I am quarantined in London, so #Tweetorial timehttps://abs.twimg.com/emoji/v2/... draggable="false" alt="💂‍♂️" title="Man guard" aria-label="Emoji: Man guard">https://abs.twimg.com/emoji/v2/... draggable="false" alt="⏰" title="Wecker" aria-label="Emoji: Wecker">

Should we treat subclinical hypothyroidism during pregnancy?

A tweetorial on physiology, overdiagnosis, risk stratification and treatment harms.

Do you treat subclinical hypothyroidism during pregnancy?https://abs.twimg.com/emoji/v2/... draggable="false" alt="❌" title="Kreuzzeichen" aria-label="Emoji: Kreuzzeichen">https://abs.twimg.com/emoji/v2/... draggable="false" alt="✅" title="Fettes weißes Häkchen" aria-label="Emoji: Fettes weißes Häkchen">

Subclinical hypothyroidism [https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">TSH, https://abs.twimg.com/emoji/v2/... draggable="false" alt="↔️" title="Links-rechts-Pfeil" aria-label="Emoji: Links-rechts-Pfeil">FT4] occurs in ~3.5% of pregnancies.

- Short differential (fig)
- No/Mild symptomatology overlaps with pregnancy, doesn& #39;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">https://www.liebertpub.com/doi/full/...

Incorrect reference range https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> overdiagnosis of approximately 1 in every 9 patients (fig)

Overdiagnosis https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> overtreatment https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> 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">https://www.liebertpub.com/doi/abs/1...

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?

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/ ">https://pubmed.ncbi.nlm.nih.gov/27187054/...

Back to subhypo, why care?

Because it is opposite of normal physiology (fig):
hCGhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts">TSH receptor stimulationhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts">FT4https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">& TSHhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="⬇️" title="Pfeil nach unten" aria-label="Emoji: Pfeil nach unten">

Also, hCGhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts">pituitary TSH receptor stimulationhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts">ultrashort feedback loophttps://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts">TSH suppression

AKA the Brokken-Wiersinga-Prummel Loop https://pubmed.ncbi.nlm.nih.gov/15588378/ ">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

Why?

- Thyroid autoimmunity: 1/3 of women with subhypo are TPOAb positive https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> 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">https://www.liebertpub.com/doi/full/...

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).

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/27879326/... href=" https://pubmed.ncbi.nlm.nih.gov/29126290/ ">https://pubmed.ncbi.nlm.nih.gov/29126290/...

https://pubmed.ncbi.nlm.nih.gov/29126290/..." title="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/... href=" https://pubmed.ncbi.nlm.nih.gov/29126290/ ">https://pubmed.ncbi.nlm.nih.gov/29126290/..." class="img-responsive" style="max-width:100%;"/>

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/... href=" https://www.nejm.org/doi/full/10.1056/NEJMoa1606205">https://www.nejm.org/doi/full/...

Antenatal Thyroid Screening and Childhood Cognitive Function | NEJM

Original Article from The New England Journal of Medicine — Antenatal Thyroid Screening and Childhood Cognitive Function

https://www.nejm.org/doi/full/10.1056/NEJMoa1106104

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)
-">https://academic.oup.com/jcem/arti... 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

Subclinical hypothyroidism during pregnancy:

* Reflects an abnormal physiology
* Use correct reference ranges to diagnose
* Risk stratify: TPOAbs, gestational age etc.
* If you treat https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> 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">https://twitter.com/TimKoreva...