And thanks for the organizing committee, and it's very hard to follow on after two eminent speakers. And we're going to shift and talk about thyroid disorders in pregnancy, and these are my disclosures. None of these works. Now, so we're going to focus around most of the talk around the 2017 guidelines, which is currently being updated. However, there have been some changes in the literature and our practice in our center shifting away a little bit from what the 2017 guidelines said based on the new evidence that has been coming along. We run a large service. We see about 1,200 thyroid women every year, mostly with an underactive thyroid or abnormal thyroid function. So before we delve into managing, we need to divide a basic understanding of what is the normal thyroid function during pregnancy and how we define normal and abnormal. And it's very critical initially to understand the critical role the thyroid hormone plays in the fetus. I would like to draw your attention to the fact that thyroid hormone is very critical in the early development of the placenta and the maintenance of the growth of the placenta, in addition to the other known effects on the somatic and brain development. We all know that it's very critical in the mothers to maintain a euthyroidism from a metabolic point of view. And achieving an euthyroid status before pregnancy is very critical. And pregnancy is a very stressful time for the thyroid gland because there is an increased demand on the thyroid gland. And what happens is that there is a progressive increase in the thyroid production. Overall, it increases by 50%. But that takes turns. It increases by 30% in the first month, and remember the 30% later on. And then it plateaus by the third month to about 60%. So the gland increases the production in order to meet the demands by the growing fetus. And the increase in the production is mediated by the HCG and then maintained by the TSH. So the HCG and the TSH share the same alpha subunit. And there is hemology in the beta subunit. And with a high concentration of HCG, what you can see is a, with a high concentration of the HCG, which happens early on in pregnancy in the first 10 to 12 weeks, what you can see is an increase in the production on T4 and a reduction in the TSH because TSH has nothing to do at this stage. Which then, TSH after 12 weeks starts to increase and go back to the levels around 20, 22 weeks. Now, the other changes that happen during pregnancy is the rise in estrogen increases the production of the thyroid binding globulins. And increasing the thyroid binding globulins, what's going to happen is going to suck all the free T4 from the, or suck a large number of the free T4 from the circulation. And what happens is there is a decline in the free T4 levels. And in about 40% of women, free T4 is usually under the reference range, the non-pregnancy reference range that we use in our practice. And high thyroid binding globulins increase free T4, the total T4 is actually increased. And if you want to focus on this over here, again, that's an increase in the HCG leads to increase in the free T4 and a reduction in the TSH. And I want to say here that in about 10% of the women, early on in pregnancy, TSH is completely suppressed, undetectable. And then the rise in the thyroid binding globulins leads to a progressive decline in free T4. Again, I want to say that 40% of the women will have free T4 under the reference range. So what would be the test that we're going to use in terms of screening for thyroid disorders in pregnancy? So outside pregnancy, TSH is the test we use for screening. And inside pregnancy, it's exactly the same. With an advantage that TSH, immunoassays directly measure the TSH, there's sensitive tests and there is a standardized test and there is a good correlation across different platforms. However, we don't actually measure free T4 directly in our usual labs. We're using immunoassays that estimate the free T4. And these estimates are impacted by albumin and globulin. And during pregnancy, it gets worse because albumin goes down. And I told you just what happens to the globulin levels. And there is a poor correlation across different platforms with the free T4. So it's hard to establish a normal free T4 levels. So we generally focus on the TSH as a screening tool. But the question remains is how we define the normal TSH. And for a long number of years, this is the way normal TFTs has been defined. Unfortunately, despite 2017 guidelines, and we're waiting for another guidelines, one of these reference ranges, particularly the one between 0.1 to 2.5 in the first trimester, it is still stuck in the mind of many practicing physicians that this is the normal range. But as I told you, if you look at data, if you look at population data, you will find that the majority of the population have the upper limit of TSH above 2.5. And if you zoom in the lower limit of normal, you'll find that most of them are lower than the 0.1 mL. And if you use this cutoff points in a population, you're probably going to over-diagnose, particularly subclinical hypothyroid disorders. So knowing that, what the American Thyroid Association did in 2017 is they recommended that you find your own reference range in your own population and use it in pregnancy. If you can do that, there are certain calculations that you can do. We know TSH goes down in pregnancy. So the lower limit of normal should be you subtract 0.4 mIU per liter. In the second trimester, subtract 0.3. And keep the upper limit of normal at 4 mIU per liter. So when we do the math over in our essays, which between this period of time has changed a little bit, our normal range that we currently use is a TSH between 0.05 to 4. And this is what we use based on our essay in our hospital. So before we delve into that, so this is what's the normal physiology and the normal changes and critical to have a normal range to work on. Now delving into hypothyroid disorders in pregnancy, which is not uncommon. Before I go there, I would like just to understand how the fetal hormone, thyroid hormone production works. So the fetus, thyroid gland, roughly in around about 12 weeks will start to function. By about 18 weeks, thyroid hormone production starts to become more efficient. And gradually, the fetus reduces the amount of thyroid hormone coming from the mother by deiodinizing it and use the iodine. And by about 22, 23 weeks gestations, it starts to reduce and pretty much block the maternal 3T4 transform. That tells us a few things. That the fetus is vulnerable for T4 deficiency early on in pregnancy. That is critical in hypothyroid woman before pregnancy. So to achieve early euthyroidism before pregnancy, maintain it as early as possible, as soon as pregnancy is confirmed. But as I'm going to delve later on, I generally feel that based on what we know, it's screening for hypothyroid disorders late is pretty much meaningless, especially after the fetus thyroid hormone has developed. So what are the adverse effects of hypothyroidism in pregnancy? The literature tells us a lot of adverse events. Mostly in the women is infertility, subfertility, and early miscarriages and hypertensive disorders. And I just, I told you early on that thyroid hormone plays a critical role in, seems to play a critical role in the placental development. And some of these adverse events are placental mediated by poor placentation. On the fetus, again, there is a many adverse events has been reported. But again, if you look at closely to them, some of them are more related to a poor placental development. So in a hypothyroid woman, it's very critical to start the treatment before pregnancy in order to reduce the fertility, in order to reduce early miscarriages. And hence, the recommendation is treat a target and keep the TSH under 2.5 milliliter national liter. And once they get pregnant, they should be told to increase the dose by 30%. This is the amount of increase in the production that usually happen under physiological levels. And you already have received or hear the talk by Professor Ghareeb about the use of levothyroxine. And that's what we use during pregnancy. And you already heard from Professor Ghareeb that the half-life of this medication is seven days. I know it's not stranger. I know you use it most of the time. And I know you all know that it interferes with food. But a very few things that are critical to understand, especially when monitoring those women during pregnancy, that generally, in order to reach a steady state, you need three to four weeks of levothyroxine before you start to see the impact of the dose. Outside pregnancy, we wait about six to eight weeks, maybe longer. During pregnancy, we wait between four to six weeks. And you have to stand against this rapid and frequent monitoring that sometimes occurs in some clinics. Now, levothyroxine has a very narrow therapeutic index. And missing a single dose a week might actually adversely impact the TSH. So it's critical part of the management is to teach the woman during pregnancy how to compensate for missing dose. Either take an extra dose the next day or tell them to take the medications three hours after the last meal. But compensating is critical. And it's very critical part of the management of hypothyroid disorders in pregnancy. Now, what we do normally do is, as I said, as early as possible, we aim for, treat them, and aiming for a TSH under 2.5 milliliter national per liter, monitor every four to six weeks. And then you can ease it off later on after you hit 20 weeks. Normally, we discharge the patient after 26 weeks gestation once we have a stabilized thyroid function. And then after delivery, we ask them to restore their pre-pregnancy dose. Now, you have noticed that we are treating patient to a target of TSH of 2.5. And we are talking about an upper limit of normal range, which run around four. And that's one of the things that can cause a little bit of the confusion with the guidelines about what's the therapeutic target and what's the diagnostic levels. And that brings us here to how you define a newly detected hypothyroidism during pregnancy. You all know that you use a TSH above the upper limit of normal with a 3T4 under the lower limit of normal. And that's the same happens in pregnancy. But you also classify women as having overt hypothyroidism if the TSH crosses 10 regardless of the 3T4 levels. And it's very critical that you all confirm the lab test, especially if it's done outside your institute that you're going to manage the woman in. And if you diagnose hypothyroidism at any point in time during pregnancy, you're probably going to treat them. And you can start a weight-based dose, or you can start a 50 micrograms of levothyroxine and then monitor every four weeks to six weeks, treat to target. And once they have two consecutive levels which are normal, they pass 26 weeks, everything is fine. You can discharge them. And then you can give instructions about what to do after delivery based on the scenario. Now I'm going to delve into the most controversial and more common problem, which is subclinical hypothyroidism that can impact up to 4% or 5% of the pregnancies. And during pregnancy, the definition is a TSH that is under 10 but above 4 with a normal 3T4. But it's very important that you always confirm these tests. In our practice, 25% of these blood tests, when we repeat them again, they are actually normal. The DSH is normal. And it's a controversial topic because there is very little evidence about benefits, and that comes from the issues related to the heterogeneity of the clinical trials. And I'm just getting this as one of the review articles that looked at this. And the heterogeneity comes from many things. One is, when is the subclinical hypothyroidism diagnosed? And the majority of the studies diagnosed this late. And what is the cutoff point that you use for the diagnosing? And everybody was using different cutoff points with different definitions of what's normal and abnormal. And one of the other issues as well, if you delve a little bit into studies that showed positive outcomes, like this, one of the old randomized control trials that showed when you treat subclinical hypothyroidism they actually do reduce miscarriages in this study. The issue was that the mean gestational age in this study, when they started levothyroxine, was 9 weeks. And almost all the miscarriages, apart from one, occurred under 11 weeks. And it's very hard to think that this is what the effect of levothyroxine... I just showed you it takes 4 weeks to reach a steady state. I don't think the levothyroxine has reached a steady state at that point in time. And many re-meta-analyses try to answer questions here about, is there a benefit of treatment? Who we can treat and what should we do? And this is one of the randomized systematic reviews that basically showed us that most of the randomized control trials we're dealing with are biased, not blinded. Observational studies have a severe risk of bias as well. They are not being adjusted for many confounders. And there is a selectivity in what they report in their outcomes. And the same analysis here tried to figure out, is there any benefit from treating women with subclinical hypothyroidism? And what they ended up with, there is benefit in reducing pregnancy loss and miscarriages. But when you look at... They looked at observational trials. There was no benefit. They looked at randomized control trials. Individually, no benefit. But they would put them together with a high level of heterogeneity. It seems to be a benefit that treating with levothyroxine reduces pregnancy loss. Another systematic meta-analysis, which was published a couple of years ago, which included nine randomized control trials, 13 cohort studies, which used the definition of subclinical hypothyroidism based on the recent ADA guidelines in 2017. And they found, collectively, no strong evidence of treating subclinical hypothyroidism on any maternal outcomes. And what they found is, if you zoom on randomized control trials, they found some benefits in reducing miscarriages, preterm labor, gestational hypertension, and small for gestational age. All of these are complications of a poor placentation. And then there was no difference if there was benefit in trials between TPA positive, TPA negative. If you take the randomized control trials out, the benefits are gone, and it's very critical. They found no evidence of impairment in childhood motor or social behavior. Now, the issue could be that, well, we're treating those women a little bit late. So if you... And if it is really an issue of a placentation, a poor placentation that we try to overcome, maybe start early. Treat them early before pregnancy. And this is another systematic review that looked at treating subclinical hypothyroid women before pregnancy and follow them up through pregnancy. And what they found is generally no benefit. But the problem is that the cutoff point for diagnosing subclinical hypothyroidism here with a TSH above 2.5, and they found no benefits apart from reducing preterm birth with a TSH above 4.0. And that can come up to... If we fine-tune our definition of subclinical hypothyroidism to a high-risk group, maybe treating those group of women early before pregnancy, maintaining it early, could be of benefit. Now, gestational hypertension and preeclampsia is another concern. Data have shown that, well, subclinical hypothyroidism is associated with it. However, it seems to be only with those with a TSH above 4, but we still don't have the benefits of treatment. Here, again, this is a complication of poor placentation, and this is a complication with a small incidence rate and will require large trials in order to answer the question of benefit with these agents. And a question that will be proposed here by William Shakespeare, should you screen all women or should you leave them alone? And guidelines will tell you, screen certain group of women, but you can argue that if you looked at these guidelines, there's very few women that you're not going to screen. I can sit on the fence here, but I can only say that I don't see any point of screening for thyroid disorders in asymptomatic women after the first trimester, given the lack of evidence of benefits. So if a woman is diagnosed in our practice with subclinical hypothyroidism in the first trimester, we do treat them. However, we send a confirmatory test. We usually start with the 50 micrograms and we treat them the same way we treat subclinical hypothyroidism. But if diagnosed after that, unlikely, or usually we don't treat them, and we monitor and reassure them. I have a very short time to go through hypothyroidism. I have seen Dr. Ali's talking up the stage. So I'm going to focus here on pre-existing hyperthyroid disorders with Graves' disease and look at certain aspects here. So this is a condition that has been associated with soft fertility, period disorders, and reduced ovulatory disorders, and a high rate of miscarriages as well. Carbamazole, methamazole, PTU are all associated with congenital anomalous, and this is an issue. And the general approach should be, if a woman have this condition, want to get pregnant, is we try to get them euthyroid, definitely on definite treatment by radioactive iodine and surgery. Very few women will accept those type of treatment. So one way is to try and get them to the lowest possible dose and stop the treatment as soon as the pregnancy is being confirmed. Now, the PTU has been... Sorry, so untreated hyperthyroidism is also associated with multiple complications if you left them untreated. And again, all of these complications seems to be coming from a poor placentation and a poor developing placenta. So it's critical, again, that you treat those women early on, get them euthyroid in order to reduce these complications. Now, PTU and carbamazole, and PTU has always been told that PTU has a lower rate of congenital malformations compared to carbamazole, and it seems that to be the case. 10 excess cases in every 1,000 deliveries in PTU and about 17 excess cases in women exposed to carbamazole or methamazole. And the classical guidelines would have told us to, in the first trimester, switch them from carbamazole to PTU. However, in this meta-analysis, they showed if you switch them, you're actually doubling the risk of congenital malformation. The patient, the woman, the fetus has been exposed to two different agents. And another meta-analysis looked at this again, compared PTU versus methamazole, and it found that, well, PTU has a lower risk of congenital malformation. How about switch? And switch seems to have a higher risk. That was not a statistically significant risk, but it was a trend towards a higher risk, not a reduced risk. So switching around, I'm not sure if it's the best scenario here. Carbamazole have other complications in terms of side effects that you all know, but in pregnancy particularly, it can cross the placenta. Apart from the congenital malformation, after the thyroid gland of the baby starts functioning after 22 weeks, it can impact the fetal thyroid hormone production. There is another thing here, which is the anti-TSH receptor antibodies that's positive in patients with Graves' disease, and they can cross the placenta. They can cause theoretically either fetal hyper or hypothyroidism. And treating women with Graves' disease, even if they have received radioactive iodine or surgery, it's better to monitor these antitraps at conception, and then at 22 weeks gestation, because if they're three times the upper limit of normal, the fetus will require monitoring for any signs of hyperthyroidism. So, if you treated everybody, all women, with hyperthyroidism to target and get their TSH normal, the mother, the fetus, are going to be exposed to these adverse events. If you left them untreated, they're going to be exposed to the impact of uncontrolled hyperthyroidism. So what do you need to do here? Because you're going to go on eggshells. As soon as the woman confirmed her pregnancy, and it's possible, the first thing is to consider, can we stop the treatment? And if we can stop the treatment, then we do that, and then we monitor the TFTs every two to three weeks. Now, the guidelines still tells us, I'm not sure what's going to happen with the new guidelines, that PTU in the first trimester consider switching afterwards. It's my own practice. I don't switch around. I think if we can stop, I stop. If I cannot stop and the woman requires, I think switching around in an uncontrolled woman, it's going to risk worsening the control, and I don't see that there is a very strong evidence for switching, but I'm not sure what the guidelines are going to tell us to do in the future. What's critical is we don't normalize the TSH. We treat the woman, the free T4, up to 1.5 times the upper limit of normal is acceptable as long as the woman have our clinically euthyroid, their normal resting pulse rate. If they are gaining weight, they're not clinically hyperthyroid, then this is unacceptable levels. You don't try to get TSH to normal, and I just mentioned about the anti-TRAV antibodies a minute ago. So, a last topic, which I'm not going to spend a lot of time here, is the relation of treatment of women with euthyroid antibody positive. There has been two large randomized control trials, one from the United Kingdom that looked at those women, not only anti-TPA positive, but their high rate of miscarriages, and they have infertility, which are high risk, and found that treating them with levothyroxine did not improve their outcome, did not improve the fertility rate, miscarriage rate, or any of the pregnancy outcome. And a mirror image of that, or a similar one to that, which I'm not going to delve too much in, was done in Scandinavian countries, and it did show exactly the same, that treating euthyroid antibody positive doesn't improve the outcomes. And again, I'm hoping that the new guidelines is going to reflect that in their recommendations. So, Dr. Ali, I'm just coming to the end of my talk, and I just hope to convince you that you need to develop a little bit of understanding of the physiological changes that's happening in pregnancy, in order to avoid undertreatment or diagnosis and overtreatment of women. It's very critical that you have a planned pregnancy, whether they're hypothyroidism or hyperthyroidism women, very critical to achieve euthyroidism in order to have an uneventful pregnancy. What the guidelines are telling you, the ATA is recommending that we establish and unify local reference range. I think you can use their recommendations, but you need to all talk the same languages of what's normal, what's abnormal in pregnancy, in order to unify the management and the diagnosis and avoid confusion to the patients who are told you have a thyroid problem, and then they come over to you and tell them, no, you don't have a thyroid problem. So far, I don't see a strong evidence that treating subclinical hypothyroidism categorically in all women is of any benefit. At this point in time, I think there might be some benefit in treating in the first trimester, but we'll wait and see what the ATA is going to tell us, and definitely anti-TPO positive euthyroid patients don't require any treatment, based on the evidence we have. So I'll stop here, and I'd like to thank you.

thyroid disorders

pregnancy

2017 guidelines

euthyroid status

subclinical hypothyroidism

thyroid hormone