Contemporary Management of Subclinical

Hypothyroidism During Pre-conception and

Pregnancy

Dilek Gogas Yavuz MDMarmara University School of Medicine

Section of Endocrinology and Metabolism

Physiologic Changes in Pregnancy

hCG stimulation of TSH-Receptors

Estrogen-mediated increase in circulating levels of TBG

•Increase in total serum T4 and Total T3 but no/minimal change in free T3 or T4 •serum TSH concentrations are appropriately reduced

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 fetoplacental unit, gravid uterus, and mother

↑ Basal metabolic rate; ↑ cardiac output

Hypermetabolic state

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

ATA guideline, Thyroid 21: 2011

TSH reference interval in nonpregnant women: 0.4-4 mIU/L

• The upper limit for total T3 and T4 levels in pregnancy may be estimated as 1.5 times the upper limit of the nonpregnant reference range for a given assay .

• Reference ranges for free T4 are method-specific, and trimester-specific reference ranges should be provided with the assay kit

Trimester-spesific reference ranges for Thyroid hormones

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.

TSH level should be

considered the most accurate

indicator of gestational

thyroid status

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)

Prevalance of eleveted TSH in pregnant women

Subclinical hypothyroidism :

2-2.5 %

Hypothyroidism: 0.3 -

0.5 %

Thyroid autoantibodies:

5-15 %.

Signs & Symptoms of Hypothyroidism Similar to symptoms of pregnancy; Vague and nonspecific Fatigue

Constipation Cold intolerance Muscle cramps Insomnia Weight gain Carpal tunnel

syndrome

Hair loss, Voice changes Intellectual

slowness +/- goiter Periorbital edema Dry skin Prolonged DTR

relaxation phase

Causes of Subclinical Hypothyroidism

SECONDARY (pituitary dysfunction)

• Hashimoto thyroiditis

• Endemic iodine deficiency

• History of ablative radioiodine therapy or thyroidectomy.

• Sheehan’s syndrome

• Lymphocytic hypophysitis

• history of a hypophysectomy.

PRIMARY (thyroid dysfunction)

Untreated HypothyroidismAssociated with Increased Risk of:

Maternal Fetal Preeclampsia gestational

hypertension Placental abruption Preterm delivery, very

preterm delivery (<32 weeks)

Increased rate of caesarean section

Postpartum hemorrhage

Preterm birth Low birth weight Perinatal morbidity and

mortality Increased NICU

admission Neuropsychological

and cognitive impairment: Congenital cretinism

– growth restriction, deafness, neuropsych impairment from severe Iodine deficiency or untreated congenital 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

The risk is greatest in overt hypothyroidism compared to subclinical

hypothyroidism

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

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 HEALTHLazarus J et al. Controlled Antenatal Thyroid Screening (CATS) Study.

vigorous debate is ongoing on the pros and cons of trating subclinical

hypothyroidism during pregnancy

Universal Screen Case Finding0

0.5

1

1.5

2

0.7 0.7

com

plicati

ons/p

ati

ent

Universal Screening vs Case Finding for Detection and Treatment of Thyroid

Dysfunction During Pregnancy

Negro R et alJ Clin Endocrinol Metabolism 2010 95:1699

NO BENEFIT to pregnancy outcome

Aim: the potential

reduction in

pregnancy

associated adverse

effects after LT4

treatment in

hypothyroid women

vs case finding

hypothyroid women

not receiving LT4Rx

Maternal Hypothyroidism and Cognitive development

John Lazarus ITC 2010

NO difference in IQ scores

100 99

0

20

40

60

80

100

120

IQ s

core

Universal Screen Control

• Controlled antenatal

thyroid screening study

• 22,000 women: ½

screened (TSH, FT4) at

mean 12.5 weeks

gestation, ½ not

screened

• Intervention: LT4

0.15mg/day if TSH

>2.5mIU/L

• Outcome: IQ testing at

3 years

OH SCH

Subclinical hypothyroidism was associated with increased fetal distress, preterm delivery,Poor vision development

and neurodevelopmental delay.

J Clin Endocrinol Metab, October 2011, 96(10):3234–3241

Should subclinical hypothyroidism be treated in pregnancy?

2011 – YES but ......

2010- NO

2012 – YES for all pregnant SCH

2012 – YES for all pregnant SCH

Optimal treatmentOral Levothytoxin (LT4)

Goal:normalise maternal serum TSH vlaues within the trimester spesific pregnancy reference range

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.

First Trimester : 0.1-2.5 mIU/L

Second trimester : 0.2-3 .0 mIU/L

Third trimester: 0.3- 3.0 mIU/L

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 m/d is recommended

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%

Hypothyroid women : pre conception

Levothyroxine titration for women with known hypothyroidism during preganancy

• 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

One option: take two additional LT4 pills/week

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

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.

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

Insufficient evidence to recommend

universal screening for thyroid disease in

pregnant women

Universal screening did not result a

decrease in adverse outcomes.

• 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 contrastAmerican Thyroid Association 2011

Serum TSH values should be obtained early in pregnancy in the following women at high risk of hypothyroidism:

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

Before pregnancy

Adjustment of LT4 doseGoal: TSH level <2.5 mIU/l

During pregnacy

Thyroid function tests should be normalised as rapidly as possibleTSH :2.5-3.0 mIU/L

Overt/subclinical hypothyroidism

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

Institute of Medicine Report, November 2010

Thank you