Thyroid Disorders in

Pregnancy

Dr.Nasser Al-Husban
Introduction
• Prior to 12 weeks' gestation maternal
thyroxine (but not fT3) crosses the placenta.
• Following binding to receptors in fetal brain
cells, thyroxine is converted intracellularly to
fT3, a process thought to be important for
normal fetal brain development.
• From 12 weeks onwards, placental changes
prevent significant passage of maternal
thyroxine and fetal thyroid function is
controlled independently of the mother,
provided that her iodine intake is adequate.
• In pregnancy, Well-designed, isolated, term
placental studies show passage to the fetal side
of only 0.008% of maternal thyroxine in normal
circumstances
 Changes in pregnancy
• The half-life of thyroxine binding globulin
extends from 15 minutes to 3 days and its
concentration triples by 20 weeks of
gestation, as the result of estrogen-driven
glycosylation.
• Total thyroid hormone levels increase and,
therefore, measurements of total T4 and total
T3 are not reliable in pregnancy.
Changes in pregnancy
• fT4 and fT3 remain relatively constant
and are the tests of choice in pregnancy:
they should be interpreted in relation to
pregnancy-specific reference ranges.
 Changes in pregnancy
• Human chorionic gonadotrophin(hCG) and thyroid
stimulating hormone (TSH) have similarities, in first
trimester, a hormone spillover syndrome can occur in
which hCG stimulates the TSH receptor and gives a
biochemical picture of hyperthyroidism. This is
particularly common in multiple pregnancy,
trophoblastic disease and hyperemesist gravidarum,
where concentrations of both total hCG and thyrotropic
subtypes can be greater .
Changes in pregnancy
• Increased glomerular filtration and greater
uptake of iodine into the thyroid gland driven
by increased total thyroxine concentration can
deplete iodine and cause or worsen iodine
deficiency.
• Transplacental transfer can also exacerbate
this but when there is severe maternal iodine
deficiency, maternal iodine trapping overrides
fetal needs, resulting in cretinism.
Changes in pregnancy
• Three deiodinase hormones control metabolism
of T4 to the more active T3 and their breakdown
to inactive compounds. The concentration of
deiodinase III increases in the placenta with
gestation, releasing iodine where it is required
for transport to the fetus and, possibly,
contributing to reduced thyroxine transfer.
Hypothyroidism
• Hypothyroidism occurs in around 1%
of pregnant women. Its management
in pregnancy remains surprisingly
contentious and complicated.
Situation 1
• Untreated hypothyroidism (low fT4,
high TSH, often symptomatic) who
require urgent initiation of treatment
with thyroxine.
Situation 2

• Previously diagnosed hypothyroidism

who may be on optimal therapy
(normal fT4 and TSH) at conception
or who may not (low fT4, high TSH);
in the latter, rapid achievement of
euthyroidism is important,
particularly in the 1 st trimester.
Situation 3

• Subclinical hypothyroidism (normal

fT4, raised TSH, asymptomatic) in
whom the place of thyroxine therapy
is debatable.
Situation 4

• Hypothyroxinaemia (low T4, normal

TSH).
Therapy
• From a maternal perspective, biochemical euthyroidism remains
the goal, as it is outside of pregnancy.
• Adjustment of thyroxine dose on the basis of clinical signs and
symptoms is particularly challenging in pregnancy.
• Both excess and deficient thyroid hormone levels cause problems
that are difficult to distinguish from those of normal pregnancy.
This results in an increased dependence upon biochemical results
and pregnancy-specific reference ranges.
• Some suggest an association between treated hypothyroidism and
adverse pregnancy outcomes, including miscarriage, pre -
eclampsia, placental abruption and prematurity.
Factors that could influence thyroxine dosage
during pregnancy
• Reduced absorption in the First trimester related to nausea and
vomiting.
• Malabsorption resulting from binding of thyroxine to newly -
commenced iron and calcium supplements.
• Suboptimal control prior to conception.
• Altered compliance, with either an improvement, resulting in an
apparent need to reduce the dosage, or a deterioration (perhaps
from false concerns of safety), resulting in apparent need to
increase the dosage.
• Normal variation in thyroxine dosage.
• The therapeutic window of thyroxine is broad, with doss
adjustments usually of 25 or 50 micrograms, i.e. by approximately
25%. Few individuals are on a tightrope of therapeutic control.
Although in pregnancy increased concentrations of thyroxine
binding proteins occur that result in an increased total thyroid
hormone pool, it is likely that, for many women, this will not in
itself necessitate dose adjustment.
• In addition, deiodinase II, the enzyme responsible for peripheral
activation of T4 to T3 in the brain, increases m concentration with
advancing gestation (when fT4 is low). This may help to explain
why thyroxine. increases are not routinely required, despite the
physiological changes explained above.
• This is reflected in the reference ranges for thyroid function,
which are broad. Some state that thyroxine doses should be
increased such that TSH falls into the lower hall of the range.
• Some feel this would be detrimental.
• Others feel that individuals have their own narrow normal range,
outside which they may develop symptoms or be at increased risk
of the longterm consequences of hypothyroidism (cardiac failure)
or hyperthyroidism (atrial fibrillation or osteoporosis).
• a In pregnancy these questions remain unanswered, as does
whether it is the circulating fT4 or TSH that is a better marker of
euthyroidism from the mother's or baby's perspective.
• Thyroid function can he influenced by
hyperemesis gravidarum in the first trimester.
• Reference ranges for thyroid hormones are /
different in pregnancy (especially in the third
trimester, when there is a move towards the
hypothyroid end of the spectrum).
• Trimester specific reference ranges should be
used in the management of thyroid disease in
pregnancy.
 Conclusions
• Women with under or untreated hypothyroidism, optimal replacement
doses should, ideally, be reached prior to conception or early in 1 st
trimester.
• Women with established hypothyroidism need to increase their dose of
thyroxin during pregnancy to maintain euthyroidism according to
trimester-specific ranges.
• Only first trimester control influences fetal wellbeing.
• Hypothyroidism itself does not influence pregnancy outcome or
complications.
• For women with hypothyroidism who intend to become pregnant and
who are on the correct dose of thyroxin, thyroid testing is needed only
prepregnancy, early in the 1 st trimester and again later in the 2 nd or 3 rd
trimester.
• The majority of their antenatal care can be midwifery -led unless risk
factor dictate otherwise.
 Hyperthyroidism
• Autoimmune thyrotoxicosis or Garrives' disease affects
around 2 per 1000 pregnancies.
• Management is more complex but less controversial
than that of hypothyroidism.
• The main tenet is to ensure euthyroidism is achieved as
early as possible in pregnancy, preferably prior to
conception, as this minimizes the likelihood of maternal
or fetal complications.
 Complications
• Maternal; PET, Congestive heart failure,
thyroid storm.
• Fetal; IUGR Prematurity, stillbirth.
 Therapy
• B-blockade, usually with propranolol hydrochloride, should be
used in pregnancy, if required, to control tachycardia, tremor or
anxiety. Concerns about fetal growth restriction are vastly
outweighed by the maternal and fetal benefits.
• Euthyroidism is achieved using the antithyroid agents
carbimazole or propylthiouracil. These block thyroid hormone
synthesis and have an immunosuppressive effect, reducing the
titer of TSH receptor stimulating antibodies and, thereby,
directly influencing the course of the disease.
Both cross the placenta in similar amounts.
• Difficult to distinguish clinically between the signs and
symptoms of hyperthyroidism and pregnancy, reliance is placed
on serial biochemical measurement.
• Failure to gain weight, despite a good appetite,
and tachycardia greater than 100 beats per
minute that fails to slow with Valsalva
manoeuvre and onycholysis (elevation of the
distal nail bed) are good indicators of
thyrotoxicosis.
• Eye signs and pretibial myxoedema do not
reflect disease activity.
• Clinical disease activity follows the titre of TSH receptor
stimulating antibodies, which rises in the first trimester and
puerperium and falls in the second and third trimesters.
• Thyroid function should be measured monthly when control is
good and more frequently when the diagnosis is new or there is a
relapse.
• Antithyroid medication is titrated against the results: Most women
can reduce their dose and almost one-third of women can stop
treatment during pregnancy, which helps prevent fetal
hypothyroidism. Most women will need to restart of increase their
dose in the puerperium to avoid a relapse.
Propylthiouracil (PTU) or Carbimazole?
• Propylthiouracil is more heavily protein-bound than
carbimazole; studies using isolated perfused human
placental lobules show similar placental transfer kinetics
for both drugs.
• No differences in fetal thyroid function measured using
cord sera were found in 77 babies whose mothers were
taking one or other of the agents.
Propylthiouracil (PTU) or Carbimazole?
• Previously: carbimazole causes aplasia cutis congenita of the scalp
in the infant, a rare congenital defect affecting 0.03% of the
general population.
• More extensive and recent work indicates, however, that this
association is either spurious or, at most, extremely rare and
should not influence the choice of drug in pregnancy.
• No other teratogenesis has been linked with antithyroid drugs.
• Pregnancies in which there is poor control in the first trimester are
more likely to be complicated by fetal anomaly than those in
which drug therapy is successfully used to achieve control.
Propylthiouracil(PTU) or Carbimazole?
• Both drugs cause agranulocytosis and pregnant
women should be reminded to report a sore
throat immediately.
• This reaction is unpredictable and is a reason not
to change agent routinely during pregnancy.
• Lactation is the period when there is some difference between the
drugs.
• Studies of radiolabeled drugs show that 0.077% of propylthiouracil
and 0.47% of carbimazole reaches breast milk. Small numbers of
babies, however, whose mothers have taken antithyroid medication
have had thyroid function monitored in the first weeks of life and
adverse effects have not been found.
• There are concerns that high doses, especially of carbimazole,
could cause neonatal hypothyroidism. Doses should be split
through the day, with feeding to occur before a dose where
possible, monitoring of neonatal thyroid function and regular
consideration given to switching to propylthiouracil.
Surgery or Radioactive iodine?
• Thyroid surgery can be carried out in pregnancy if required, most
usually in the second trimester.
• Indications include: compression from a large goiter, suspicion of
malignancy and failed antithyroid therapy.
• Surgery: pregnancy associated increase in the vascularity of the
thyroid and so should only be undertaken by an experienced
thyroid surgeon.
• Radioactive iodine crosses the placenta and binds to and destroys
the fetal thyroid. It is totally contraindicated in pregnancy.
Lactation should be stopped (preferably 4 weeks if it is given in
the puerperium.
Fetal & Neonatal consequences of
thyrotoxicosis
• Fetal or neonatal problems relating to well controlled Graves' disease are
rare.
• TSH receptor stimulating antibodies cross the placenta and the risk of
fetal Graves' disease after 20 weeks (the gestational age at which the
fetal thyroid can respond to these antibodies) is directly proportional to
their titre (although even at the highest titres the risk is very low).
• It is very important that women who have had Graves' disease in the past
treated by surgery or radioactive iodine, as well as those actively being
treated for the condition during pregnancy, have this antibody measured.
Women with positive results should be monitored for signs of fetal
thyrotoxicosis, including tachycardia, excessive movements, fetal growth
restriction, oligohydramnios and goitre.
• Fetal Graves' disease can cause premature delivery in untreated women.
 Fetal & Neonatal consequences of
thyrotoxicosis
• Craniosynostosis and associated intellectual
impairment.
• Hydrops fetalis.
• Intrauterine death.
• Polyhydramnios related to oesophageal pressure.
• Obstructed labour from neck extension related to
goitre.
 Fetal & Neonatal consequences of
thyrotoxicosis
• Management is usually based on delivery if the gestational
age is sufficiently advanced.
• It this is not appropriate, high doses of propylthiouracil or
carbimazole should be given to the mother and the
response titrated against the fetal heart rate; the pregnant
woman can take thyroxine if she becomes clinically
hypothyroid and this will not cross the placenta. Although
fetal reference ranges for thyroid function are known, fetal
blood sampling is not routinely needed unless the
diagnosis is in doubt.
Fetal & Neonatal consequences of
thyrotoxicosis
• At delivery, thyroid function should be measured using cord blood.
Rarely, hypothyroidism is reported secondary to transplacental
passage of antithyroid drugs, this is usually self -limiting.
• Hyperthyroidism is also occasionally detected, although this more
typically presents 7-10 days postnatally, since the half-life of
maternally-derived antithyroid drugs is shorter than that at TSH
receptor antibodies.
• Parents should be warned to look for changes in their baby, such
as weight loss or poor feeding.
• Neonatal treatment, when required, rarely lasts for more than a few
months.
Hyperemesis Gravidarum
• Hyperemesis gravidarum is the term for vomiting in the first half of
pregnancy that is sufficiently severe to cause dehydration requiting
intravenous fluids, weight loss and/ or abnormalities in liver function
(secondary to starvation) or thyroid function tests.
• This, usually transient, hyperthyroidism (suppressed TSH and high or
very high fT4) occurs in over 60% of pregnancies with sever hyperemesis
and is caused by the TSH-like effect of the beta subunits of hCG.
• Some pregnancies, either the total concentration of hCG is increased (in
multiple or molar pregnancies) or the beta subunits of hCG have a greater
ability to bind to TSH receptors.
• This biochemical hyperthyroidism must he differentiated from the rare,
first trimester presentation of Graves' disease with vomiting, by taking a
detailed history and by ensuring a return to biochemical normality as the
hyperemesis resolves.
Hyperemesis Gravidarum
• By 19 weeks' gestation, one series reported that fT4
levels had fallen to normal and TSH had escaped full
suppression in all women.
• Typically, in women with hyperemesis gravidarum, the
symptoms clearly postdate the pregnancy, the woman is
washed out, deflated and tired, there are no eye signs or
goitre and tachycardia responds to intravenous
rehydration. The absence of thyroid autoantibodies is
helpful in supporting hyperemesis.
Hyperemesis Gravidarum
• Therapy; correcting the metabolic insults of prolonged
vomiting and minimizing further vomiting.
• There is usually no place for antithyroid medication, as
there is no intrinsic increase in thyroid activity, the
duration of hyperemesis gravidarum is usually relatively
short and the antithyroid medication crosses the placenta
and has the potential to make the fetus hypothyroid.
• When hCG-related thyrotoxicosis IS treated, antithyroid
medication is either ineffective or very high doses are
needed.
 Iodine Deficiency
• The WHO: worldwide, 2 billion people are iodine
deficient and more than 20 million have adverse
neurological sequelae secondary to in utero iodine
deprivation.
• Worldwide, neurological cretinism is the leading
preventable cause of mental handicap. It affects
2-10% of people in iodine deficient areas and
causes mild mental handicap in a further 10-50%.
(significant negative impact on the economy of
afflicted regions).
 Iodine Deficiency
• The developing cochlea, cerebral neocortex and basal
ganglia are most sensitive to iodine deficiency, especially
in the second trimester, resulting in deaf-mutism,
intellectual deficiency and spastic motor disorder.
• Less severe maternal iodine deprivation spares hearing,
speech and motor function but causes mental handicap
(myxoedematous cretinism), presumably because the
mother is able to transfer enough T4 and iodine and the
fetus is subsequently able to make enough T3 to protect
these functions.
 Iodine Deficiency
• In areas of endemic iodine deficiency, pregnant women usually have low or
very low T4 and normal T3, with raised TSH levels and a compensatory
goitre. This supports the physiological pathways but that maternal T3 is not
enough to protect the fetal brain, which needs intracellular T3 (derived
from circulating T4). In these circumstances, there is not enough maternal
T4 to be transferred, even if deiodinase II is suppressed, nor enough iodine
to allow fetal production of T4.
• Changes in renal clearance of iodine and increased thyroxine binding
globulin exacerbate the level of iodine deficiency in susceptible
populations.
• Iodine administration prior to conception or up to the second trimester can
protect the fetal brain and, when given early enough, reduce miscarriage
and later pregnancy losses.
• Programmes to deliver annual boluses of iodine to susceptible women are
difficult to sustain and, unfortunately, national programmes to iodinate
flour, salt or water continue to flounder.
Thyroid Storm
• Thyroid storm requires prompt recognition,
aggressive reversal of thyroidotoxins with
antithyroid drugs (ATDs), and supportive
management of signs and symptoms.
Antithyroid agents are propylthiouracil and
methimazole.
• The standard practice is to give an initial loading dose
of 300mg to 600mg propylthiouracil enterally and then
150mg to 300mg every 6 hours.
• 1f a patient cannot take the solution by mouth,
propylthiouracil can be administered via the nasogastric
tube or can be compounded by the pharmacy and given
as a rectal suppository. Iodides are commonly given
because they rapidly inhibit the release of thyroid
hormones. Iodides are administered several hours alter
propylthiouracil therapy is initiated to avoid the buildup
of hormones stored in the thyroid gland.
• A saturated solution of potassium iodide is given orally in dosages
of 2 to 5 drops every 8 hours, or sodium iodide is given
intravenously in dosages of 0.5 to l g every 8 hours.
• Beta blockers such as propranolol should be given to help decrease
some of the thyrotoxic effects on the cardiovascular system.
• Additional supportive measures: administration of intravenous
fluids for dehydration, antipyretics to control of hyperthermia (a
cooling blanket may be necessary), nutritional support, correction
of possible electrolyte imbalances, and use of glucocorticoids,
which also inhibit conversion of T4 to T3 and prevent adrenal
insufficiency.
• If sedation is required, barbiturates are most often used because they
lower the levels of thyroid hormones by increasing the catabolism of the
hormones.
• Oxygen should be used as needed for possible increased oxygen
demands.
• Because of the hypermetabolic state of thyroid storm, medication are
metabolized faster than normal. Therefore, higher and more frequent
doses may be required to control the thyrotoxicosis.
• Patients in thyroid crisis require close assessment and monitoring of
cardiovascular status, including continuous cardiac monitoring and
frequent monitoring of vital signs. Significant changes should be reported
immediately.
• During this period, careful monitoring of the fetus is also a critical
element of management.
• Current recommendations are to avoid delivery during thyroid storm
unless the condition of the fetus demands prompt delivery.
Many Thanks