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Should we treat subclinical hypothyroidism during pregnancy?
A tweetorial on physiology, overdiagnosis, risk stratification and treatment harms.
Do you treat subclinical hypothyroidism during pregnancy?
Should we treat subclinical hypothyroidism during pregnancy?
A tweetorial on physiology, overdiagnosis, risk stratification and treatment harms.
Do you treat subclinical hypothyroidism during pregnancy?
Subclinical hypothyroidism [
TSH, 
FT4] occurs in ~3.5% of pregnancies.
- Short differential (fig)
- No/Mild symptomatology overlaps with pregnancy, doesn't distinguish
- Consistent associations of modestly increased risk of miscarriage, preterm birth and low birth weight.
![Subclinical hypothyroidism [TSH, FT4] occurs in ~3.5% of pregnancies.- Short differential (fig)- No/Mild symptomatology overlaps with pregnancy, doesn't distinguish- Consistent associations of modestly increased risk of miscarriage, preterm birth and low birth weight.](https://pbs.twimg.com/media/EgrfxXAWoAELtAO.jpg "Subclinical hypothyroidism [TSH, FT4] occurs in ~3.5% of pregnancies.- Short differential (fig)- No/Mild symptomatology overlaps with pregnancy, doesn't distinguish- Consistent associations of modestly increased risk of miscarriage, preterm birth and low birth weight.")
TSH, FT4] occurs in ~3.5% of pregnancies.- Short differential (fig)
- No/Mild symptomatology overlaps with pregnancy, doesn't distinguish
- Consistent associations of modestly increased risk of miscarriage, preterm birth and low birth weight.
First, how to get the diagnosis right?
- Use of the correct reference range is pivotal (grey area of figure).
So, do not use 2.5/3.0 mU/L cut-offs
Note: Any TSH above 10 mU/L = overt hypothyroidism (or lab artefact)
https://www.liebertpub.com/doi/full/10.1089/thy.2016.0457
- Use of the correct reference range is pivotal (grey area of figure).
So, do not use 2.5/3.0 mU/L cut-offs
Note: Any TSH above 10 mU/L = overt hypothyroidism (or lab artefact)
https://www.liebertpub.com/doi/full/10.1089/thy.2016.0457
Incorrect reference range 
overdiagnosis of approximately 1 in every 9 patients (fig)
Overdiagnosis overtreatment increased risk of harm
Note: plenty of data on BMI/ethnicity ref ranges, but no evidence this is clinically meaningful
https://www.liebertpub.com/doi/abs/10.1089/thy.2018.0475
overdiagnosis of approximately 1 in every 9 patients (fig)Overdiagnosis
overtreatment increased risk of harmNote: plenty of data on BMI/ethnicity ref ranges, but no evidence this is clinically meaningful
https://www.liebertpub.com/doi/abs/10.1089/thy.2018.0475
However, you need FT4 for your diagnosis as well..
Large inter assay differences in FT4 do not allow guidelines to provide any fixed FT4 limits
Best option = adopt a ref range from literature
Why not use the total T4 instead?
Large inter assay differences in FT4 do not allow guidelines to provide any fixed FT4 limits
Best option = adopt a ref range from literature
Why not use the total T4 instead?
Bad idea:
- >99% = bound
Thus: biologically unavailable & reflection of TBG/estrogen
- Literature on ref ranges very poor (very poor data for 150% of non-pregnancy ref range)
- Poor reflection of HPT axis (fig)
- No associations with adverse outcomes
https://pubmed.ncbi.nlm.nih.gov/27187054/
- >99% = bound
Thus: biologically unavailable & reflection of TBG/estrogen
- Literature on ref ranges very poor (very poor data for 150% of non-pregnancy ref range)
- Poor reflection of HPT axis (fig)
- No associations with adverse outcomes
https://pubmed.ncbi.nlm.nih.gov/27187054/
Back to subhypo, why care?
Because it is opposite of normal physiology (fig):
hCGTSH receptor stimulationFT4& TSH
Also, hCGpituitary TSH receptor stimulationultrashort feedback loopTSH suppression
AKA the Brokken-Wiersinga-Prummel Loop https://pubmed.ncbi.nlm.nih.gov/15588378/
Because it is opposite of normal physiology (fig):
hCG
TSH receptor stimulationFT4& TSHAlso, hCG
pituitary TSH receptor stimulationultrashort feedback loopTSH suppressionAKA the Brokken-Wiersinga-Prummel Loop https://pubmed.ncbi.nlm.nih.gov/15588378/
Women with gestational subclinical hypothyroidism exhibit a decreased thyroid functional capacity.
Upper: no association of hCG with subhypo
Lower: no FT4 increase with higher hCG in subhypo
Upper: no association of hCG with subhypo
Lower: no FT4 increase with higher hCG in subhypo
Why?
- Thyroid autoimmunity: 1/3 of women with subhypo are TPOAb positive impaired thyroidal response to hCG (upper fig)
Yet, also TPOAb neg subhypo no association with hCG (lower left). Other subhypo risk factors (upper right) or other causes may play a role.
- Thyroid autoimmunity: 1/3 of women with subhypo are TPOAb positive
impaired thyroidal response to hCG (upper fig)Yet, also TPOAb neg subhypo no association with hCG (lower left). Other subhypo risk factors (upper right) or other causes may play a role.
So, to treat or not to treat?
Risk stratification is key!
Below: overview of ATA guidelines (green = no treatment, red = treatment).
We’ll get to gray zone..
https://www.liebertpub.com/doi/full/10.1089/thy.2016.0457
Risk stratification is key!
Below: overview of ATA guidelines (green = no treatment, red = treatment).
We’ll get to gray zone..
https://www.liebertpub.com/doi/full/10.1089/thy.2016.0457
Risk stratification using TPOAb status is based on abnormal physiology (above) + small RCT (to follow)
Also on observational studies that show: high TSH + TPOAb positivity = high-risk group (examples below).
Also on observational studies that show: high TSH + TPOAb positivity = high-risk group (examples below).
How about RCTs of levothyroxine treatment?
1 positive, showing lower risk preterm birth (below)
Note: study started with old ref ranges, LT4 benefit for TSH >4 is another argument for use of current ref ranges
https://pubmed.ncbi.nlm.nih.gov/27879326/
https://pubmed.ncbi.nlm.nih.gov/29126290/
1 positive, showing lower risk preterm birth (below)
Note: study started with old ref ranges, LT4 benefit for TSH >4 is another argument for use of current ref ranges
https://pubmed.ncbi.nlm.nih.gov/27879326/
https://pubmed.ncbi.nlm.nih.gov/29126290/
Other RCTs did not risk stratification:
- 1 (over)treated (150ug/day), start week 13
- 1 treated with 75ug/day, start week 18
Based on RCTs:
- Still unsure if treatment is beneficial
- If you treat: start early, don’t overtreat
https://www.nejm.org/doi/full/10.1056/NEJMoa1106104
https://www.nejm.org/doi/full/10.1056/NEJMoa1606205
- 1 (over)treated (150ug/day), start week 13
- 1 treated with 75ug/day, start week 18
Based on RCTs:
- Still unsure if treatment is beneficial
- If you treat: start early, don’t overtreat
https://www.nejm.org/doi/full/10.1056/NEJMoa1106104
https://www.nejm.org/doi/full/10.1056/NEJMoa1606205
How about that grey zone?
Guidelines: consider treatment, individualize
Think about:
- Abnormal physiology: subhypo despite high hCG (twin, 8-11 wks)
- High TSH
- High-normal TPOAb titer ( https://academic.oup.com/jcem/article/103/2/778/4731739)
- High pretest probability of subhypo related adverse outcomes
Guidelines: consider treatment, individualize
Think about:
- Abnormal physiology: subhypo despite high hCG (twin, 8-11 wks)
- High TSH
- High-normal TPOAb titer ( https://academic.oup.com/jcem/article/103/2/778/4731739)
- High pretest probability of subhypo related adverse outcomes
If you decide to treat:
Beware of overtreatment!
High FT4 associated with lower birth weight, child IQ and cerebral gray mass (fig).
For example start with 50ug daily and titrate after 2-4 weeks
Beware of overtreatment!
High FT4 associated with lower birth weight, child IQ and cerebral gray mass (fig).
For example start with 50ug daily and titrate after 2-4 weeks
Subclinical hypothyroidism during pregnancy:
* Reflects an abnormal physiology
* Use correct reference ranges to diagnose
* Risk stratify: TPOAbs, gestational age etc.
* If you treat Don’t overtreat
* Reflects an abnormal physiology
* Use correct reference ranges to diagnose
* Risk stratify: TPOAbs, gestational age etc.
* If you treat
Don’t overtreat
I hope this was useful!
For other very good tweetorials, follow those who inspired me
@tony_breu
@CPSolvers
@ebtapper
@ash_bo21
@AvrahamCooperMD
@MiddeldorpS
@Leo_ReapDO
#thyroidchat
More time to spare?
A hyperthyroidism tweetorial: https://twitter.com/TimKorevaar/status/1273208949253312512
For other very good tweetorials, follow those who inspired me
@tony_breu
@CPSolvers
@ebtapper
@ash_bo21
@AvrahamCooperMD
@MiddeldorpS
@Leo_ReapDO
#thyroidchat
More time to spare?
A hyperthyroidism tweetorial: https://twitter.com/TimKorevaar/status/1273208949253312512
