Transcript De Groot et al. JCEM 2012, 2543–2565

Outline
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Transient thyrotoxicosis of pregnancy
Graves disease during pregnancy
Hypothyroidism and pregnancy
Iodine nutrition and pregnancy
Thyroid disease and pregnancy
Changes in thyroid physiology in
pregnancy
Transient thyrotoxicosis of
pregnancy (TTP)
TTP: Prevalence
• Close to 20% of pregnant women have a
suppressed TSH and normal free T4
• In about 2.4% pregnant women had low
TSH ( less than 0.20 mU/liter) and high
free T4 index concentration.
TTP:Racial differences
• In some studies (Yeo et al., 2001) the
frequency of transient gestational hyper
thyroid-ism reached 11% for Asian women
• Gestational thyrotoxicosis is at least 10-fold
more frequent than hyperthyroidism due to
graves disease
TTP: natural history
Mirror curve of TSH and HCG
concentrations
Glinoer et al., 1990,The Endocrine Society
TTP:
Role of HCG
• In normal pregnancy, when hCG levels are
highest at 10–12 wk gestation, there is
suppression of serum TSH levels,
presumably due to slight increases in free
thyroxine concentration driven by high hCG
values
• These abnormalities are exaggerated in twin
pregnancies and hyperemesis gravidarum
Role of HCG quality
• Elevations of thyroid hormone and
suppression of TSH are not entirely
correlated with hCG levels
• An increase in acidic forms of hCG have
demonstrated in hyperemesis gravidarum .
unusual glycosylation patterns of hCG are
common in hydatidiform moles which
frequently present as hyperemesis
gravidarum
• A mutant TSH receptor
TTG: TSH receptor mutation
Rodien et al. Human Reproduction Update,2004, 95-105
Hyperemesis gravidarum and
hyperthyroidism
Definition of HG
• Hyperemesis gravidarum, defined as severe
vomiting in early pregnancy that causes
more than 5% weight loss, dehydration, and
ketonuria and occurs in 0.5–10 cases per
1000 pregnancies
• Gestational transient thyrotoxicosis has
been observed in up to two thirds of women
suffering from hyperemesis gravidarum
Distinction between gestational
transient thyrotoxicosis and
Graves' disease
Distinction between gestational transient
thyrotoxicosis and Graves' disease
1.charachteristics of hyperemesis
gravidarum are present in former .
2.Goitre is usually but not necessarily
absent in the former
3.No past history of thyroid disease is
reported by the patient or her family.
4.Ophthalmic examination reveals no
abnormality, in contrast to half of patients
with graves disease. Graves' disease.
Distinction between gestational transient
thyrotoxicosis and
Graves' disease:TFT
• Antithyroid antibodies are usually absent in
gestational transient thyrotoxicosis. In
particular, TSHR antibodies are absent
• Serum free T3 is elevated less frequently in
GTT compared with graves disease
Treatment
• Clinical symptoms usually are mild
• Close observation of the course of the
clinical presentation and thyroid hormone
abnormalities is indicated.
• Beta blockers such as metoprolol may be
helpful and may be used with obstetrical
agreement
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Key massges
• Transient thyrotoxicosis of pregnancy should
differentiated from hyperthyroidism solely based
on clinical judgment
• Subjects with TTP should be observed carefully
and treated with appropriate beta blockers if have
sever symptoms of thyrotoxicosis
Graves disease during pregnancy
Prevalence
• Prevalence of hyperthyroidism in pregnancy
0.1 to 0.4%
• About 85% of cases are Graves’disease
De Groot et al. JCEM,2012: 2543–2565
Clinical course of Graves in
pregnancy
First trimester
 Second and third trimester
Puerperium
Clinical manifestations
• Symptoma are non specific and may be
mimicked by normal pregnancy.
• Significance of goiter
• TFT must be interpreted in the context of
the normal gestational changes of decreased
serum TSH and increased T4and T3 levels
De Groot et al. JCEM,2012: 2543–2565
Maternal complications of
hyperthyroidism in pregnancy
Manissto etal.JCEM, 2013,
2725-2733
Fetal complications
• Low birth weight
• Fetal hypothyroidism
(overtreatment of mother)
• Fetal central congenital hypothyroidism
(undertreatment of maternal hyperthyroidism)
• Fetal thyrotoxicosis placental passage of TSI
• Fetal death
De Groot et al. JCEM,2012: 2543–2565
Neonatal Graves
Treatment:
Goal
• Goal of therapy : maintaining free T4 or FTI
upper limit of the non pregnant reference range.
evidence level :B (1QQEE)
De Groot et al. JCEM 2012, 2543–2565,
Treatment:
Choosing ATD
• PTU is recommended as the first-line drug
for treatment of hyperthyroidism during the
first trimester of pregnancy
• Monitoring liver function is recommended
every 3–4 wk and encourage patients to
promptly report any new symptoms of
hepatitis
level: C; evidence, poor (2QEEE)
De Groot et al. JCEM 2012, 2543–2565,
Treatment:
Choosing ATD
• AACE recommend clinicians change
treatment of patients from PTU to MMI
after the completion of the first trimester.
• After switching from PTU to MMI, thyroid
function should be assessed after 2 wk
and then at 2- to 4-wk intervals
( level: B; evidence, fair (1QQEE)
De Groot et al. JCEM 2012, 2543–2565,
Aplasia cutis
Thyroidectomy
Indications :
• patients with severe adverse reaction to
ATD therapy
• persistently high doses of ATD are required
over 30mg/d of MMI or 450 mg/d of PTU
• Non adherence to ATD.
Optimal timing of surgery: second
trimaster
level: C; evidence, fair (2QEEE)
De Groot et al. JCEM 2012, 2543–2565,
Subclinical hyperthyroidism
• No evidence of benefit of treatment of
subclinical hyperthyroidism during
pregnancy
• Treatment could potentially adversely affect
fetal outcome
level: C; evidence, fair (2QEEE)
De Groot et al. JCEM 2012, 2543–2565,
Key massages
• Goal of treatment in maternal hyperthyroidism is
achieving free T4 or FTI in upper limit normal
• TFT should be carry out at least monthly and
stepwise decreasing antithyroid drugs during
pregnancy is recommended to achieve above goal
• PTU is recommended in firs trimester
• Methimazole is recommended in second and third
trimester
Hypothyroidism in pregnancy
Epidemiology
• The prevalence of overt hypothyroidism in
pregnancy is estimated at 0.3 – 0.5 respectively .
• Endemic iodine deficiency and chronic
autoimmune thyroiditis in iodine repleted areas
are the most common cause of hypothyroidism in
pregnant women worldwide.
Mandel et al. Clin Endocrinol Metab 2004 ; 18 : 213 -24
Epidemiology
• Thyroid autoantibodies are found in 5–15%
of women during childbearing age.
• Subclinical hypothyroidism occurs in 2–3%
of pregnant women .
DeVivo et al. Thyroid 2010 20:633–637
Clinical manifestations
• A high index of suspicion is therefore required,
especially in women with a predisposition to
thyroid disease such as a personal or family
history of thyroid disease, the presence of goiter
or the coexistence of other autoimmune
disorders like type 1 diabetes.
Expert Opin. Pharmacother. (2008) 9(13):2281-2293
Complications
Maternal complications
Manissto etal.JCEM, 2013, 2725-2733
Fetal complications
JE Haddow et al., N Engl J
Med.1999;341:529-555
Maternal thyroid failure and
average child IQ scores1
Control
Untreated
(p = 0.005)
94
96
98
100 102
104 106 108
• The IQ scores of children
whose mothers had
untreated hypothyroidism
during pregnancy were
significantly lower than those
of the control children.
• IQ scores for children whose
mothers were being treated
for hypothyroidism during
pregnancy were similar to
those of the control children.
IQ Score
Control, n = 124
Untreated hypothyroidism, n = 48
1. Adapted from: JE Haddow et al., N Engl J Med.
1999;341:529-555
Other fetal complications
Untreated maternal overt hypothyroidism is
associated with low birth and more fetal and
perinatal death
Haddow et al. N Engl J Med 1999, :549–555
Subclinical hypothyroidism
during pregnancy
• Definition : Serum TSH concentration
above the upper limit of the trimesterspecific reference range with a normal free
T4 or FTI
• In the first trimester, the “normal” range is
reduced to 0.1–2.5 mIU/liter .
De Groot et al. JCEM 2012, 2543–2565,
Subclinical hypothyroidism
during pregnancy
• Women with gestational SCH have more
preterm deliveries
• Effect on long term neurological
development in the offspring are
controversial.
Casey et al.Obstet Gynecol 2005, 105:239–245
Anti TPO positive euthyroid
women
European Journal of Endocrinology (20
Treatment
If hypothyroidism has been diagnosed before
pregnancy, it is recommended adjustment of
the preconception T4 dose to reach before
pregnancy a TSH level < 2.5mIU/liter.
Level of evidence, poor (2,QEEE)
De Groot et al. JCEM 2012, 2543–2565,
Treatment :
Goal
• TSH level <2.5 mIU/liter in the first
trimester
• TSH level <3 mIU/liter in second and third
trimesters .
• Thyroid function tests should be remeasured
within 30–40 d and then every 4–6 wk.
recommendation level: A; evidence, good(1
QQQQ)
De Groot et al. JCEM 2012, 2543–2565,
Increased L-T4 Requirements in Pregnancy
• L-T4 requirements may increase 25-40%, usually
in the first half of pregnancy
• 25% of those with initial normal TSH in 1st
trimester and 37% of those with initial normal
serum TSH in 2nd trimester will later require
dosage increases .
Hypothyroidism in Pregnancy
Larsen et al 2003
Increased Requirement?
• Elevated TBG levels
• Increased inner ring degradation of T4 and
T3 by the placenta
• Increased transplacental transport of T4
• Increased volume of T4 distribution
Increments of levothyroxine in
first trimester
The average increments of levothyroxine are:
• 25–50 mcg/d for serum TSH 5-10 mIU/liter
• 50–75 mcg/d for serum TSH 10-20mIU/liter
• 75–100 mcg/d for serum TSH >20 mIU/liter
De Groot et al. JCEM 2012, 2543–2565,
Treatment :
after delivery
After delivery, most hypothyroid women need
to decrease the T4 dosage they received
during pregnancy to the prepregnancy dose.
Recommendation level:A; evidence, good
(1QQQQ)
De Groot et al. JCEM 2012, 2543–2565,
Iodine nutrition during pregnancy
Iodine nutrition and pregnancy
• Women in the childbearing age should have
an average iodine intake of 150 mcg/d.
• During pregnancy and breastfeeding,
women should increase their daily iodine
intake to 250mcg/d on average.
USPSTF recommendation level: A;
evidence, good (1QQQE).
De Groot et al. JCEM 2012, 2543–2565,
Iodine nutrition and pregnancy
• Iodine intake during pregnancy and
breastfeeding should not exceed twice the
daily recommended nutrient in-take (RNI)
for iodine,ie: 500 mcg iodine per day.
•
USPSTF recommendation level: I; evidence, poor
(2QEEE)
De Groot et al. JCEM 2012, 2543–2565,
Iodine nutrition and pregnancy
• Taking once-daily prenatal vitamins contain
150–200 mcg iodine and that this be in the
form of potassium iodide or iodate
• Ideally, supplementation should be started
before conception.
• Preparations containing iron supplements
should be separated from thyroid hormone
administration by at least 4h.
USPSTFrecommendation lev-el: B; evidence, fair (2QQQ)
De Groot et al. JCEM 2012, 2543–2565,
Iodine nutrition and pregnancy
• Breastfeeding women should maintain a
daily intake of 250mcg/d of iodine to ensure
that breast milk provides 100mcg iodine per
day to the infant.
• USPSTF recommendation level: A; evidence,
good (1QQQE)
De Groot et al. JCEM 2012, 2543–2565,
Key massges
• Maternal hypothyroidism is a risk factor for
obstetric outcome and fetal neurodevelopment
• Increasing levothyroxine throghout pregnancy
should be done to ensure TSH<2.5 in first
trimester and TSH<3 in second and third trimester
• Pregnant and breastfeed women should receive
multivitamins containing 150-200 mcg/d iodine
N Engl J Med 2004;351:241-9.
• Aim : To identify precisely the timing and amount of
levothyroxine adjustment required during pregnancy.
• Methods: Women with hypothyroidism who were
planning pregnancy were observed prospectively before
and throughout their pregnancies. Thyroid function,
human chorionic gonadotropin, and estradiol were
measured before conception, approximately every two
weeks during the first trimester, and monthly thereafter.
The dose of levothyroxine was increased to maintain the
thyrotropin concentration at preconception values
throughout pregnancy.
2007;335;300-302 BM
2007;335;300-302 BMJ
Agenda
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Epidemiological and clinical aspects
Changes in thyroid physiology in pregnancy
Effects on obstetric and fetal outcomes
Effects on fetal neurodevelopment
Therapeutic aspects
Screening
Abalovich et al. • Guideline: Thyroid Dysfunction during
J Clin
Metab, August 2007, 92(8)
and
afterEndocrinol
Pregnancy
Summary
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The prevalence of overt and subclinical hypothyroidism in pregnancy is
estimated at 0.3 – 0.5 and 2 – 3% respectively
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The main cause of hypothyroidism in iodine-replete populations is chronic
autoimmune thyroiditis
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Observational data suggest that SCH may be associated with poor obstetrical
outcomes.
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The clinical data certainly suggest that pediatric neurodevelopment is affected
by maternal thyroid status, but there has not been a clinical trial that
specifically addresses isolated subclinical hypothyroidism and
neurodevelopmental outcomes
Summary…
• Hypothyroxinemia ( low T4 and normal TSH ) in early gestation may
be an independent determinant of neurodevelopment
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with Only one RCT has shown that LT4 can reduce poor obstetrical
outcomes in euthyroid Ab positive subjects
• The current literature does not support routine screening and treatment
,thus targeted case finding seems to be reasonable.
• A United States multicenter, randomized trial is currently underway to
answer the question of whether screening and treatment of
hypothyroxinemia or subclinical hypothyroidism have a long-term
effect on pediatric neurodevelopment (clinicaltrials.gov identifier:
NCT00388297).
Summary….
• The thyroxine dose often needs to be incremented by 4–6 wk
gestation and may require a 30–50% increment in dosage.
• Levothyroxine requirements may increase as early as the fifth
week of gestation.
• Greater increases in thyroxine are generally required for women
without residual functioning thyroid tissue such as following
radioiodine ablation or thyroidectomy
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TSH < 2.5 mU/l in the first trimester and < 3 mU/l in later
pregnancy should be aims of treatment.
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