TSH Level in Pregnancy
Gita Majdi
PGY4 Endocrinology Fellow
May 2014
Outline:
• TFT in pregnancy
• What is the normal range for TSH in pregnancy?
• Trimester-specific reference ranges
• ATA Guidelines for:
- Normal TSH in pregnancy
- Who should be screened?
The major changes in thyroid function during pregnancy are:
1- Increase in serum thyroxine-binding globulin (TBG)
concentrations
2-Stimulation of the thyrotropin (TSH) receptor by human
chorionic gonadotropin (hCG)
3-The gland increases 10% in size during pregnancy in iodinereplete countries and by 20%–40% in areas of iodine
deﬁciency.
4-Production of thyroxine (T4) and triiodothyronine (T3)
increases by 50%, along with a50% increase in the daily
iodine requirement.
Reduced clearance rate of thyroxine-binding globulin (TBG)
with increased sialylation: a mechanism for estrogeninduced elevation of serum TBG concentration.
AUAin KB, Mori Y, Refetoff S
SOJ Clin Endocrinol Metab. 1987;65(4):689.
How do thyroid function tests change
during pregnancy?
• Following conception, circulating total T4 (TT4) and T4 binding globulin (TBG)
concentrations increase by 6–8 weeks and remain high until delivery.
• Thyrotropic activity of hCG results in a decrease in serum TSH in the first trimester.
• Most studies also report a substantial decrease in serum FT4 concentrations with
progression of gestation .
• SerumFT4 measurements in pregnant women are complicated by increased TBG and
decreased albumin concentrations that can cause immunoassays to be unreliable .
Therefore the analytical method used for serum FT4 analysis should be taken into
consideration.
Glinoer D 1997 The regulation of thyroid function in Pregnancy.
Pathways of endocrine adaptation from physiology to pathology. Endocr Rev 18:404–433.
• Timing and Magnitude of Increases in Levothyroxine Requirements
during Pregnancy in Women with Hypothyroidism
• Erik K. Alexander, M.D., Ellen Marqusee, M.D., Jennifer Lawrence,
M.D., Petr Jarolim, M.D., Ph.D., George A. Fischer, Ph.D., and P. Reed
Larsen, M.D.
• N Engl J Med 2004; 351:241-249July 15, 2004DOI:
10.1056/NEJMoa040079
Changes in Maternal Hormone
Concentrations and the
Levothyroxine Dose during
Gestation. The graphs depict
the best-fit curves for serum
thyrotropin (range, 0.5 to 5.0
μU per milliliter), the free
thyroxine index (range, 5 to
11), the fractional increase in
the dose of levothyroxine, the
maternal estradiol
concentration (range, 10 to 80
pg per milliliter), and the
concentration of human
chorionic gonadotropin (range,
less than 5 U per liter)
throughout pregnancy in the
14 women who required an
increase in the levothyroxine
dose during a full-term
pregnancy. To convert the
values for estradiol to
picomoles per liter, multiply by
3.67.
• 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.
• 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.
• 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.
• Thus a normal reference range for pregnancy should be usedTo
compensate, some kits have provided different free T4 normal ranges
for pregnant patients, usually lower than those of nonpregnant
patients.
Source: Uptoate
Thyroid hormones, thyrotropin (TSH), and
thyroglobulin mean ratios by trimester
(values relative to 1-year postpartum). Ratios
were calculated for each woman relative to
her own baseline (postpartum). The means
of the ratios are shown.
Trimester-Specific Changes in Maternal
Thyroid Hormone, Thyrotropin, and
Thyroglobulin Concentrations During
Gestation: Trends and Associations Across
Trimesters in Iodine Sufficiencyublished in
final edited form as:
Thyroid. Dec 2004; 14(12): 1084–1090.
doi: 10.1089/thy.2004.14.1084
Trimester-specific reference ranges
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
2.99mU/L .
Thus, 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
Panesar et al. [12], 2001
China
343
cohort
2.5th, 97.5th
n = 158
0.03–2.3
n = 117
0.03–3.1
n = 76
0.13–3.5
Soldin et al. [6], 2007
USA
261
cross-sectional
2.5th, 97.5th
n = 71
0.24–2.99
n = 83
0.46–2.95
n = 62
0.43–2.78
Switzerland
2272
cross-sectional
2.5th, 97.5th
n = 783
0.09–2.82
n = 528
0.2–2.79
n = 501
0.31–2.9
Marwaha et al. [16], 2008
India
541
cross-sectional
5th, 95th
n = 107
0.6–5
n = 137
0.43–5.78
n = 87
0.74–5.7
Bocos-Terraz et al. [17], 2009
Spain
1198
cross-sectional
2.5th, 97.5th
n = 481
0.03–2.65
n = 243
0.12–2.64
n = 297
0.23–3.56
Yu et al. [14], 2010
China
538
cohort
2.5th, 97.5th
n = 301
0.02–3.65
n = 301
0.36–3.46
n = 301
0.44–5.04
Yan et al. [18], 2011
China
505
cross-sectional
2.5th, 97.5th
n = 168
0.03–4.51
n = 168
0.05–4.5
n = 169
0.47–4.54
Azizi et. al, 2012 [19]
Iran
261
cohort
5th, 95th
n = 216
0.2–3.9
n = 216
0.5–4.1
n = 216
0.6–4.1
Haddow et al. [20], 2004
USA
1126
cohort
5th, 95th
n = 1005
0.08–2.73
n = 1005
0.39–2.70
—
United Arab Emirates
1140
cross-sectional
—
United Arabs
0.06–8.3, n = 97
other Arabs 0.04–9.3, n = 122
Asians
0.12–7.4, n = 79
United Arabs
0.17–5.9
other Arabs
0.23–5.7
Asians
0.3–5.5
—
Lambert-Messerlian et al. [22], 2008
USA
9562
cohort
98th, 2th
n = 9562
0.13–4.15
n = 9562
0.36–3.77
—
Santiago et al. [23], 2011
Spain
429
cross-sectional
97th, 3th
n = 279
0.23–4.18
n = 210
0.36–3.89
—
Karakosta et al. [24], 2011
Greece
425
cohort
2.5th, 97.5th
n = 143
0.05–2.53
n = 260
0.18–2.73
—
Stricker et al. [15], 2007
Dhatt et al. [21], 2006
J Thyroid Res. 2013; 2013: 651517.
Published online Jun 9,
2013. doi: 10.1155/2013/651517
• 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 US to achieve
this level of daily intake, the ATA recommends that women from the US
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 US .
The tolerable upper intake amount for iodine, as established by European
and US expert committees, ranges from 600 to 1100 mcg daily for adults and
pregnant women >19 years of age.
Guidelines of the American Thyroid Association
for the Diagnosis and Management of Thyroid Disease
During Pregnancy and Postpartum
The American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum
Alex Stagnaro-Green (Chair),1 Marcos Abalovich,2 Erik Alexander,3 Fereidoun Azizi,4 Jorge Mestman,5
Roberto Negro,6 Angelita Nixon,7 Elizabeth N. Pearce,8 Offie P. Soldin,9
Scott Sullivan,10 and Wilmar Wiersinga11
What is the normal range for TSH
in each trimester
RECOMMENDATION 1
• Trimester-specific reference ranges for TSH, as defined in populations
with optimal iodine intake, should be applied.
RECOMMENDATION 2
• If trimester-specific reference ranges for TSH are not available in the
laboratory, the following reference ranges are recommended:
1- first trimester, 0.1–2.5 mIU/L;
2-second trimester, 0.2–3.0 mIU/L;
3- third trimester, 0.3–3.0 mIU/L.
• RECOMMENDATION 3
-The optimal method to assess serum FT4 during pregnancy is measurement
of T4 in the dialysate or ultrafiltrate of serum samples employing on-line
extraction/liquid chromatography/tandem mass spectrometry (LC/MS/MS).
• Level A
• RECOMMENDATION 4
-If FT4 measurement by LC/MS/MS is not available, clinicians should use
whichever measure or estimate of FT4 is available in their laboratory, being
aware of the limitations of each method. Serum TSH is a more accurate
indication of thyroid status in pregnancy methods. Level A
definitions of OH and SCH in pregnancy?
• Elevations in serum TSH during pregnancy should be defined using
pregnancy-specific reference ranges.
• OH is defined as an elevated TSH (>2.5 mIU/L) in conjunction with a
decreased FT4 concentration.
• Women with TSH levels of 10.0 mIU/L or above, irrespective of their
FT4 levels, are also considered to have OH.
• SCH is defined as a serum TSH between 2.5 and 10 mIU/L with a
normal FT4 concentration.
• How is isolated hypothyroxinemia defined in pregnancy?
Normal maternal TSH concentration in conjunction with FT4
concentrations in the lower 5th or 10th percentile of the reference
range.
Should isolated hypothyroxinemia
be treated in pregnancy?
• ATA:
• To date, no randomized, interventional trial of LT4 therapy has been
performed in pregnant women with isolated hypothyroxinemia.
• As limited data exist suggesting harm from isolated hypothyroxinemia
and no interventional data have been published, the committee does not
recommend therapy for such women at present.
RECOMMENDATION :
• Isolated hypothyroxinemia should not be treated in pregnancy.
Level C-USPSTF
• Antenatal Thyroid Screening and Childhood Cognitive Function
• John H. Lazarus, M.D., Jonathan P. Bestwick, M.Sc., Sue Channon,
D.Clin.Psych., Ruth Paradice, Ph.D., Aldo Maina, M.D., Rhian Rees,
M.Sc., Elisabetta Chiusano, M.Psy., Rhys John, Ph.D., Varvara
Guaraldo, M.S.Chem., Lynne M. George, H.N.C., Marco Perona,
M.S.Chem., Daniela Dall'Amico, M.D., Arthur B. Parkes, Ph.D.,
Mohammed Joomun, M.Sc., and Nicholas J. Wald, F.R.S.
• N Engl J Med 2012; 366:493-501February 9, 2012DOI:
10.1056/NEJMoa1106104
Randomization and
Follow-up of the Study
Participants. The women
were recruited from 10
centers in the United
Kingdom and 1 center in
Italy. Exclusion criteria
were an age of less than
18 years, a gestational
age of more than 15
weeks 6 days, twin
pregnancies, and known
thyroid disease.
On receipt of samples,
women were randomly
assigned with the use
of a computergenerated block design
to the screening or
control group.
In the United Kingdom, levels of serum
thyrotropin and free T4 were measured
with the use of
immunochemiluminescence (ADVIA
Centaur, Siemens Healthcare Diagnostics).
The 95% range of thyrotropin levels was
0.15 to 3.65 mIU per liter, and the 95%
range of free T4 levels was 8.4 to 14.6
pmol per liter (0.65 to 1.13 ng per
deciliter).
In Turin, levels of serum thyrotropin and
free T4 were measured with the use of an
immunofluorescence method
(AutoDELFIA, PerkinElmer Life and
Analytical Sciences). The 95% ranges of
thyrotropin and free T4 were 0.11 to 3.50
mIU per liter and 7.15 to 11.34 pg per
milliliter, respectively.
• Patients in the screening group who had positive results were treated
with levothyroxine (recommended starting dose, 150 μg per day).
• Levels of thyrotropin and free T4 were checked 6 weeks after the start
of levothyroxine therapy and at 30 weeks' gestation, with adjustment
of the dose as necessary.
• The target thyrotropin level was 0.1 to 1.0 mIU per liter.
no significant difference in IQ scores
between 3-year-old children born to women
who were randomly assigned to the
screening group at about 12 weeks' gestation
and treated for reduced thyroid function
before 20 weeks' gestation (median, 13
weeks 3 days) and children born to women
with reduced thyroid function who were
randomly assigned to the control group.
There were also no significant betweengroup differences in analyses limited to the
women who adhered to treatment.
• Current guidelines do not recommend routine antenatal screening for
hypothyroidism in pregnancy.
• This study provides support for these guidelines, since they found no
benefit of routine screening for maternal hypothyroidism at about 12
to 13 weeks' gestation in the prevention of impaired childhood
cognitive function.
• Because of insufficient evidence to support universal TSH screening in
the first trimester, most professional societies, including the ATA, the
Endocrine Society, and the American College of Obstetricians and
Gynecologists (ACOG) recommend targeted case finding rather than
universal screening.
•
-
The ATA recommends measurement of serum TSH in pregnant women if:
they are symptomatic
from an area of known moderate to severe iodine insufficiency
have a family or personal history of thyroid disease
thyroid peroxidase antibodies (TPOAb)
type 1 diabetes
history of preterm delivery or miscarriage
history of head or neck radiation
morbid obesity (BMI ≥40 kg/m2)
infertility
age >30 years
• Levothyroxine treatment in euthyroid pregnant women with
autoimmune thyroid disease: effects on obstetrical complications.
• AUNegro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H
• SOJ Clin Endocrinol Metab. 2006;91(7):2587. This was a prospective
study. A total of 984 pregnant women were studied from November
2002 to October 2004; 11.7% were thyroid peroxidase antibody
positive (TPOAb(+)).
INTERVENTION: TPOAb(+) patients were divided into two groups:
group A (n = 57) was treated with LT(4),
group B (n = 58) was not treated.
The 869 TPOAb(-) patients (group C) served as a normal population control group.
MAIN OUTCOME MEASURES: Rates of obstetrical complications in treated and untreated groups were measured.
RESULTS: At baseline, TPOAb(+) had higher TSH compared with TPOAb(-);
TSH remained higher in group B compared with groups A and C throughout gestation.
Free T(4) values were lower in group B than groups A and C after 30 wk and after parturition.
Groups A and C showed a similar miscarriage rate (3.5 and 2.4%, respectively), which was lower than group B
(13.8%) [P<0.05; relative risk (RR), 1.72; 95% confidence interval (CI), 1.13-2.25; and P<0.01; RR = 4.95; 95% CI =
2.59-9.48, respectively].
Group B displayed a 22.4% rate of premature deliveries, which was higher than group A (7%) (P<0.05; RR = 1.66;
95% CI = 1.18-2.34) and group C (8.2%) (P<0.01; RR = 12.18; 95% CI = 7.93-18.7).
CONCLUSIONS: Euthyroid pregnant women who are positive for TPOAb develop impaired thyroid function, which is
associated with an increased risk of miscarriage and premature deliveries. Substitutive treatment with LT(4) is able
to lower the chance of miscarriage and premature delivery.
ATA Guidelines:
• Euthyroid women (not receiving LT4) who are Tab +ve require
monitoring for hypothyroidism during pregnancy.
• Serum TSH should be evaluated every 4 weeks during the
first half of pregnancy and at least once between 26 and 32
weeks gestation.
Level B
ATA Guidelines:
• In women being treated with ATDs in pregnancy, FT4 and TSH should
be monitored approximately every 2–6 weeks.
• The primary goal is a serum FT4 at or moderately above the normal
reference range. Level B
ATA Gidelines:
• Thyrotoxic women should be rendered euthyroid before attempting
pregnancy. Level A
• PTU is preferred for the treatment of hyperthyroidism in the first
trimester. Patients on MMI should be switched to PTU if pregnancy is
confirmed in the first trimester.
• Following the first trimester, consideration should be given to
switching to MMI.
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