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subclinical hypothyroidism in pregnancy
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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
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