subclinical hypothyroidism in pregnancy

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

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

29. Overt/subclinical hypothyroidism
Before pregnancy
Adjustment of LT4 dose During pregnacy
Goal: TSH level <2.5 mIU/l
Thyroid function tests should be
normalised as rapidly as possible
TSH :2.5-3.0 mIU/L

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

31. Thank you
Institute of Medicine Report, November 2010