the counseling that parents get from us is sort of understanding that, "Look, this is something we want you to understand the severity of, but we also want you to understand that it doesn't have to be a devastating diagnosis because it is imminently treatable and there are good medicines to treat it. The treatment itself is one pill a day or a one to two pills a day and thus readily administrable even to babies, right from when they're very first born.”
Dr. Neeta Goli:
What are the most common barriers that you have to babies being appropriately treated, if any?
Dr. Soumya Adhikari:
Appropriate treatment is an interesting phrase because on the one hand appropriateness starts with recognizing the importance of early recognition and really jumping on this as fast as one can, when it raises its concerns in the early neonatal period. Delaying treatment because, “Oh, it's just a mild problem,” and then kids slipping through the cracks is certainly one of the things that we kind of fight against if you will, and trying to get everybody to understand the importance of early intervention. From a parental perspective, the challenge is in fact, the catch 22. You have a perfectly healthy looking beautiful newborn baby in front of you with no outward manifestations of illness whatsoever.
Dr. Soumya Adhikari:
Parents go through a sense of loss, when the first time that you learn that there is something "wrong" with your beautiful baby, there is an adaptation period of coming to terms with that and coming to accept that. Everybody responds to that in a slightly different way, but certainly in some cases, it's a little bit harder to get somebody to understand and appreciate the potential seriousness of not taking something that they can't see, which is levels of hormone in the body being really low as seriously as we need them to take it, to really achieve optimal treatment goals.
Dr. Neeta Goli:
Yeah. That would be tough. I'm sure there's some parents who go through a denial period as well, who have difficulty processing the diagnosis. As with any other diagnosis of a newborn or child.
Dr. Soumya Adhikari:
Yeah, a little bit of human nature involved in all of that. I don't blame any parents who struggle with that a little bit. I think it's our job to help them navigate those waters and come to terms with, again, that dichotomy of it's so simple to treat, but the consequences of not treating can be so significant.
Dr. Neeta Goli:
Absolutely. Then just as an anecdote, when I was in training, I actually cared for an elementary school-aged patient who unfortunately had untreated congenital hypothyroidism. The child had significant developmental delay, was non-verbal, not toilet trained. Thankfully we did get the child on treatment and they did have improvement in their developmental milestones, but were still delayed for their age in terms of longer term, can you discuss long-term consequences of untreated congenital hypothyroidism?
Dr. Soumya Adhikari:
Well, you're describing something that thankfully we don't see much of, which is probably what makes it memorable, is the rareness of it all. Because of the presence of practically universal newborn screening and because of the availability of a fairly cheap treatment for children who are affected and because of the iodine that's available in diets in terms of just diminishing the overall prevalence of the condition in the first place, we don't see much of what you just described. Thankfully, because those are the most significant consequences of untreated, severe congenital hypothyroidism, which is the significant growth delays you can have. Nine, 10, 11 year old children who still looked like they were four and five if they have true significant congenital hypothyroidism, that's never been picked up on and never been appropriately treated.
Dr. Soumya Adhikari:
Then probably even worse than the physical manifestations, there are the significant permanent risks to neurodevelopmental potential and neurocognitive potential. The loss of IQ that can result from months or years of untreated hypothyroidism is something you can never fully recover from. In fact, we don't harp on this too much, but for babies with the most severe forms of congenital hypothyroidism, even early treatment, for the most part, we focus on the fact that that normalizes developmental potential. There is a little bit of a hint in the literature of look, the babies with the most severe forms of disease, is there some difference in comparing them to their siblings in terms of IQ scores and such things, that one can never fully make up sometimes.
Dr. Neeta Goli:
It really reinforces the need to follow up on those newborn screens and act appropriately.
Dr. Soumya Adhikari:
Yeah. We will, in the early part, in the early part of our getting to know these families, lay out a roadmap, not only of here's what you need to do, here's how you treat, but then here's the monitoring protocol as well, which is pretty intense in the first year of life, meaning the first three or four months of life we'll follow these babies’ levels about monthly. Then about every two months over the course of the first year of life and then gradually less and less as they get older and older.
Dr. Neeta Goli:
Okay. Is there anything else you think would be useful for our listeners to know that we haven't gotten the chance to talk about yet?
Dr. Soumya Adhikari:
Can I end with two, I guess, endocrine pearls that are important to us who do pedi endo and just to minimize the risk of these things slipping through the cracks, I guess. We talked very superficially about the role that pituitary deficiencies can play in the discussion around neonatal hypothyroidism. That it's not always a thyroid problem, especially in a state like Texas, where our primary screen is T4 levels. We can do our newborn screen, occasionally pick up on cases of secondary hypothyroidism or pituitary deficiency, meaning TSH deficiency as well. I'd say two things about that from a primary care provider’s perspective, just on the off chance one is ever in the position of having to be an early decision-maker in the sequence of events. If you ever have a baby born with a diagnosis of hypothyroidism that leads to a diagnosis of secondary hypothyroidism, meaning TSH deficiency, then the risk of course, is everything we just talked about. But in addition, you have to screen the baby for every other pituitary function and whether there's anything else deficient, other than TSH, that's been found to be deficient through the newborn screen. Converse to everything you've heard me say for much of this, which is “hurry up and treat, hurry up and treat, time is of the essence.” In a child with TSH deficiency, you never want to treat a baby with thyroid supplements until you're absolutely certain that the child is also not a ACTH deficient, meaning that they are making adequate amounts of cortisol, because treating hypothyroidism in a child with concurrent adrenal insufficiency can induce an adrenal crisis. You never want to be the cause of doing any harm, obviously. That's something that just kind of be aware about.
Dr. Soumya Adhikari:
Then sort of a peripheral pearl, I guess, in relation to pituitary deficiencies and what else might be wrong in such. If you ever have a child born with a micropenis, which can also be present in a child with low thyroid hormone levels, TSH deficiency, gonadotropin deficiency, micropenis concurrently present. Even before you call us, before you call endo, check their blood sugar, meaning we probably have some time to figure out why the boy’s genitals are small, but in the meantime, it's quite possible that the child's blood sugars have been low for maybe even hours already, even as a neonate. You want to catch and intervene to remedy that right away.
Dr. Neeta Goli:
Okay. Thank you. That's good for us to know. Well, to end today's episode, do you have any other advice for our listeners while they care for newborns?
Dr. Soumya Adhikari:
No. Not much else beyond everything we just talked about. Thanks for giving me the opportunity to jump in and join you.
Dr. Neeta Goli:
Absolutely. Thank you so much for joining us today for this discussion.
Dr. Soumya Adhikari:
Absolutely.
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.