Hypothyroidism in pregnancy

Nor Shaffinaz Yusoff Azmi Jabatan Perubatan Hospital Sultanah Bahiyah Kedah

Agenda

1. Epidemiology and clinical characteristics of maternal hypothyroidism

2. Prevention and management of fetal hypothyroidism 3. Summary

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Up to 3% of pregnancies are complicated by hypothyroidism

Most cases (2.0–2.5% of all pregnancies) are due to subclinical hypothyroidism

0.3–0.5% of cases are due to overt hypothyroidism

How common is hypothyroidism during pregnancy?

Overt hypothyroidism

3 Männistö T. Expert Rev Endocrinol Metab 2013;8:537-47.

Subclinical hypothyroidism

Local estimates of trimester-specific reference ranges for TSH should be available, as these vary between populations

If no local reference range is available, international guidelines suggest the following:

Trimester-specific reference ranges for TSH during pregnancy

Trimester US guideline (reference range) EU guideline

(upper limit of normal)

1st 0.1–2.5 mU/L 2.5 mU/L

2nd 0.2–3.0 mU/L 3.0 mU/L

3rd 0.3–3.0 mU/L 3.5 mU/L

4 Stagnaro-Green A et al. Thyroid 2011;21:1081-125; Lazarus J et al. Eur Thyroid J 2014;3:76-94.

Local estimates of trimester-specific reference ranges for fT4 should also be available

Overt hypothyroidism occurs where TSH is above the reference range (>2.5 mU/L) with reduced levels of fT4

TSH >10 mU/L signifies overt hypothyroidism whatever the T4 level

Subclinical hypothyroidism occurs where TSH is >2.5 mU/L but <10 mU/L, with normal T4

Diagnosing hypothyroidism in pregnancy

Condition Diagnostic criteria

Overt hypothyroidism

TSH with reduced fT4

TSH >10 mU/L irrespective of fT4

Subclinical hypothyroidism

TSH (but <10.0 mU/L) + normal fT4

5 Stagnaro-Green A et al. Thyroid 2011;21:1081-125; Lazarus J et al. Eur Thyroid J 2014;3:76-94.

Thyroid adaption to pregnancy

High oestrogen levels increase thyroxine binding globulin

More thyroid hormone binding capacity in serum Transient decrease in free thyroid hormones increases TSH

hCG levels peak near the end of the first trimester

hCG has thyroid stimulating activity

Passage of thyroid hormones through the placenta alters maternal thyroid hormone metabolism

Deiodination by placental type 3 iodothyronine deiodinase Increased maternal T4 turnover Especially important during the second half of the pregnancy

Stimulation of the mother’s thyroid gland

25–50% increase in LT4 requirement during pregnancy Increased iodine requirement during pregnancy

6 Glinoer D. Best Pract Res Clin Endocrinol Metab 2004;18:133-52.

New diagnosis:

Iodine-replete areas: autoimmune (Hashimoto’s) thyroiditis

Iodine-deficient areas: inadequate iodine intake

Pre-existing thyroid disease:

Inadequate iodine intake (iodine-deficient areas)

Euthyroid Hashimoto‘s thyroiditis (5-15% of all women)

Previous thyroid surgery

Previous radioiodine therapy

Secondary hypothyroidism (pituitary disease)

7 Männistö T. Expert Rev Endocrinol Metab 2013;8:537-547; Lazarus J et al. Eur Thyroid J 2014;3:76-94.

Main causes of hypothyroidism in pregnancy

Complications of hypothyroidism during pregnancy

8 Männistö T. Expert Rev Endocrinol Metab 2013;8:537-547; Lazarus J et al. Eur Thyroid J 2014;3:76-94.

Mother

Pre-eclampsia

Need for Caesarian

Gestational diabetes

Placental abruptions

Infertility

Miscarriage

anemia

Postpartum haemorrhage

Goitre

Child Malformations

Respiratory problems

Anaemia

Sepsis

Need for ICU treatment

Large or small for

gestational age

Pre-term delivery

Neurocognitive defects

It has been recognised for decades that maternal hypothyroidism results in impaired neuropsychological outcome for the offspring

Reduced IQ (long-term – demonstrated at ages up to 9 y)

Impaired performance on multiple neuropsychological tests

Impaired psychomotor development

Cretinism (associated with severe endemic hypothyroidism)

Even subclinical hypothyroidism damages the developing foetus

Mild increase in TSH in women predicted poorer function of offspring on all of 15 neuropsychological tests + average 7- point IQ reduction

Low T4 levels in apparently healthy women predict impaired neuropsychological development in offspring

Children of mothers with normal T4 but with anti-TPO antibodies are at risk of impaired neuropsychological

development

Increased risk of premature birth in mothers with subclinical hypothyroidism may contribute to impaired neuropsychological outcomes in offspring

9 Chan S et al. J Endocrinol 2000;165:1-8; Gharib H et al. Endocr Pract 1999;5:367-8; Casey BM et al. Obstet Gynecol 2005;105:239-45.

Adverse consequences of maternal hypothyroidism for the foetus

The thyroid gland in the developing foetus does not become active until the second trimester

Thus, maternal thyroid hormones are vital for supporting the development of the CNS in the

foetus

T3 and T4 are detectable in foetal brains before the developing thyroid gland becomes active

Maternal T4 remains correlated with T4 in the foetal cerebro-cortical areas of the brain even after the foetus begins making its own T4

30% of T4 in cord blood at term is derived from the mother

Intelligence of offspring in endemic hypothyroid areas correlates with the circulating T4 level of the mother

Compensatory mechanisms in the foetal brain are unlikely to counteract the adverse effect

of maternal hypothyroidism on the developing brain

Enhanced uptake of T4 in the foetal brain

Increased expression of deiodinases (which convert T4 to activeT3)

10 Chan S et al. J Endocrinol 2000;165:1-8; Gharib H et al. Endocr Pract 1999;5:367-8.

Maternal thyroid hormones and the child’s developing brain

10 y follow-up for prevalence of attention deficit/ hyperactivity disorder (ADHD) in regions with moderate vs. mild iodine deficiency1:

69% in an area of moderate iodine deficiency

0% in an area of mild iodine deficiency

Also, IQ was18 points lower for moderate vs. mild iodine deficiency

Prevalence of developmental delaya in offspring of mothers with mildly reduced T4 measured at age 18 mo – determined according to when received iodine supplementation2:

Iodine supplement at 4–6 gestational weeks: 0%

Iodine supplement at 12–16 gestational weeks: 25%

Iodine supplement delivery: 37%

aNeurocognitive performance measured using the Brunet-Lézine scale.

10 1. Vermiglio F et al. J Clin Endocrinol Metab 2004;89:6054-60; 2. Berbel P et al. Thyroid 2009;19:511-9.

Influence of iodide supply on neurocognitive development

Thyroid disease in pregnancy

Prevention and management of maternal hypothyroidism

1. Iodine replete regions

Developed nations

Effective salt iodization where necessary

• E.g. >90% of US households consume iodized salt

2. Iodine deficient regions

About 2 billion individuals live in iodine-deficient regions

Often in developing nations

Leading cause of hypothyroidism in these regions

Salt iodization programmes help, but it is difficult to reach remote areas

Continuing problem of endemic goitre and cretinism

Iodine deficiency is believed to be responsible for a loss of 13.5 IQ points in iodine-deficient regions

Iodine deficiency is the most common form or preventable brain damage in

children

Two worlds

13 World Health Organisation (2004).

Stagnaro-Green A et al. Thyroid 2011;21:1081-125; Lazarus J et al. Eur Thyroid J 2014;3:76-94; De Groot L et al.

Recommended levels of iodine intake for a woman who is pregnant, breast feeding or planning a pregnancy are:

Iodine requirements in pregnancy

Population ATA/AACE WHO and ETA ES

Planning

pregnancy

150 g/day 250 g/day 250 g/day

Pregnant 220 g/day 250 g/day 250 g/day

Breast-feeding 290 g/day 250 g/day 250 g/day

J Clin Endocrinol Metab, 2012;97: 2543-565.

AACE: American Association of Clinical Endocrinologists ATA: American Thyroid Association ES: Endocrine Society ETA: European thyroid Association WHO: World Health Organisation

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Stagnaro-Green A et al. Thyroid 2011;21:1081-125; Lazarus J et al. Eur Thyroid J 2014;3:76-94

De Groot L et al. J Clin Endocrinol Metab, 2012;97: 2543-565 Jodid® Prescribing Information.

European Thyroid Association:

150–250 g/day of iodine via a potassium iodide supplement

50 g/day of iodine via a potassium iodide supplement where salt iodization has been implemented successfully

Do not exceed 500 g/day iodine intake

American Thyroid Association/American Association of Clinical Endocrinologists:

150 -290 mg/day of iodine (potassium iodide) for all pregnant or lactating women

This is not widely achieved in the USA

Supplementation needs vary outside the USA according to the level of natural environmental iodide and salt iodization

Endocrine Society

250 mg/day of iodine (iodide or iodate) for all pregnant or lactating women

Indication for a potassium iodide supplement in pregnancy or lactation:

150-290 mg/day of iodine (iodide)

Iodine supplementation in iodine-deficient regions

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Use trimester-specific TSH ranges where available (see earlier slide)

Treat overt hypothyroidism in pregnancy

But do not treat isolated hypothyroxinaemia

Treat pregnant women with subclinical hypothyroidism only if they are positive for TPO Abs

Monitor patients with subclinical hypothyroidism regularly for progression to overt hypothyroidism

Use oral levothyroxine (not T3 or desiccated thyroid preparations)

Treat to normalise trimester-specific TSH

Women on levothyroxine should increase their dose by about 25–30% as soon as they suspect they are pregnant

Monitor TSH 4-weekly during the first half of the pregnancy (≥ once at 26–32 w)

Revert to the preconception dose after delivery

Measure TSH at about 6 w post-partum

Selenium supplementation is for TPO-Ab positive patients is not supported

Stagnaro-Green A et al. Thyroid 2011;21:1081-125.

Hypothyroidism: recommendations for pregnancy from ATA/AACE

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Treat pregnant patients with overt hypothyroidism (or subclinical hypothyroidism with anti-

TPO antibodies) with levothyroxine tablets

50–80% of women receiving oral levothyroxine need to increase their dosage during

pregnancy

More likely for women without functional thyroid tissue (e.g. after radioablation of the thyroid)

Prescribe 9 tablets/week instead of 7/week when pregnancy is first detected for women

already receiving levothyroxine

E.g. after the first missed menstrual period or positive pregnancy test

This strategy provides a 29% increase in dose

Avoids hypothyroidism in the first trimester

Mimics the natural increase in T4 during a normal pregnancy

Conduct confirmatory thyroid hormone testing immediately

Stagnaro-Green A et al. Thyroid 2011;21:1081-125

Prescribing levothyroxine in pregnancy according to US guidelines

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Summary

1. Physiological changes during pregnancy requires more iodine for

synthesis of thyroxine

2. Hypothyroidism causes both fetal and maternal complications

3. Thyroxine in the developing fetal brain is mainly by the maternal source

until delivery

4. Cretinism and lower IQ in the child can be prevented by ensuring

adequate iodine intake and normal range of TSH and FT4 during pre-

pregnancy, pregnancy and lactation period

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THANK YOU FOR YOUR ATTENTION

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