Dr. Daniel Aronov
A pregnant woman has come to you for her first antenatal appointment. She’s perfectly healthy with no signs or symptoms of thyroid disease. You arrange the gamut of blood tests: full blood exam, blood group, HIV, etc., but do you also check her Thyroid Stimulating Hormone levels (TSH) to screen for thyroid problems? And if she ends up having subclinical hypothyroidism, do you treat it? This week we look at the evidence, the guidelines and the history to try and answer this question.
The story of treating subclical hypothyroidism in pregnancy unfortunately, follows a very common formula in medicine:
Here’s how it goes:
- Step 1: Data from observational studies suggest a strong association between an abnormal blood test and disease.
- Step 2: Guidelines jump on this data very quickly and make strong recommendations to fix the blood test if it’s abnormal to try and reduce said disease.
- Step 3: This practice quickly becomes the standard of care.
- Step 4: Only after this has become standard of care is a good quality randomised controlled trial finally conducted to actually test the recommendations by the guidelines – to see if fixing the abnormality on the blood test actually improves the disease.
- Step 5: The randomised controlled trial/s shows that fixing the abnormal blood test has absolutely no impact on the disease to which it is associated.
The worst part about this formula is step 6: That it often takes years or decades for practice to change now that there is good evidence that what we were doing was wrong.
Let’s follow the history of treating subclinical hypothyroidism and see how it fits this formula to a tea!
But first let’s define our terms: Subclinical hypothyroidism is when the TSH is elevated, but the thyroid hormone or T4 is within the normal range. So there must be some low thyroid hormone process going on, because it’s stimulating TSH to make more but the system is compensating and maintaining normal thyroid hormone levels. Theres another term called hypothyroxinaemia – this is the reverse – where there is low T4 but the TSH is within normal range. Then you can get a low T4 plus a high TSH – and this would just be called straight up hypothyroidism. But I would argue that you could even split this into two: symptomatic hypothyroidism and non-symptomatic hypothyroidism. Non-symptomatic hypothyroidism would be where the patient has low T4 and a high TSH but feels completely fine with no symptoms or signs of hypothyroidism whatsoever.
So let’s go through our little formula:
Step 1: Data from observational studies suggest a strong association between an abnormal blood test and disease.
We have known for over a hundred years that hypothyroidism is associated with adverse pregnancy and neonatal outcomes, like mental retardation. That’s when it was discovered that overt hypothyroidism, where patients were iodine deficient and had symptomatic hypothyroid disease was associated with impaired brain function in the baby. But what about if the women are totally asymptomatic but have a low thyroid hormone or a high TSH? Well, in 1999 two studies came out to show that even in these women, there is an association with poor brain development of the child.
One study measured the TSH in 25,216 pregnant women and found that those with TSH levels in the top 0.3% ended up having children with lower IQ scores
The second study followed 220 pregnant women and found that babies born to mothers with lower T4 at the time of pregnancy did worse on psychomotor development scores.
So there seems to be a pretty consistent association. The problem is, there was absolutely no evidence that fixing the thyroid hormone levels leads to better outcomes. But that didn’t stop Step 2 of our association formula from going full steam ahead.
Step 2: Guideline committees make strong recommendations to fix the abnormal blood test to try and reduce the disease.
Well, it certainly hasn’t been universally accepted in all guidelines, but some big guidelines have definitely taken this information and said every pregnant women should be tested with a thyroid function test, and any high TSH or any low T4 should be corrected, even if they are completely asymptomatic. In 2005, for example the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society came out with a joint statement that every pregnant women should be screened for subclinical hypothyroidism and treated. One review found that based on the thresholds that some of these guidelines were recommending treatment, 15% of all pregnant women would need to take thyroid hormone.
Step 3: This practice becomes standard of care.
Certainly in my experience, I have noticed that pregnant women get treated for their subclinical hypothyroidism, especially if they end up under the care of an endocrinologist. I’m sure it’s not universal but I think it is very common.
Step 4: randomised controlled trials are finally done to test whether fixing said blood test abnormalities will actually reverse or improve the disease to which they are associated
Let’s start with the CATS study or the Controlled Antenatal Thyroid Screening study, which was published in NEJM in 2012.
They study took 21,846 pregnant women and checked their TSH and T4 levels within the first 16 weeks of pregnancy. They were then randomised into two group:
The first group was the screening group: in this group the treating team were given the results of the TSH and T4 tests straight away, and if the TSH was high or the T4 was low or both, they were put on thyroxine.
The second group was the control group and in this group, they took the blood sample but froze it straight away, stored it at -40 degrees Celsius, and only after delivery, thawed it out and measure the TSH and T4.
390 women in the screening group tested positive for hypothyroidism, either with a high TSH or low thyroid hormone or both, and so were treated, while 404 women in the control group tested positive for hypothyroidism but were not treated because the results were only available after delivery.
The primary outcome was cognitive function of the the babies born to these mothers at age 3.
And….there was no difference between the groups. The IQ score was the same whether you had abnormal thyroid hormone levels and you got treatment or whether you had abnormal thyroid hormone levels and you didn’t get treatment. There was also no difference in preterm birth, birth weight, etc.
In March of 2017, the second randomised controlled trial looking into this had come out. It was also published in the New England Journal of Medicine, and Brian Casey was the lead author.
It was actually 2 trials: One trial was testing whether treating subclinical hypothyroidism during pregnancy improves cognitive function in their baby. While the second trial was testing whether treating hypothyroxinaemia in pregnancy improves cognitive function in their baby.
They screened 97,228 pregnant women with thyroid function testing before 20 weeks gestation. 3057 of them ended up having subclinical hypothyroidism (TSH>4mU) and of these, 677 fit all the inclusion criteria, gave consent and underwent randomisation to either get thyroid hormone therapy or not. That was study 1 – The subclinical hypothyroidism study. Study 2 was the hypothyroxinaemia study. 2805 of the 100,000 women ended up having hypothyroxinaemia, where the T4 level was low but TSH was normal. 526 of those underwent randomisation.
They were all randomised to either take levothyroxine or placebo. Every month they got a blood test and adjusted the levothyroxine dose if they needed, in order to keep the TSH level (study 1) or T4 level (study2) in the normal range. They did sham dose adjustments in the placebo group as well. For every real dose adjustment they did in the levothyroxine group, they did a sham dose adjustment to someone in the placebo group. It’s great. The goal was to keep the TSH level between 0.1mU/L and 2.5mU/L for study 1. For study 2, the goal was to keep the T4 level between 0.86 and 1.9 ng per decilitre (11 and 24.5 pmol/L).
The primary outcome was a full scale IQ test at age 5 in the baby that eventuated from this pregnancy. Secondary outcomes were other cognitive, motor and language scores at 12 and 24 months and a bunch of other developmental tests like behaviour and social competence were done at different stages of follow up. They also looked at a bunch of pregnancy and neonatal outcomes as well.
So what did they find? Let’s start with the pregnancy and neonatal outcomes: There was absolutely no difference. In preterm birth, preeclampsia, placental abruption, apgar scores, admission to NICU, nothing! No difference in either of the studies. So if you treat a low T4 or a high TSH with thyroid hormone, there is absolutely no impact on pregnancy or neonatal outcomes.
Now let’s move onto the neurodevelopment and behavioural outcomes. They were able to follow these kids up to the age of 5 in 96% of the cases. There was no difference in IQ scores and no difference in any of the other developmental scores either. Nothing. And again, this was in both trials. So whether you had a high TSH or a low T4, doesn’t matter…fixing it does not help anything to do with pregnancy.
Treating either subclinical hypothyroidism (high TSH, normal T4) or hypothyroxinaemia (low T4, normal TSH) with levothyroxine in pregnancy does not have any impact on pregnancy outcomes (such as preterm birth, preeclampsia, gestational diabetes or placental abruption), it does not have any impact on neonatal outcomes (such as apgar scores, admission to NICU, stillburth, miscarriage, or neonatal death) and it does not have anyone impact on the childs neurodevelopment or behaviour.
- Website: www.ebmpodcast.com
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- Casey 2017: http://www.nejm.org/doi/full/10.1056/NEJMoa1606205
- CATS study 2012: http://www.nejm.org/doi/10.1056/NEJMoa1106104