1. Contemporary Management of
Subclinical Hypothyroidism
During Pre-conception and
Pregnancy
Dilek Gogas Yavuz MD
Marmara University School of Medicine
Section of Endocrinology and Metabolism
2. Physiologic Changes in Pregnancy
Estrogen-mediated increase in
circulating levels of TBG
hCG stimulation of TSH-
Receptors
•Increase in total serum T4 and Total T3 but no/minimal change in free T3 or T4
•serum TSH concentrations are appropriately reduced
3. Effects Of Pregnancy
On Thyroid Physiology
Physiologic Change Thyroid-Related Consequences
↑ Serum thyroxine-binding globulin ↑ Total T4 and T3; ↑ T4 production
↑ Plasma volume ↑ T4 and T3 pool size; ↑ T4 production; ↑
cardiac output
D3 expression in placenta ↑ T4 production
First trimester ↑ in hCG ↑ Free T4; ↓ basal thyrotropin; ↑ T4
production
↑ Renal I- clearance ↑ Iodine requirements
↑ T4 production; fetal T4 synthesis
during second and third trimesters
↑ Oxygen consumption by ↑ Basal metabolic rate; ↑ cardiac output
fetoplacental unit, gravid uterus, and
mother
4. Trimester-spesific reference
ranges for TSH
TSH (mIU/L) lower limit upper limit
First trimester 0.1 2.5
Second trimester 0.2 3.0
Third trimester 0.3 3.0
TSH reference interval in nonpregnant women: 0.4-4 mIU/L
ATA guideline, Thyroid 21: 2011
5. Trimester-spesific reference
ranges for Thyroid hormones
• The upper limit for total T3 and T4 levels in
pregnancy may TSH level as 1.5 times the
be estimated
upper limit of thebe considered the
should nonpregnant reference range
for a given most accurate indicator
assay .
of gestational
thyroid status
• Reference ranges for free T4 are method-
specific, and trimester-specific reference ranges
should be provided with the assay kit
The measurement of free T3 and T4 levels in pregnancy is difficult, owing to a high
circulating level of TBG and a decreased level of circulating albumin, which might
decrease the reliability of immunoassays.
6. Definitions:
Hypothyroidism: An eleveted TSH in conjuction
with a decreased fT4 concentration
Subclinical hypothyroidism: Serum TSH
concentration above the upper limit of the
trimester-spesific reference range with normal T4
(TSH:2.5-10 mIU/L and normal T4)
7. Prevalance of eleveted TSH
in pregnant women
Subclinical hypothyroidism : 2-2.5 %
Hypothyroidism: 0.3 - 0.5 %
Thyroid autoantibodies: 5-15 %.
8. Signs & Symptoms of Hypothyroidism
Similar to symptoms of pregnancy; Vague and nonspecific
Fatigue Hair loss,
Constipation Voice changes
Cold intolerance Intellectual slowness
Muscle cramps +/- goiter
Insomnia Periorbital edema
Weight gain Dry skin
Carpal tunnel syndrome Prolonged DTR
relaxation phase
9. Causes of Subclinical Hypothyroidism
PRIMARY SECONDARY
(thyroid dysfunction) (pituitary dysfunction)
• Hashimoto thyroiditis
• Sheehan’s syndrome
• Endemic iodine
deficiency • Lymphocytic
hypophysitis
• History of ablative
radioiodine therapy or • history of a
thyroidectomy. hypophysectomy.
10. Untreated Hypothyroidism
Associated with Increased Risk of:
Maternal Fetal
Preeclampsia Preterm birth
Low birth weight
gestational
Perinatal morbidity and
hypertension
mortality
Placental abruption Increased NICU admission
Preterm delivery, very Neuropsychological and
preterm delivery (<32 cognitive impairment:
weeks) Congenital cretinism –
Increased rate of growth restriction,
deafness, neuropsych
caesarean section
impairment from severe
Postpartum hemorrhage Iodine deficiency or
untreated congenital
hypothyroidism
11. The risk is greatest in overt hypothyroidism
compared to subclinical hypothyroidism
Subclinical Overt
Hypothyroidism
Spontaneous abortion 10-70% 60%
Preeclampsia 0-17% 0-44%
Abruption 0% 0-19%
Stillbirth/fetal loss 0-3% 0-12%
Anemia 0-2% 0-31%
Postpartum hemorrhage 0-17% 0-19%
Preterm birth 0-9% 20-31%
1Montoro et al, Ann Intern Med 1981; 2Davis et al, Obstet Gynecol 1988; 3Leung et al,Obstet Gynecol 1993; 4Wasserstrum et al, Clin
Endocrinol 1993; 5Glinoer, Thyroid Today, 1995,6Allan et al, J Med Screen 2002; 7Abalovich et al, Thyroid 2002; 8Stagnaro-Green et
al, Thyroid, 2005; 9Sahu et al, Arch Gynecol Obstet 2009L,aFranchi, Thyroid 2005
12.
13. Should hypothyroidism be treated in
pregnancy?
Treatment of overt hypothyroidism during pregnancy is mandatory
TSH ↑ and T4 ↓
TSH >10 mIU/L irrespective level of T4
no prospective randomised controlled trials of LT4 intervention
Overt hypothyroidism is associated with an increased risk of
miscarriage and preterm delivery, as well as decreased IQ and
low birth weight in offspring
NATURE REVIEWS | ENDOCRINOLOGY, Nov 2012
14. vigorous debate is ongoing on the pros and cons of
trating subclinical hypothyroidism during pregnancy
MATERNAL HEALTH
Negro R et al, Universal Screening vs Case Finding
for Detection and Treatment of Thyroid Dysfunction
During Pregnancy, J Clin Endocrinol Metabolism
2010 95:1699
FETAL HEALTH
Lazarus J et al. Controlled Antenatal
Thyroid Screening (CATS) Study.
15. Universal Screening vs Case Finding for Detection and
Treatment of Thyroid Dysfunction During Pregnancy
NO BENEFIT to pregnancy outcome
2
Aim: the potential
reduction in pregnancy complications/patient
1.5
associated adverse effects
after LT4 treatment in 1 0.7 0.7
hypothyroid women vs
0.5
case finding hypothyroid
women not receiving 0
LT4Rx Universal Screen Case Finding
Negro R et alJ Clin Endocrinol Metabolism 2010 95:1699
16. Maternal Hypothyroidism and Cognitive
development
NO difference in IQ scores
• Controlled antenatal thyroid
screening study 120
• 22,000 women: ½ screened 100
(TSH, FT4) at mean 12.5 weeks 80 100 99
IQ score
gestation, ½ not screened 60
• Intervention: LT4 0.15mg/day 40
if TSH >2.5mIU/L 20
• Outcome: IQ testing at 3 years 0
Universal Screen Control
John Lazarus ITC 2010
17. Subclinical hypothyroidism was associated with increased fetal
distress, preterm delivery,Poor vision development and neurodevelopmental
delay. OH SCH
J Clin Endocrinol Metab, October 2011, 96(10):3234–3241
18. Should subclinical hypothyroidism
be treated in pregnancy?
2010- NO
2011 – YES but ......
2012 – YES for all pregnant SCH
2012 – YES for all pregnant SCH
19. Optimal treatment
Oral Levothytoxin (LT4)
Goal:normalise maternal serum TSH vlaues within the
trimester spesific pregnancy reference range
First Trimester : 0.1-2.5 mIU/L
Second trimester : 0.2-3 .0 mIU/L
Third trimester: 0.3- 3.0 mIU/L
Levothyroxine ingestion should be separated from prenatal vitamins
containing iron, iron and calcium supplements and soy products by at
least 4 hours to ensure adequate absorption.
20. Hypotiroidism diagnosed during
pregancy
Overt hypothyroid: if treatment naive, begin LT4
at 100-125mU/L or 1-2mcg/kg/day
If TSH concentration is 2.5-10 mIU/L a starting
levothyroxine dose of 50 /d is recommended
21. Hypothyroid women : pre conception
Pre conception education of hypothyroid women and
optimization of LT4 dosage
Check thyroid function tests as soon as pregnancy confirmed
Increased LT4 dosage required in majority of woman
Average dose increase about 30%
22. Levothyroxine titration for women with
known hypothyroidism during preganancy
One option: take two additional LT4 pills/week
• Adjust levothyroxine in 25-50mcg increments
with goal TSH 0.5- 2.5-3.0 mU/L
• TIMING for increase as early at 7-8 weeks gestation
23. pregnant hypothyroid women who taking LT4:
monitorising
TSH levels need to be evaluated every 4 weeks during the
first 20 weeks of gestation
measured at least once during the second half of pregnancy
more frequently if euthyroidism has not been achieved.
Check TSH 4-6 weeks after each dose adjustment
Yassa J Clin Endocrinol Metab 2010 95:3234
24. Levothyroxine Drug Facts
Pregnancy: Category A
Breastfeeding: Safe
Not contraindicated. Levothyroxine is excreted
into breastmilk in small quantities
Drug interactions:
Interfere w/absorption:
Iron salts, Antacids, Calcium salts
Separate ingestion by >4 hours.
25. Isolated maternal hypothyroxinemia
normal TSH
free T4 below 0.86 ng/dl.
In the first half of pregnancy,
prevalence 1.3%.
not associated with adverse perinatal
outcome
26. Universal screening did not
result a decrease in adverse
outcomes.
Insufficient evidence to
recommend universal
screening for thyroid disease
in pregnant women
27. Serum TSH values should be obtained early in pregnancy in
the following women at high risk of hypothyroidism:
• Age >30 years
• Family history of thyroid disease
• Symptoms of thyroid dysfunction or the presence of goitre
• History of thyroid dysfunction or prior thyroid surgery
• Prior therapeutic head or neck irradiation
• Positive results of TPO autoantibody testing
• T1DM or other autoimmune disorders
• Infertility
• History of miscarriage or preterm delivery
• Morbid obesity (BMI ≥40 kg/m2)
• Residence in an area of known moderate-to-severe iodine deficiency
• Use of amiodarone or lithium, or recent administration of iodinated
radiologic contrast
American Thyroid Association 2011
28. Thyroid autoimmunity
Anti TPO ab (+) or Anti TG Ab (+)
• Who are euthyroid in the early stages of pregancy
are at risk of developing Subclinical /overt
hypothyroidism.
• Should be monitored every 4-6 week for elevation
of TSH above the normal range of pregnancy
30. Universal screening of heathy women for thyroid
dysfunction is not recommended
high risk individuals for thyroid illness
should be screened with prenatal TSH
Universal screening for the presence of anti TPO
anibodies is not recommended
As an endcorinogist I observe an increase number of consultasion for abnormal thyroid function test in pregnant women Pregnancy has a considerable effect on maternal thyroid function. And turkey is in iodine deficient area During the first trimester of pregnancy, maternal serum TSH levels are significantly lower than prepregnancy levels as a result of cross-reactivity of human chorionic gonadotropin (hCG), which is secreted by the placenta, to the TSH receptor on the thyroid gland.The pattern of changes in serum concentrations ofthyroid function studies and hCG according to gestationalage. The shaded area represents the normal range ofthyroid-binding globulin, total thyroxine, thyroid-stimulatinghormone or free T4 in the nonpregnant woman.TBG,thyroid-binding globulin; T4, thyroxine; TSH, thyroid-stimulatinghormone. Modified from Brent GA. Maternal thyroidfunction: interpretation of thyroid function
Significant but reversible changes thyrıid hormone metabolism aims to meet the increased metabolilic needs during pregnancy.
Consequently thyroid function test results of healthy pregnant women differ than those of healthy non pregnant women.thyroid function tests should be interpreted usingpregnancy spesific or trimester-specific TSH and T4 reference ranges for pregnant women. Reference range of TSH lower throughout the pregnancy. upper limit of normal for TSH in the first trimester of pregnancy is approximately 2.5 otal T4 and T3 levels during pregnancy are 1.5-fold higher than in nonpregnant women. Reference ranges for free T4 are method-specific, and trimester-specific reference ranges should be provided with the assay kit
subclinical hypothyroidism represents early, mild thyroid failureSubclinical hypothyroidism is more common in iodinesufficient countriesWomen with TSH levels of 10 or above irrespective of their ft4 levels ara also considered to have OH.SCH is defined as a serum TSH between 2.5-10 with normal t4 concentration
İt wouldbe anticipated that the such percenteges would be higher in areas of iodine insufficiency
The symptoms of hypothyroidism are neither sensitivenor specifi c.Work up any woman with symptoms or personal history of thyroid disease
Subclinical hypothyroidism is more common in iodinesufficient countriesSubclinical hypothyroidism is more common in iodinesufficient countries, and iodine supplementation mightincrease the incidence
Hypothyroidism has been shown to be associated with an increased risk of adverse maternal and fetal outcomes.he risk of these complications is greater in women with overt, rather than subclinical, hypothyroidism.NBS: 1/4000 w/ congenital cretinism. First few days usually mom’s hormones are still present.gHTN – strong associated b/t inadequately treated hypothyroidism and pre-eclampsia;that it is an acceptable cause of reversible HTN in the non-pregnant population as wellControversial whether subclinical hypothyroidism carries this risk…
the risk of these complications is greater in women with overt, rather than subclinical, hypothyroidism.Overt hypothyroidism is associated with an increased risk of miscarriage and preterm delivery, as well as decreased IQ and low birthweight in offspringThe risk of complications during pregnancy is lower in women with subclinical, rather than overt hypothyroidism. However, in some studies, women with subclinical hypothyroidism were also reported to be at increased risk for severe preeclampsia, preterm delivery, and/or pregnancy loss It is uncertain if the children of women with subclinical hypothyroidism are at risk for neuropsychological impairment.subbclinical hypothyroidism is associated with an increased risk of pregnancy complicationsHypothyroidism can have adverse effects on pregnancy outcomes, depending upon the severity of the biochemical abnormalities.
of miscarriage and preterm delivery, as well as decreased IQ and low birthweight in offspring.14,16 Treatment of overt hypothyroidism during pregnancy is, therefore, mandatory and consists of levothyroxine therapy adjusted to achieve a normal trimester-specific serum TSH level. whereas treatment for subclinical hypothyroidism in pregnancy remains controversial
vigorous debate is ongoing on the pros and cons of trating subclinical hypothyroidism during pregnancy
Subclinical hypothyroidism is also associated with an increased risk of miscarriage and preterm delivery, and decreased IQ in offspring.7,15,18,19 However, treatment of subclinical hypothyroidism is not universally advocated, as only one study has shown that such treatment decreases the occurrence of adverse events in the mother and fetusSCH may be associated with an adverse outcomefor both the mother and offspring. In retrospective studies,and in prospective studies on women with SCH and TPOAb, T4 treatment improved obstetrical outcome, but ithas not been proved to modify long-term neurological development in the offspring
TSH monitor required in pregnancy.In women being treated with levothyroxine before becoming pregnant, TSH levels need to be evaluated every 4 weeks during the first 20 weeks of gestation and should be measured at least once during the second half of pregnancy,26 and more frequently if euthyroidism has not been achieved.