The functioning of thyroid
gland is significantly altered by pregnancy. The production of thyroxine (T4)
and triiodothyronine (T3), increase almost one and half times in pregnancy. In
healthy women these changes take place seamlessly as a part of normal
physiology of pregnancy but many women with borderline thyroid status develop abnormalities
in functioning of thyroid gland during pregnancy. Thyroid dysfunction during pregnancy
is widely prevalent. That is why thyroid function is assessed commonly during pregnancy.
The symptoms of hypothyroidism during pregnancy and in
nonpregnant state are similar. The manifestations can range from fatigue, hair
fall, dry skin, intolerance to cold, gain in weight and constipation. Many of
these symptoms occur commonly in pregnancy and identification of hypothyroidism
on the basis of symptoms can be misleading. Pregnant women with hypothyroidism
often do not manifest any symptoms. Subclinical hypothyroidism (SCH) in usually
asymptomatic and detected only on laboratory testing.
To meet the metabolic demands during pregnancy, the thyroid
physiology is altered that are manifested in changes in thyroid function tests.
The changes include elevated T4-binding globulin (TBG), that raise the total T4
and T3 levels by 1.5 times higher than in nonpregnant state. Besides, high
serum human chorionic gonadotropin (hCG) levels, particularly in early
pregnancy, result in a reduction in serum thyroid stimulating hormone (TSH)
levels in first trimester.
If population and trimester-specific reference ranges for TSH
are not available, an upper reference cut off of approximately 4 mU/L can be
used. Trimester specific reference values for free T4 (FT4) should be provided
with the assay kits. High levels of bound T4 in pregnancy can make assessment
of FT4 challenging. Assays based on 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 ranges should take into
account the 50% increase in TBG occurring in pregnancy. Thyroid peroxidase
(TPO) antibodies are elevated in 30-60% of pregnant women with an elevated TSH.
The risk of complications is higher in women with SCH and positive TPO
antibodies compared to those with negative TPO antibodies. If the serum TSH is >2.5 mU/L, estimation
of TPO antibodies should be done. TPO antibody positivity can tilt the decision
to start T4 treatment in pregnant women with TSH between 2.5 to 4.0 mU/L and
can also help to predict the risk of postpartum thyroid dysfunction.
The diagnosis of primary hypothyroidism during pregnancy is
based upon the finding of an elevated serum TSH level, calculated using
population and trimester-specific TSH ranges for women with pregnancy. Any
women with symptoms suggestive of hypothyroidism should undergo a TSH
estimation. There is inadequate evidence to recommend for or against routine screening
for thyroid dysfunction of asymptomatic pregnant women but estimation of TSH is
commonly done in first trimester of pregnancy in clinical practice.
As per the recommendation of the American Thyroid Association
(ATA) 2017 guidelines the following trimester-specific
ranges and cutoffs can be considered when local assessments are not available.
In the first trimester, the lower reference value of TSH can be decreased by
0.4 mU/L, while the upper reference range is reduced by 0.5mU/L. This usually corresponds
to a TSH upper reference limit of 4.0mU/L. 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 4.0 mU/L, FT4 or total T4 value should be estimated to differentiate
between SCH and overt hypothyroidism.
Hypothyroidism can have adverse effects on pregnancy
outcomes, depending upon the severity of the biochemical abnormalities:
?Maternal hypothyroxinemia (isolated low maternal FT4)
hypothyroidism — Uncorrected overt hypothyroidism in pregnancy is unusual
(0.3-0.5% of screened women). Anovulation in hypothyroid women and increased
rate of first trimester spontaneous abortion (often undetected) are responsible
for this finding.
In continuing pregnancies, hypothyroidism has been
associated with an increased risk of several complications, including:
?Preeclampsia and gestational hypertension
?Nonreassuring fetal heart rate tracing
?Preterm delivery, including very preterm delivery (before
?Low birth weight
?Increased cesarean section rate
?Perinatal morbidity and mortality
?Neuropsychological and cognitive impairment in the child
hypothyroidism — SCH is more common than overt hypothyroidism. In areas
with iodine sufficiency, 2.0 to 2.5% of screened women have SCH. Women with SCH
have a lower chance to develop complication than those with overt disease.
In some but not all studies, women with SCH 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 SCH are at risk for neuropsychological
impairment. Observational studies suggest a possible association between SCH in
pregnancy and impaired cognitive development in children. Women with SCH and positive
TPO antibodies have a tendency towards higher risk of adverse pregnancy
outcomes. The risk of complications increases in TPO positive women with TSH
>2.5 mU/L but was not consistently demonstrated in TPO negative women until
TSH values exceeded 5 to 10 mU/L. Pregnancy
outcome for women undergoing in vitro fertilization may be worse among those
with preconception TSH values higher than 2.5 mU/L.
free T4 — Isolated maternal hypothyroxinemia is defined as a maternal FT4 level in the lower 2.5 to 5 percentile of
the reference range along with a TSH concentration in normal range. Isolated
maternal hypothyroxinemia has not been clearly demonstrated to be associated
with worsening of perinatal and neonatal outcome. In a multicenter trial, women
with isolated maternal hypothyroxinemia, T4 supplementation 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.
Overt Hypothyroidism – All pregnant women with newly diagnosed,
overt hypothyroidism (elevated TSH >4 mU/L, with low T4) should be treated with
Subclinical Hypothyroidism – Most authorities suggest treatment
of pregnant women with SCH (elevated TSH > 4 mU/L with normal T4), irrespective
of TPO antibody status.
TSH 2.6 to 4 mU/L – T4 therapy may be considered for women
with TPO antibody positive women with TSH concentrations >2.5 mU/L and below
T4 therapy is
not recommended for TPO antibody negative women with a normal TSH (TSH <4.0 mU/L). In women with TSH between 2.6 and 4 mU/L who are not treated with thyroid hormone, TSH should be reassessed later during pregnancy. Euthyroidism (TSH <2.5 mU/L) with TPO antibody positive and recurrent miscarriage – Some authorities consider T4 therapy in pregnant euthyroid women with history of recurrent miscarriage and positive TPO antibody status. Low FT4, Normal TSH – There is no evidence to consider treatment. Dosing Recommendations The treatment of choice for correction of hypothyroidism in pregnancy is the same as in nonpregnant patients: synthetic T4. The purpose of T4 replacement in pregnancy is to restore euthyroidism as soon as possible. T4 should be taken on an empty stomach, ideally an hour before breakfast. ? TSH >4
mU/L with low free T4: Close to full
replacement dose (around 1.6 mcg/kg body weight per day)
? TSH >4 mU/L,
with normal free T4: Intermediate dose (around 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 or below 2.5 mU/L. If the TSH remains above the target
range, the dose of T4 can be increased by 12 to 25 mcg/day. TSH measurement
should be done every 4 weeks in the first half of pregnancy because dose
adjustments are often required. TSH can be monitored less often (at least once
each trimester) in the latter half of pregnancy, as long as the dose is
Goal preconception TSH — Women with
prior hypothyroidism who are planning to conceive should optimize their thyroid
hormone replacement. The target preconception serum TSH level is between the
lower reference limit and 2.5 mU/L.
Early dose adjustments — T4 dose
requirements may increase during pregnancy in women with preexisting
hypothyroidism. Hypothyroid women after detection of pregnancy should
preemptively increase their T4 dosage by around 30 percent and notify their
clinician as soon as possible. Subsequent adjustment in dosage are made upon the
basis of serum TSH estimates done every 4 weeks until TSH normalizes.
untreated (or incompletely treated) hypothyroidism can adversely affect
pregnancy, no data suggest that women with adequately treated subclinical or
overt hypothyroidism have an increased risk of any obstetrical complication. There
is no indication for any additional obstetric monitoring in pregnancies of women
with either SCH or overt disease who are being monitored and treated correctly.