Thyroid Disease & Pregnancy - 2018 Updates and Ongoing Questions - Erik K. Alexander, MD
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Thyroid Disease & Pregnancy -
2018 Updates and Ongoing Questions
Erik K. Alexander, MD
Chief, 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. Hypothyroidism
ii. TPO Ab status
iii. Hyperthyroidism
III. Screening for thyroid disease during
pregnancy?
A lot of new Data…
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# Publications
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2000 2008 2016
ATA 2017 Guidelines:
Erik K. Alexander, MD Elizabeth Pearce, MD
(co-chair) (co-chair)
Members:
Greg Brent – UCLA, VA Healthcare System
Christy Dosiou – Stanford Medical Center
Expertise & Active Research
Susan Mandel – U Penn Medical Center
Peter Laurberg – Arhaus Medical Center, Denmark
Robin Peeters – Erasmus Medical Center, Netherlands International Representation
John Lazarus – Cardiff University, England
Rosalind Brown – Childrens Hospital, Boston
Pediatric & Surgical Input
Herb Chan – Univ Wisconsin Medical Center
Bill Grobman – Northwestern Univ Medical Center
Scott Sullivan – S. Carolina Medical Center
Obstetrical Expertise
Similar to the 2011 Guidelines:
Chapters on:
I. Hypothyroidism
II. Hyperthyroidism
III. Iodine Metabolism & Supplementation
IV. Thyroid Nodules & Thyroid Cancer
V. Thyroid Function Tests
VI. Thyroid Autoimmunity (TPO Ab)
VII. Screening for Disease
VIII.Post Partum Disease
New to the 2017 Guidelines:
Based upon feedback, surveys & expert input:
Chapters on:
I. Lactation & Thyroid Disease
II. Infertility & Assisted Reproduction
III. Prenatal, Neonatal, & Postnatal
Considerations
Broader Discussion:
IV. Surgical Considerations
Complex Clinical Discussions:
2017 Thyroid & Pregnancy Guidelines:
Complex Area of Discussion:
I. How to define Hypothyroidism,
& When to Recommend Treatment?
Case #1a - Hypothyroidism
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).
Would you recommend treatment?Case #1b
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).
Would you recommend treatment?Case #1c
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).
Would you recommend treatment?Spectrum of Maternal Thyroid Status
Mild (subclinical) Mild (subclinical)
Hypothyroidism Hyperthyroidism
Moderate Moderate
Hypothyroidism Hyperthyroidism
Myxedema Thyroid Storm
Coma (severe) (severe)
EuthyroidSpectrum of Maternal Thyroid Status
Mild (subclinical) Mild (subclinical)
Hypothyroidism Hyperthyroidism
Moderate Moderate
Hypothyroidism Hyperthyroidism
Myxedema Thyroid Storm
Coma (severe) (severe)
Euthyroid
UNSAF SAF
E RiskEto Fetus &
Pregnancy: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 ?Dangers of overt maternal hypothyroidism:
~13yo Untreated Cretin
Courtesy: P. Reed Larsen• 4 Family Members
from Congo (Zaire).
• All age 15-20 yo
• 1 euthyroid male and
3 females with severe
longstanding
hypothyroidism.
Courtesy: F. DelangeBut 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 3.0mIU/L
IV. Other healthy populations / ethnicities appear to have
different TSH ranges (0.5-5.0mIU/L) in pregnancyIs 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).
mean:
-2SD: +2SD:
Chinese population
reference range: TSH:
(mIU/L)
0.14 4.87
(Pregnancy week 4-12)
If >2.5mIU/L used: 28% hypothyroid (5 mil births/year):
If >4.9mIU/L used: 4% hypothyroid (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).
mean:
-2SD: +2SD:
All patients: TSH 0.06 4.51
Dutch: TSH 0.12 4.72
Moroccan: TSH 0.01 3.99
Turkish: TSH 0.04 4.50
Surinamese: TSH 0.01 3.85
Korevaar, et al. JCEM 2013;98:3678Similar data from Spain
Castillo 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).
mean:
-2SD: +2SD:
Spanish population
reference range: TSH:
(mIU/L)
0.1 4.7
(Pregnancy week 4-12)
Similar report from Catalonia: >2SD – TSH 5.7mIU/L
Similar report from Andalusia: >2SD – TSH 4.2mIU/L
Casillo Lara, et al. BMC Pregnancy Childbirth. 2017;17:438Difficult 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;27:315.2017 Thyroid & Pregnancy Guidelines:
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 Ab
positive appear to have an increased risk of miscarriage
IV. Until now, testing for TPO Ab status has not routinely
been recommended.Case #2a
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”?
How would you respond?Case #2b
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”?
How would you respond?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
Miscarriage Risk:
TSH 0.3-2.5, TPO neg 2.2%
TSH 0.3-2.5, TPO positive 5.7%
TSH 2.5-5.2, TPO neg 3.5%
TSH 2.5-5.2, TPO positive 10.0%
TSH 5.2-10, TPO neg 7.1%
TSH 5.2-10, TPO positive 15.2%
TPO Ab status augments the harm of elevated TSH levels
Liu, et al. Thyroid 2014;24:1642TPO 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
Miscarriage Risk:
TSH >2.5 vs.Should you treat &
What is the Evidence:
Alexander, et al. Thyroid 2017;27:315.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 TSH
with Premature Delivery
Dose-dependent positive association of TPO Ab
with Premature Delivery
Impact of TPO Ab was linear, and extended
below the ‘normal range cut-off’.
Perhaps the TPO Ab titer matters as well,
even into the normal range
Korevaar TIM, et al. JCEM 2017 (Dec); EpubCase #2b
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”?
How would you respond?Treating Euthyroid, TPO Ab+ Women
Reduces Miscarriage Rate?
984 Pregnant Women:
115 TPO Ab positive
57 Treated 58 Not 869 TPO Ab negative
L-T4 (~50ug/d) Treated (Controls)
Endpoints:
1. Miscarriage 3.5% 13.8%* 2.4%
Rates:
2. Premature
Delivery:
7.0% 22.4%* 8.2%
Negro, JCEM 2006; * pTreating Euthyroid, TPO Ab+ Women
Reduces Miscarriage Rate?
Supporting Evidence:
LaPoutre – Retrospective Cohort Analysis
• 537 Consecutive women with singleton pregnancy – all with
TSH 1mIU/L Initiated 50mcg daily. Other half not treated.
• Miscarriage – Reduced from 16% to 0% with LT4 treatment
LaPoutre, et al. Gynecol Obstet Invest 2012;74:265LT4 Treatment in TPO+ women:
Newly Pregnant
Before Pregnancy –
normal conception
Before Pregnancy –
IVF/ART
Alexander, et al. Thyroid 2017;27:315.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
Miscarriage Rate: Successful Pregnancy
Received Levothyroxine: 10.3% 35.7%
NS NS
No Levothyroxine: 10.6% 37.7%
Administration of LT4 to euthyroid, TPO Ab+ women
did NOT improve results of IVF/ART
Wang H, et al. JAMA 2017;318:2190In TPO Ab+ women, should you
measure anything else?
Maternal serum hCG?
Premature Delivery, or
Preterm PROM
High TSH, low hCG: Decreased (graded effect)
P2017 Thyroid & Pregnancy Guidelines:
Active Area of Discussion:
III. Is low-normal freeT4 harmful (in
the setting of a normal TSH) ?Case #3
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)
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 T3
II. 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 & variabilityThe 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
If Pregnant Mother has freeT4 lowest 5th % (normal TSH)
Ghassabian, et al Child’s IQ (age 6) – decreased 4.3pts
Korevaar, et al ~3x increased risk premature delivery
Roman, et al 4x increased risk autistic symptoms
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;74:733Does 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:
Low FreeT4 1st Trimester Increase risk GDM
Low FreeT4 3rd Trimester Increased Preeclampsia
Uncertainties – Data not reproduced. Difficulty with multifaceted /
composite endpoint; No intervention
Zhang Y, et al. PLOS One 2017;12(5). PMID 28542464Is 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:
Higher maternal freeT4 lower Birth Weight
Higher maternal freeT4 lower head & abd circumference,
No associations with maternal TSH
Association studies raise many questions. Raising maternal FreeT4
may not be without risk to the fetus
Johns et al. JCEM 2018;103:1349How to (can we?) integrate all
these variable?
What level of What level of
TSH matters? freeT4 matters?
Is TPO Ab positivity What is your
important? ethnicity?
When during When during
pregnancy are pregnancy are
you testing? you treating?2017 Thyroid & Pregnancy Guidelines:
Active Area of Discussion:
IV. How to Treat Maternal Graves’ Disease,
Especially early in Gestation?Case #3a
24yo female presents for care and is seeking
pregnancy. She has Graves’ disease, currently
treated with 5mg daily MMI. She feels well.
TSH – 0.2mIU/L (nl:0.5 – 5.0mIU/L).
FreeT4 – 1.5ng/dL (nl:0.9-1.7ng/dL)
What would you recommend now?
What would you recommend once pregnant?Case #3b 24yo female presents for care newly pregnant (5 wks). She has Graves’ disease, currently treated with 7.5mg daily MMI. She feels well. TSH – 0.2mIU/L (nl:0.5 – 5.0mIU/L). FreeT4 – 1.6ng/dL (nl:0.9-1.7ng/dL) 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 overtreatmentDanish 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
Serious Birth Defects:
I. Medication During Pregnancy:
PTU 8.0%
Methimazole 9.1% P=ns
PTU & Methimazole 10.1%
II. ONLY Pre-Pregnancy ATD Use: 5.4% PAlexander, et al. Thyroid 2017;27:315.
Preconception counselling:
Alexander, et al. Thyroid 2017;27:315.2017 Thyroid & Pregnancy Guidelines:
Active Area of Discussion:
V. Should we universally assess the thyroid
function in newly pregnant women?Recent Data:
All Associate Maternal TSH with harm:
• Taylor et al, JCEM 2014 Increased Miscarriage Risk when TSH>2.5,
and climbing impressively if >4.5mIU/L
• Zhang, PLOS One 2017 Metaanalysis 1980-2015. 9 high qual studies.
If non-treated SCH, higher rate miscarriage
• Mannisto, JCEM 2013 >223,000 deliveries. Maternal hypoT4
increased obstetrical complications
• Anderson, JCEM 2017 1153 Children born to mothers. HypoT4 in
early pregnancy a/w lower IQ @ 5yrs
Finnish Cohort (>9300 pregnancies) – increase
• Pakkila F, JCEM 2014
TSH increased girls’ ADHD risk
Prospective, >3315 pregnancies. Subclinical
• Liu H et al. Thyroid 2014
hypoT4 increase miscarriage risk in China
>8000 pregnancies in China. Subclinical
• Chen LM, PLoS One, 2014 hypoT4 increases HTN, PROM, IUGR,
LBWProspective, Randomized Intervention – 17wks
Treatment of Maternal Hypothyroidism Does Not Improve Fetal Cognition
97,226 pregnancies screenedProspective, 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.
Primary Endpoint: IQ
High TSH Detected & Control Group:
Treated at ~12wks:
99 vs. 100
Lazarus et al. NEJM. 2012Prospective, 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.
Follow up IQ testing at 9.5yo
Mothers Treated for Thyroid Dysfunction (TSH 1.1)
Mothers Not Treated for Dysfunction (TSH 4.1) No
Mothers with NO Dysfunction (TSH 3.6) Difference
Lazarus et al. JCEM 2018 (epub)Prospective, Randomized Intervention – 9 wks
Treatment of Maternal Hypothyroidism May(?not)
Reduce Pregnancy Complications:
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”.
1.8
1.6
1.4 P< NS
Complications /
1.2
“High-risk”
Not -Treated
1
0.8
0.6
Treated
Treated
Treated “Low-risk”
0.4
0.2
0
Universal Screening Case Finding
Negro et al. JCEM 95:1699-1707, 2010Prospective, Randomized Intervention – 9 wks
Treatment of Maternal Hypothyroidism May(?Not)
Reduce Pregnancy Complications:
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”.
1.8
1.6
1.4
PUncertainties 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 screening
Spanish Society of Endocrinology and Nutrition universal screening
Indian Thyroid Society universal screening
Indian National Guidelines selective testing of high-risk women
China universal screeningSummary:
• 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!
Alexander, NEJM 2004; Kaplan, Thyroid 1992; Mandel, NEJM 1990You can also read
