PreMeeting - Pregnancy and Thyroid - Alexander...

Thyroid Disease & Pregnancy -2018 Updates and Ongoing Questions

Erik K. Alexander, MDChief, Thyroid Section, Division of Endocrinology

Brigham & Women’s Hospital Professor of Medicine, Harvard Medical School

DISCLOSURES

No Relevant Disclosures.

Outline:

I. The last 5-10 years – tremendous data, new ATA guidelines; many uncertainties

II. Active cases and discussion:i. Hypothyroidismii. TPO Ab statusiii. Hyperthyroidism

III. Screening for thyroid disease during pregnancy?

A lot of new Data…

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ATA 2017 Guidelines:

Greg Brent – UCLA, VA Healthcare SystemChristy Dosiou – Stanford Medical CenterSusan Mandel – U Penn Medical CenterPeter Laurberg – Arhaus Medical Center, DenmarkRobin Peeters – Erasmus Medical Center, NetherlandsJohn Lazarus – Cardiff University, EnglandRosalind Brown – Childrens Hospital, BostonHerb Chan – Univ Wisconsin Medical CenterBill Grobman – Northwestern Univ Medical CenterScott Sullivan – S. Carolina Medical Center

Erik K. Alexander, MD Elizabeth Pearce, MD

Expertise & Active Research

International Representation

Pediatric & Surgical Input

Obstetrical Expertise

(co-chair) (co-chair)

Members:

Similar to the 2011 Guidelines:

I. HypothyroidismII. HyperthyroidismIII. Iodine Metabolism & SupplementationIV. Thyroid Nodules & Thyroid CancerV. Thyroid Function TestsVI. Thyroid Autoimmunity (TPO Ab)VII. Screening for DiseaseVIII.Post Partum Disease

Chapters on:

New to the 2017 Guidelines:

I. Lactation & Thyroid DiseaseII. Infertility & Assisted ReproductionIII. Prenatal, Neonatal, & Postnatal

Considerations

Based upon feedback, surveys & expert input:

Chapters on:

Broader Discussion:

IV. Surgical Considerations

Complex Clinical Discussions:

Complex Area of Discussion:

I. How to define Hypothyroidism, & When to Recommend Treatment?

2017 Thyroid & Pregnancy Guidelines:

32yo healthy Caucasian female presents for care and is found to be newly pregnant (estimated 14 weeks gestation). She takes no medications. She notes mild fatigue. On exam a goiter is questioned, prompting measurement of serum TSH. The value returns at 22.6 mIU/L (normal 0.5 – 5.0mIU/L).

Case #1a - Hypothyroidism

Would you recommend treatment?

29yo healthy African American female presents for care and is found to be newly pregnant (estimated 12 weeks gestation). She takes no medications. She notes mild fatigue. On exam a goiter is questioned, prompting measurement of serum TSH. The value returns at 7.6 mIU/L(normal 0.5 – 5.0mIU/L).

Case #1b


29yo healthy Turkish female presents for care and is found to be newly pregnant (estimated 9 weeks gestation). She takes no medications. She notes mild fatigue. On exam a goiter is questioned, prompting measurement of serum TSH. The value returns at 3.5 mIU/L (normal 0.5 – 5.0mIU/L).

Case #1c


Spectrum of Maternal Thyroid Status

Euthyroid

Mild (subclinical) Hyperthyroidism

Mild (subclinical) Hypothyroidism

Moderate Hyperthyroidism

Moderate Hypothyroidism

Thyroid Storm (severe)

MyxedemaComa (severe)

Spectrum of Maternal Thyroid Status

Euthyroid

Mild (subclinical) Hyperthyroidism

Mild (subclinical) Hypothyroidism

Moderate Hyperthyroidism

Moderate Hypothyroidism

Thyroid Storm (severe)

MyxedemaComa (severe)

Risk to Fetus & Pregnancy:

SAFE

UNSAFE

Uncertainties:

Euthyroid

I. Where do we draw these lines?II. How do we define each

category?III. How do we balance the risks

and benefits of any i t ti ?

Courtesy: P. Reed Larsen

~13yo Untreated CretinDangers of overt maternal hypothyroidism:

• 4 Family Members from Congo (Zaire).

Courtesy: F. Delange

• All age 15-20 yo

• 1 euthyroid male and 3 females with severe longstanding hypothyroidism.

But most patients:

• Young, generally healthy• Iodine sufficient (at least

moderately)• Hashimoto’s Disease• Have easy access to

healthcare• Importantly: TSH elevation

will be (very) mild

Background:Available data creates a paradox?

Data: I. Treatment of overt maternal hypothyroidism (TSH

>10mIU/L or TSH freeT4) widely accepted. Note – no randomized interventional trial data

II. Increasingly, subclinical hypothyroidism (TSH <10mIU/L) treated on basis of pregnancy/miscarriage risk.

III. How is an ‘elevated’ TSH defined? One prospective trial (Negro, et al) may demonstrate benefit when >3.0mIU/L

IV. Other healthy populations / ethnicities appear to have different TSH ranges (0.5-5.0mIU/L) in pregnancy

Is TSH >3.0mIU/L really the cutoff ?

Li, et al : (prospective screening)• >7,000 women: 4800 pregnant + 2000 women seeking future pregnancy• Excluded women if: 1) fam hx of thyroid dz, 2) TPO Ab+, 3) goiter.• Reference range defined as >2SD from mean (95% of cohort).

Chinese population reference range: TSH: 0.14 4.87

(Pregnancy week 4-12)

mean:+2SD:-2SD:

If >2.5mIU/L used:If >4.9mIU/L used:

28% hypothyroid (5 mil births/year):4% hypothyroid (<1mil births/year):

(mIU/L)

Li, et al. JCEM 2014;99:73

Ethnicity Impacts TSH ‘normalcy’:Korevaar & Medici, et al :

• ~4,000 women: Generation R Study – screened 13wks.• Excluded women if: TPO Ab+, known thyroid dz, or Assist Reproduction• Reference range defined as >2SD from mean (95% of cohort).

Dutch:

Korevaar, et al. JCEM 2013;98:3678

Moroccan:Turkish:Surinamese:

All patients: 0.06 4.51

mean:+2SD:-2SD:

TSH0.12 4.72TSH

0.01 3.99TSH0.04 4.50TSH

0.01 3.85TSH

Similar data from SpainCastillo Lara, et al : (prospective screening)

• >100 women: newly pregnant. 1st trimester• Excluded women if: 1) fam hx of thyroid dz, 2) TPO Ab+, 3) goiter.• Reference range defined as >2SD from mean (95% of cohort).

Spanish population reference range: TSH: 0.1 4.7

(Pregnancy week 4-12)

mean:+2SD:-2SD:

Similar report from Catalonia: >2SD – TSH 5.7mIU/L

(mIU/L)

Casillo Lara, et al. BMC Pregnancy Childbirth. 2017;17:438

Similar report from Andalusia: >2SD – TSH 4.2mIU/L

Difficult Translation:Where to define ‘abnormality’?

Questions: I. Does a reference range calculation mean that no ‘harm’ is

conveyed by maternal thyroid status in that range?

II. Can a physician truly know the reference range for his/her population? How should one take ethnicity into account?

Downstream Impact: Defining ‘abnormal’ cut-off’s also defines when LT4 should be started, and what the treatment targets should be.

Difficult Translation:Where to define ‘abnormality’?

2018 Standard: I. A more generous TSH threshold (up to ~4.0) seems to be

highly appropriate for defining ‘hypothyroidism’

II. Do your best to ‘know’ your populations baseline thyroid function. Know and understand your ethnicities.

ATA 2017 Guidelines

Alexander, et al. Thyroid 2017;27:315.

Complex Area of Discussion:

II. Does TPO Antibody status matter? If so, Why?


Background:Understanding the Influence of TPO Ab?

Data: I. The harm attributable to maternal hypothyroidism has long

been assumed to be caused directly by the low levels of maternal hormone itself

II. Increasingly, TPO Ab status is independently shown to amplify the harmful effects of maternal hypothyroidism

III. Even euthyroid (nl TSH) mothers who are TPO Abpositive appear to have an increased risk of miscarriage

IV. Until now, testing for TPO Ab status has not routinely been recommended.

37yo female is newly pregnant (9 weeks). She is euthyroid and not receiving LT4. However, workup of a ‘goiter’ 3years ago confirmed TPO Ab positivity. Today, she has a moderate goiter, TSH is 3.6 mIU/L, and TPO Ab 520 IU/mL (normal 0-20 IU/mL). Given her age, the patient is worried about miscarriage, and asks if TPO Ab will influence this. She asks if anything “can be done”?

Case #2a

How would you respond?

37yo female is newly pregnant (9 weeks). She is euthyroid and not receiving LT4. However, workup of a ‘goiter’ 3years ago confirmed TPO Ab positivity. Today, she has a moderate goiter, TSH is 4.4 mIU/L, and TPO Ab 18 IU/mL (normal 0-20 IU/mL). Given her age, the patient is worried about miscarriage, and asks if TPO Ab will influence this. She asks if anything “can be done”?

Case #2b


TPO Ab status Modifies the Risk of Maternal Hypothyroidism

Liu, et al : (prospective cohort study)• Screened 3,315 women ‘low-risk’ women at 4-8 weeks gestation• Assessed TSH, FreeT4, and TPO Ab status• Primary Endpoint - Miscarriage

TSH 0.3-2.5, TPO neg 2.2%Miscarriage Risk:

TPO Ab status augments the harm of elevated TSH levelsLiu, et al. Thyroid 2014;24:1642

TSH 2.5-5.2, TPO neg

TSH 5.2-10, TPO neg

TSH 2.5-5.2, TPO positive

TSH 5.2-10, TPO positive

TSH 0.3-2.5, TPO positive 5.7%

3.5%10.0%

7.1%15.2%

TPO Ab status May Modify the Risk more than Hypothyroidism

Seungdamrong, etal: (2 prospective cohort studies)• Prospective, PRE-PREGNANCY serum from 1,468 infertile women • Assessed TSH, FreeT4, and TPO Ab status• Primary Endpoint – Conception Rate, Miscarriage, Live Birth Rates

TSH >2.5 vs. <2.5mIU/L P=NSMiscarriage Risk:

Seungdamrong, et al. Fertil Steril 2017; Oct (epub)

TSH TPO negTSH TPO positive

• Similar conception rates (33.3 vs. 36.3%, p=NS)

• Higher miscarriage rates (43.9% vs. 25.3%, p<0.01)

• Lower live birth rates (17.1% vs. 25.4%, p<0.01)

Should you treat & What is the Evidence:


Does the level of TPO Ab matter?Korevaar et al:

• data from 3 prospective birth cohorts (association study)• n=11,212 pregnant women in total; Blood drawn before 20weeks• Primary Endpoint – Pre-Mature Delivery

Dose-dependent positive association of TSHwith Premature Delivery

Perhaps the TPO Ab titer matters as well, even into the normal range

Korevaar TIM, et al. JCEM 2017 (Dec); Epub

Dose-dependent positive association of TPO Ab with Premature DeliveryImpact of TPO Ab was linear, and extended below the ‘normal range cut-off’.

37yo female is seeking pregnancy. She is euthyroid and not receiving LT4. However, workup of a ‘goiter’ 3years ago confirmed TPO Ab positivity. Today, she has a moderate goiter, TSH is 1.9 mIU/L, and TPO Ab 758 IU/mL (normal 0-20 IU/mL). Given her age, the patient is worried about infertility, and asks if TPO Ab will influence this. She asks if anything “can be done”?

Case #2b


Treating Euthyroid, TPO Ab+ Women Reduces Miscarriage Rate?

Negro, JCEM 2006; * p<0.05

57 Treated L-T4 (~50ug/d)

984 Pregnant Women:115 TPO Ab positive

58 Not Treated

869 TPO Ab negative(Controls)

1. Miscarriage Rates:

2. Premature Delivery:

Endpoints:

3.5%

7.0% 22.4%* 8.2%

13.8%* 2.4%

Treating Euthyroid, TPO Ab+ Women Reduces Miscarriage Rate?

LaPoutre, et al. Gynecol Obstet Invest 2012;74:265

Supporting Evidence: LaPoutre – Retrospective Cohort Analysis

• 537 Consecutive women with singleton pregnancy – all with TSH <3.5mIU/L• In TPO Ab Positive Cohort, half treated when TSH >1mIU/L Initiated 50mcg daily. Other half not treated.• Miscarriage – Reduced from 16% to 0% with LT4 treatment

LT4 Treatment in TPO+ women:


Newly Pregnant

Before Pregnancy –normal conception

Before Pregnancy –IVF/ART

LT4 treatment of euthyroid, TPO Ab+ women does not improve ART outcome

Wang H, et al: (prospective, randomized trial)• Prospective, randomized trial of 600 women in China• ALL have normal thyroid function, but +TPO Ab• Primary Endpoint – Miscarriage & Pregnancy Rate

10.3%

Miscarriage Rate:

Wang H, et al. JAMA 2017;318:2190

Received Levothyroxine:

No Levothyroxine: 10.6%

35.7%

Successful Pregnancy

37.7%NS NS

Administration of LT4 to euthyroid, TPO Ab+ women did NOT improve results of IVF/ART

In TPO Ab+ women, should you measure anything else?

Maternal serum hCG?

Korevaar TIM, JCEM 2017;102:3360

Increased (graded effect)

Premature Delivery, orPreterm PROM

High TSH, low hCG:P<0.01

High TSH, high hCG:

Decreased (graded effect)

Intriguing initial data. Not separately validated.

Active Area of Discussion:

III. Is low-normal freeT4 harmful (in the setting of a normal TSH) ?


29yo healthy female presents for care and is found to be newly pregnant (estimated 9 weeks gestation). She takes no medications. She notes mild fatigue. On exam a goiter is questioned, prompting testing.

TSH – 2.1mIU/L (nl:0.5 – 5.0mIU/L). FreeT4 – 0.9ng/dL (nl:0.9-1.7ng/dL)

Case #3

What would you recommend?

Background:The Uncertain meaning of nl TSH, low fT4?

Data:I. TSH is a surrogate measurement for total hormone levels.

Its may be more logical to measure T4 or T3II. Increasingly low (or low-normal) maternal free T4 is

associated with adverse fetal/pregnancy outcomes

III. There are NO interventional trials.Treating low T4 would suppress TSH which has been associated with risk.

IV. Measurement of FreeT4 hormone concentrations are fraught with analytic error & variability

The Generation R data:Generation R study:

• Population-based birth cohort in Rotterdam, the Netherlands• Followup of Children from fetal life onward• 7069 pregnant women enrolled early pregnancy; 5100 evaluable TFT’s

Ghassabian, et al

If Pregnant Mother has freeT4 lowest 5th % (normal TSH)

Uncertainties – for several parameters, no linear effect was identified (only a ‘threshold’). All data from single cohort - reanalyzed.

Ghassabian, et al. JCEM 2014;99:2383; Korevaar, JCEM 2013;98:4382; Roman, et al, Ann Neurol 2013;74:733

Child’s IQ (age 6) – decreased 4.3pts Korevaar, et al ~3x increased risk premature deliveryRoman, et al 4x increased risk autistic symptoms

Does low FreeT4 during 1st versus 3rd trimester matter?:

Zhang et al:• Large cohort association study; no intervention • 6,031 women in China; TSH, FreeT4 1st & 3rd timesters• Primary Endpoint: Pregnancy outcomes

Findings:

Uncertainties – Data not reproduced. Difficulty with multifaceted / composite endpoint; No intervention

Zhang Y, et al. PLOS One 2017;12(5). PMID 28542464

Low FreeT4 1st Trimester Increase risk GDMLow FreeT4 3rd Trimester Increased Preeclampsia

Is there any harm from raising FT4?:

Johns et al• Large cohort analysis of maternal tft’s & fetal growth• 439 pregnant women in Boston• Measurement of fetal growth (ultrasound) & birth weight

Findings:

Association studies raise many questions. Raising maternal FreeT4 may not be without risk to the fetus

Johns et al. JCEM 2018;103:1349

Higher maternal freeT4 lower Birth WeightHigher maternal freeT4 lower head & abd circumference, No associations with maternal TSH

What is your ethnicity?

When during pregnancy are you treating?

What level of freeT4 matters?

What level of TSH matters?

Is TPO Ab positivity important?

When during pregnancy are you testing?

Howto(canwe?)integrateallthesevariable?


IV. How to Treat Maternal Graves’ Disease, Especially early in Gestation?


24yo female presents for care and is seeking pregnancy. She has Graves’ disease, currently treated with 5mg daily MMI. She feels well.


Case #3a

What would you recommend now?What would you recommend once pregnant?

24yo female presents for care newly pregnant (5 wks). She has Graves’ disease, currently treated with 7.5mg daily MMI. She feels well.


Case #3b

What would you recommend now?

Background:Treating severe maternal Hyperthyroidism

Data: I. The data confirming ‘when’ to initiate treatment, and

‘what’ level to target on treatment, are imperfect.

II. New data suggest both MMI and PTU are teratogenic, though profiles differ.

III. Question – is there any danger from maternal hyperthyroidism itself ? Can MMI/PTU be stopped?

III. Most important – the greatest danger is overtreatment

Danish Registry Study:Andersen et al:

• Population-based cohort in Denmark (n=817,093) 1996-2008• Prescription medication and birth defects assessed by national registry• >2000 women exposed to ATD during pregnancy

PTUI. Medication During Pregnancy:

Andersen, et al. JCEM 2014;98:4373

8.0%Methimazole 9.1%PTU & Methimazole 10.1%

Serious Birth Defects:

II. ONLY Pre-Pregnancy ATD Use:

III. No history ATD Use at any time: 5.7%5.4%

P=ns

P<0.01

Preconception counselling:



V. Should we universally assess the thyroid function in newly pregnant women?


Recent Data:

• Taylor et al, JCEM 2014

• Zhang, PLOS One 2017

• Mannisto, JCEM 2013

• Anderson, JCEM 2017

• Pakkila F, JCEM 2014

• Liu H et al. Thyroid 2014

• Chen LM, PLoS One, 2014

Increased Miscarriage Risk when TSH>2.5, and climbing impressively if >4.5mIU/L

Metaanalysis 1980-2015. 9 high qual studies. If non-treated SCH, higher rate miscarriage

>223,000 deliveries. Maternal hypoT4 increased obstetrical complications

1153 Children born to mothers. HypoT4 in early pregnancy a/w lower IQ @ 5yrs

Finnish Cohort (>9300 pregnancies) – increase TSH increased girls’ ADHD risk

Prospective, >3315 pregnancies. Subclinical hypoT4 increase miscarriage risk in China

>8000 pregnancies in China. Subclinical hypoT4 increases HTN, PROM, IUGR, LBW

All Associate Maternal TSH with harm:

97,226 pregnancies screened <20 wks

526 randomized to LT4 vs. placebo

B Casey et al. NEJM. 2017;276:815

Hypothyroxinemia(TSH 0.08-3.99, fT4 <0.86)

Subclinical Hypothyroidism(TSH ≥4.0, nl fT4)

677 randomized to LT4 vs. placebo

Mean 17 wks at randomization; IQ testing (WPPSI) in children at age 5

Prospective, Randomized Intervention – 17wksTreatment of Maternal Hypothyroidism Does Not Improve Fetal Cognition

Prospective, Randomized Intervention – 12wks Treatment of Maternal Hypothyroidism Does

Not Improve Fetal Cognition

Lazarus et al :(prospective, randomized)• 22,000 women: ½ Screened (TSH, fT4) at 12 wks; ½ Not Screened• Intervention Arm – TSH >2.5 triggered 150mcg LT4 daily.• IQ testing of offspring at 3 & 9 years.

Lazarus et al. NEJM. 2012

Primary Endpoint: IQHigh TSH Detected &

Treated at ~12wks:Control Group:

99 100vs.

Prospective, Randomized Intervention – 12wks Treatment of Maternal Hypothyroidism Does

Not Improve Fetal Cognition

Lazarus et al :(prospective, randomized)• 22,000 women: ½ Screened (TSH, fT4) at 12 wks; ½ Not Screened• Intervention Arm – TSH >2.5 triggered 150mcg LT4 daily.• IQ testing of offspring at 3 & 9 years.

Lazarus et al. JCEM 2018 (epub)

Follow up IQ testing at 9.5yoMothers Treated for Thyroid Dysfunction (TSH 1.1)

No Difference

Mothers Not Treated for Dysfunction (TSH 4.1)

Mothers with NO Dysfunction (TSH 3.6)

Prospective, Randomized Intervention – 9 wksTreatment of Maternal Hypothyroidism May(?not)

Reduce Pregnancy Complications:

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Universal Screening Case Finding

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Negro et al:(prospective, randomized)• 4,562 prospective Intervention at 9wks when TSH>3mIU/L. Composite Endpt.• Only low-risk TPO+ population studied w/ randomized intervention – Rx: LT4 or not• “Conclusion” misleading: “No benefit to Universal Screening”.

Negro et al. JCEM 95:1699-1707, 2010

“High-risk”

“Low-risk”

P< NS

Prospective, Randomized Intervention – 9 wksTreatment of Maternal Hypothyroidism May(?Not)

Reduce Pregnancy Complications:

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Universal Screening Case Finding

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Negro et al:(prospective, randomized)• 4,562 prospective Intervention at 9wks when TSH>3mIU/L. Composite Endpt.• Only low-risk TPO+ population studied w/ randomized intervention – Rx: LT4 or not• “Conclusion” misleading: “No benefit to Universal Screening”.

Negro et al. JCEM 95:1699-1707, 2010

“High-risk”

“Low-risk”

P<0.05

Uncertainties regarding Screening• Can we intervene early enough in

pregnancy to make a difference ?• What endpoint are we seeking to improve?

– If miscarriage, benefit in screening >12-14 weeks substantially lessens.

• What TSH (or FreeT4) would trigger an intervention?

ETA guidelines majority support universal screeningSpanish Society of Endocrinology and Nutrition universal screeningIndian Thyroid Society universal screeningIndian National Guidelines selective testing of high-risk womenChina universal screening

Summary:

Alexander, NEJM 2004; Kaplan, Thyroid 1992; Mandel, NEJM 1990

• Evaluating & treating thyroid illness during pregnancy is complex.

• Awaiting future data, maternal hypothyroidism (mild or severe) is generally considered dangerous during pregnancy, and avoided when possible. But…what is the upper-limit of TSH? Importance of TPO Ab positivity. Check hCG?

• Data now clearly associate teratogenic effects with both MMI and PTU. Increasingly, no treatment early in gestation is the most favorable option - unless severely ill?

• New factors, new molecules, & new investigations will continue to move the field forward – 2018 & beyond!

Thank you!

PreMeeting - Pregnancy and Thyroid - Alexander...

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