Introduction mU/L can be used. Trimester-specific reference ranges for

Introduction

 

Pregnancy has significant effects on thyroid function and on
the course of thyroid diseases. Production of the thyroid hormones, thyroxine
(T4), and triiodothyronine (T3), increases by nearly 50%, in conjunction with a
separate 50% increase in the daily iodine requirement. These physiological changes
happen seamlessly in healthy women, but thyroid dysfunction can occur in many
pregnant women with borderline thyroid reserve. The burden of thyroid disease
affecting women, before, during, or directly after pregnancy, is substantial. For
these reasons thyroid function is frequently assessed during the gestation
period. However, accurate assessment of maternal thyroid function during
pregnancy remains difficult, and interpretation of laboratory testing differs from
the nonpregnant patient. Although the management of overt hypothyroidism in
pregnancy is fairly standardized, there are contradictory opinion regarding
initiating treatment for subclinical hypothyroidism in pregnancy.

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Clinical
manifestations

 

The range of clinical symptoms of hypothyroidism during
pregnancy is similar to those that occur in nonpregnant patients and may
include fatigue, cold intolerance, constipation, and weight gain. Symptoms may
be overlooked or attributed to the pregnancy itself as some of the symptoms of
hypothyroidism are similar to those of pregnancy. Many patients are asymptomatic.
Subclinical hypothyroidism in most situations is asymptomatic and detected only
on investigating.

 

 

Laboratory
findings

 

To meet the increased metabolic needs during a normal
pregnancy, there are changes in thyroid physiology that are reflected in altered
thyroid function tests. These changes include an increase in T4-binding
globulin (TBG), which results in total T4 and T3 concentrations that are higher
than in nonpregnant women. In addition, high serum human chorionic gonadotropin
(hCG) levels, particularly during early pregnancy, result in a reduction in
first trimester serum thyroid-stimulating hormone (TSH) concentrations.

If the laboratory does not provide population and
trimester-specific reference ranges for TSH, an upper reference limit of approximately
4 mU/L can be used. Trimester-specific reference ranges for free T4 (FT4) should
be provided with the assay kits. Measuring FT4 in the presence of high
concentrations of bound T4 has proved to be challenging. Accurate assays based
on classical methods of separation like equilibrium dialysis or ultrafiltration
are laborious, time-consuming, expensive, and not widely available. FT4
measurement is performed by indirect analog immunoassays by the majority of
clinical laboratories, largely because of its ability to be quickly performed on
automated platforms.  Measurement of
total T4 may be superior to immunoassay measurement of FT4 in pregnant women.
However, reference values should take the 50% increase in TBG witnessed during
pregnancy into account. Thyroid peroxidase (TPO) antibodies are elevated in 30-60%
of pregnant women with an elevated TSH. Women who have subclinical
hypothyroidism with positive TPO antibodies have a higher risk of pregnancy
complications than those whose TPO antibodies are negative.  If the serum TSH is >2.5 mU/L, TPO
antibodies should be measured. The presence of TPO antibodies may be useful for
making treatment decisions in women with borderline thyroid function tests (eg,
TSH 2.5 to 4.0 mU/L) and in predicting the development of hypothyroidism and
the risk of miscarriage and postpartum thyroid dysfunction.

 

 

Diagnosis

 

The diagnosis of primary hypothyroidism during pregnancy is
based upon the finding of an elevated serum TSH concentration, defined using
population and trimester-specific TSH reference ranges for pregnant women. TSH
should be measured in any women with symptoms of hypothyroidism. There is not
enough evidence to recommend routine screening of asymptomatic women for
hypothyroidism in pregnancy but is commonly practiced.

 

The American Thyroid association (ATA) guidelines published
in 2017 recommends the following trimester-specific ranges and cutoffs when
local assessments are not available. In the first trimester, the lower
reference range of TSH can be reduced by approximately 0.4 mU/L, while the upper
reference range is reduced by approximately 0.5mU/L. For the typical patient in
early pregnancy, this corresponds to a TSH upper reference limit of 4.0mU/L.
This reference limit should generally be applied beginning with the late first
trimester, weeks 7–12, with a gradual return towards the nonpregnant range in
the second and third trimesters. Women with central hypothyroidism from
pituitary or hypothalamic disease will not have elevated TSH concentrations
during pregnancy.For women in the first trimester of pregnancy with a TSH above
the population and trimester-specific upper limit of normal or above 4.0 mU/L
when local reference ranges are not available, a FT4 or total T4 should be
measured.

 

 

Pregnancy
Complications

 

Hypothyroidism can have adverse effects on pregnancy
outcomes, depending upon the severity of the biochemical abnormalities:

 

?Overt hypothyroidism

?Subclinical hypothyroidism

?Maternal hypothyroxinemia (isolated low maternal FT4)

 

Overt
hypothyroidism — Overt hypothyroidism (elevated TSH, reduced FT4)
complicating pregnancy is unusual (0.3 to 0.5 %of screened women). Two factors
contribute to this finding; some hypothyroid women are anovulatory, and
hypothyroidism (new or inadequately treated) complicating pregnancy is
associated with an increased rate of first trimester spontaneous abortion.

 

In continuing pregnancies, hypothyroidism has been
associated with an increased risk of several complications, including:

?Preeclampsia and gestational hypertension

?Placental abruption

?Nonreassuring fetal heart rate tracing

?Preterm delivery, including very preterm delivery (before
32 weeks)

?Low birth weight

?Increased rate of cesarean section

?Postpartum hemorrhage

?Perinatal morbidity and mortality

?Neuropsychological and cognitive impairment in the child

 

 

Subclinical
hypothyroidism — Subclinical hypothyroidism (elevated TSH, normal free T4)
is more common than overt hypothyroidism, occurring in 2.0 to 2.5% of screened
women in iodine-sufficient regions. The risk of complications during pregnancy
is lower in women with subclinical, rather than overt, hypothyroidism.

In some but not all studies, women with subclinical
hypothyroidism were reported to be at increased risk for severe preeclampsia,
preterm delivery, placental abruption, and/or pregnancy loss compared with
euthyroid women. It is uncertain if the children of women with subclinical
hypothyroidism are at risk for neuropsychological impairment. Observational studies
suggest an association between subclinical hypothyroidism in pregnancy and
impaired cognitive development in children.

Assessment of antibody status is important because women
with subclinical hypothyroidism and positive TPO antibodies tend to have higher
risk of adverse pregnancy outcomes. The risk of pregnancy-specific
complications increases in TPO-positive women with TSH >2.5 mU/L but was not
consistently apparent in TPO-negative women until TSH values exceeded 5 to 10
mU/L. In addition, limited data suggest that pregnancy outcome for women
undergoing in vitro fertilization may be worse among those with preconception
TSH levels higher than 2.5 mU/L.

 

Low maternal
free T4 — Isolated maternal hypothyroxinemia is defined as a maternal  FT4 concentration in the lower 2.5 to 5
percentile of the reference range, in conjunction with a normal TSH. The effect
of isolated maternal hypothyroxinemia on perinatal and neonatal outcome is
unclear. In a multicenter trial, women with isolated maternal hypothyroxinemia,
thyroxine therapy did not show significant differences in neurodevelopmental or
behavioral outcomes in the children at five years of age. In addition, there
were no significant differences in the frequencies of preterm delivery, preeclampsia,
gestational hypertension, miscarriage rate, or other maternal or fetal
outcomes.

 

Treatment

 

Indications
for treatment

Overt Hypothyroidism – All pregnant women with newly diagnosed,
overt hypothyroidism (elevated TSH >4 mU/L, with low T4) should be treated
with thyroid hormone.

 

Subclinical Hypothyroidism – Most authorities suggest treatment
of pregnant women with subclinical hypothyroidism (elevated TSH > 4 mU/L with
normal T4), regardless of TPO antibody status.

 

TSH 2.6 to 4 mU/L – T4 therapy may be considered for TPO
antibody positive women with TSH concentrations >2.5 mU/L and below the
upper limit of the pregnancy-specific reference range.  

T4 therapy is
not recommended for TPO antibody negative women with a normal TSH (TSH within
the pregnancy-specific reference range or 4
mU/L with low free T4:  Close to full
replacement dose (approximately 1.6 mcg/kg body weight per day)

? TSH >4 mU/L,
with normal free T4: Intermediate dose (approximately 1 mcg/kg per day)

? TSH 2.6 to
4 mU/L: If a decision has been made to treat, low dose (typically 50 mcg daily)

Monitoring and dose adjustments — After
initiation of T4 therapy, the patient should be reevaluated and serum TSH
measured in four weeks. The goal is to maintain TSH in the lower half of the
trimester-specific reference range. If not available, a goal TSH of