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THYROID ADAPTATION
DURING NORMAL
PREGNANCY
DR ABOTORABI
PERINATOLOGIST
• The thyroid gland is a
bilobed gland composed of
spherical follicles
• Each follicle has a colloid
center surrounded by a
single layer of follicle cells
• Intimately involved with the
follicle cells are
parafollicular C
cells,lymphatic drainage
channels, and capillary
networks.
• Iodide ions are actively transported from the blood
onto the apical surface of the follicle cells and are
oxidized to iodine through the action of thyroid
peroxidase
• The thyroid gland regulates the amount of iodide it
actively traps and can withstand fluctuations in dietary
supply.
• In the lumen, colloid iodide is incorporated into the
tyrosine residues of thyroglobulin (also made in the
follicle cells) to produce inactive mono-iodotyrosine
and di-iodotyrosine.
• This process is known as organification of iodide.
• Combinations of these products lead to the formation of
the active thyroid compounds thyroxine (T4) and triiodothyronine (T3), which are released into the capillary
network at the apical surface of follicle cells having
re-entered from the colloid at their basal
surface(endocytosis)
• Pregnancy is a state of relative iodine deficiency
because of increased renal loss (increased
glomerular filtration rate in the early first trimester) and
transfer of iodine to the developing fetus.
• To compensate, the thyroid gland increases its uptake
of iodine from the blood.
• If the supply is insufficient, cellular hyperplasia and
goiter result.
• Although a physiologic goiter may be seen on ultrasound
examination by a change in gland size of 10 to 20%, this
change is not clinically detectable.
• A clinically apparent goiter suggests iodine deficienry or
pathology
• The fetal thyroid gland begins to form at 5 weeks'
gestation and has some function at 10 weeks, but it is
only autonomous at 12 weeks, when T3, T4 and TSH
levels can be measured in fetal serum
• Levels continue to increase until 35 to 37 weeks'
gestation, when they reach adult levels.
• The fetal thyroid concentrates iodine at a significantly
higher rate than the maternal thyroid.
• Diagnostic scanning or uptake with radioactive tracers,
such as iodine- 131 or technetium-99, or radioactive
iodine therapy should be avoided because of the risks of
exposure to the developing fetus.
hCG and thyroid function
• hCG is one of a family of glycoprotein hormones,
including TSH, with a common alpha-subunit and a
unique beta-subunit.
• there is considerable homology between the betasubunits of hCG and TSH
• As a result, hCG has weak thyroid-stimulating activity
• In a human thyroid cell-culture assay, as an example, 1
microU of hCG was equivalent to 0.0013 microU of
TSH
• Serum hCG concentrations increase soon after
fertilization and peak at 10 to 12 weeks.
• During this peak, total serum T4 and T3
concentrations increase.
• Serum free T4 and T3 concentrations increase slightly,
usually within the normal range, and serum TSH
concentrations are appropriately reduced
• The reason for this increase may be to provide the fetus
with T4 before it becomes autonomous.
• These changes must be considered when a diagnosis of
hyperthyroidism is contemplated in early pregnancy,
especially in the context of hyperemesis gravidarum,
where hCG secretion may be exaggerated, or in
trophoblastic disease, where it is grossly elevated
• The increase in hCG that occurs in early pregnancy
"spills over" and stimulates the TSH receptor,
suppressing TSH and increasing T4.
Thyroid physiology
• The major changes in thyroid function during pregnancy
are an increase in serum thyroxine-binding globulin
(TBG) concentrations and
• stimulation of the thyrotropin (TSH) receptor by human
chorionic gonadotropin (hCG).
Thyroxine binding globulin
•
During pregnancy, serum TBG concentrations rise
almost two-fold because estrogen increases TBG
production and TBG sialylation, which results in
decreased clearance of TBG
• To maintain adequate free thyroid hormone
concentrations during this period, thyroxine (T4) and
triiodothyronine (T3) production by the thyroid gland
must increase
• Total T4 and T3 concentrations rise during the first half
of pregnancy, plateauing at approximately 20 weeks of
gestation, at which time a new steady state is reached
and the overall production rate of thyroid hormones
returns to prepregnancy rates.
• TBG excess leads to an increase in both serum total T4
and T3 concentrations
• TWO thirds of women with hyperemesis have abnormal
thyroid function test results in the absence of thyroid
disease, with 30% having undetectable TSH, 60%
having suppressed TSH, and 59% having an elevated
free T4 level
• Little T4 crosses the placenta after the first trimester, and
the placenta is relatively impermeable to TSH and T3
• Thyroid-releasing hormone, antithyroid medications
(propylthiouracil, carbimazole, and methimazole), and
iodine cross the placenta and may alter the fetal
physiology
• Pregnanry causes an increase in thyroid-binding globuIin
(and transthyretin) through the effecs of estrogen,which
increases synthesis and decreases clearance
• The elevation is present at 2 weeks' gestation and peaks
at 20 weeks' gestation
• This elevation necessitates a small increase in the
production of T4 1-3% and T3 until this plateau is
reached total T3 and T4 are elevated
• Because only the free hormone is biologically active,
only free hormone measurements are used in pregnancy
• TSH decreases in early pregnancy, but may increase in
the third trimester although some authors have not
shown this finding
• Concentrations of free T4 decrease in the second half
of pregnancy (below the range seen outside pregnanry)
• Peripheral conversion of free T4 to free T3 is
enhanced, and this increased efficiency may be in
preparation for the exertions of labor and delivery
• However, in 10 to 20 percent of normal women, serum
TSH concentrations are transiently low or undetectable
• In a report of 63 women with extremely high hCG
concentrations (>200,000 IU/L), TSH was <0.2
microU/mL in 67 percent of samples and free T4 was
above 1.8 ng/dL in 32 percent of samples. All women
whose hCG was greater than 400,000 IU/L had a
suppressed TSH concentration
• This transient, usually subclinical, hyperthyroidism
should be considered a normal physiologic finding.
• It is not known if this action of hCG benefits the mother
or fetus.
• Later in pregnancy, as hCG secretion declines, serum
free T4 and T3 concentrations decline and serum TSH
concentrations rise slightly to or within the normal range
Trimester-specific reference ranges
• Because of the changes in thyroid physiology during
pregnancy, the Guidelines of the American Thyroid
Association (ATA) for the Diagnosis and Management of
Thyroid Disease During Pregnancy and Postpartum
recommend using trimester-specific reference ranges
for TSH and method and trimester-specific reference
ranges for serum free T4
• Commercial laboratories should provide these reference
ranges, but many commercial laboratories currently do
not do this.
• In several population studies, the lower limit of the
reference range for TSH in healthy pregnant women
during the first trimester ranged from 0.03 to 0.1
mU/L
• In one of the largest population-based studies (over
13,000 pregnant women), the reference range (2.5 to
97.5th percentile) for TSH in the first trimester was 0.08
to 2.99 mU/L
•
if the laboratory does not provide trimester-specific
reference ranges for TSH (mU/L), the following reference
ranges can be used:
• ●First trimester 0.1 to 2.5
• ●Second trimester 0.2 to 3.0
• ●Third trimester 0.3 to 3.0
• Some studies report a decrease in free T4 during
pregnancy, others report no change or even an
increase
• Direct free T4 measurements may be unreliable during
pregnancy.
• Measurement of free T4 in the dialysate or ultrafiltrate of
serum samples using liquid chromatography/tandem
mass spectrometry appears to be the most reliable, and
when this method is used, free T4 concentrations were
shown to decrease gradually with advancing
gestational age, particularly between the first and
second trimester
• This assay is relatively expensive and not universally
available.
• Other free T4 assays (and probably free T3 assays)
frequently fail to meet performance standards in
pregnant patients, owing to increases in TBG and
decreases in albumin concentrations that cause the
immunoassay to be unreliable
• To compensate, some kits have provided different free
T4 normal ranges for pregnant patients, usually lower
than those of nonpregnant patients
• As an alternative, serum total T4 measurements, which
are more reliable during pregnancy, can be measured to
assess thyroid function
• When free T4 measurements appear discordant with
TSH measurements, serum total T4 should be
measured.
• Total T4 and T3 levels during pregnancy are 1.5-fold
higher than in nonpregnant women due to TBG excess..
• The World Health Organization (WHO) recommends 250
mcg of iodine daily during pregnancy and lactation.
• The Institute of Medicine recommends daily iodine intake
of 220 mcg during pregnancy and 290 mcg during
lactation.
• For women in the United States to achieve this level of
daily intake, the ATA recommends that women from the
United States receive a supplement of 150 mcg of iodine
daily during pregnancy and lactation, which is the dose
included in the majority of prenatal vitamins marketed in
the United States
• The tolerable upper intake amount for iodine, as
established by European and United States expert
committees, ranges from 600 to 1100 mcg daily for
adults and pregnant women >19 years of age.