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 2
How common is hypothyroidism during pregnancy? 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 Overt hypothyroidism Subclinical hypothyroidism 3 Männistö T. Expert Rev Endocrinol Metab 2013;8:537-47.
Trimester-specific reference ranges for TSH during pregnancy 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 US guideline (reference range) EU guideline (upper limit of normal) 1st 0.1 2.5 mu/l 2.5 mu/l 2 nd 0.2 3.0 mu/l 3.0 mu/l 3 rd 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.
Diagnosing hypothyroidism in pregnancy 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 Condition Overt hypothyroidism Subclinical hypothyroidism Diagnostic criteria TSH with reduced ft4 TSH >10 mu/l irrespective of ft4 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.
Main causes of hypothyroidism in pregnancy 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.
Complications of hypothyroidism during pregnancy 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 8 Männistö T. Expert Rev Endocrinol Metab 2013;8:537-547; Lazarus J et al. Eur Thyroid J 2014;3:76-94.
Adverse consequences of maternal hypothyroidism for the foetus 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.
Maternal thyroid hormones and the child s developing brain 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 T 3 and T 4 are detectable in foetal brains before the developing thyroid gland becomes active Maternal T 4 remains correlated with T 4 in the foetal cerebro-cortical areas of the brain even after the foetus begins making its own T 4 30% of T 4 in cord blood at term is derived from the mother Intelligence of offspring in endemic hypothyroid areas correlates with the circulating T 4 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 T 4 in the foetal brain Increased expression of deiodinases (which convert T 4 to activet 3 ) 10 Chan S et al. J Endocrinol 2000;165:1-8; Gharib H et al. Endocr Pract 1999;5:367-8.
Influence of iodide supply on neurocognitive development 10 y follow-up for prevalence of attention deficit/ hyperactivity disorder (ADHD) in regions with moderate vs. mild iodine deficiency 1 : 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 delay a in offspring of mothers with mildly reduced T4 measured at age 18 mo determined according to when received iodine supplementation 2 : 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.
Thyroid disease in pregnancy Prevention and management of maternal hypothyroidism
Two worlds 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 13 World Health Organisation (2004).
Iodine requirements in pregnancy Recommended levels of iodine intake for a woman who is pregnant, breast feeding or planning a pregnancy are: 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 AACE: American Association of Clinical Endocrinologists ATA: American Thyroid Association ES: Endocrine Society ETA: European thyroid Association WHO: World Health Organisation 14 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.
Iodine supplementation in iodine-deficient regions 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) 15 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.
Hypothyroidism: recommendations for pregnancy from ATA/AACE 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 16 Stagnaro-Green A et al. Thyroid 2011;21:1081-125.
Prescribing levothyroxine in pregnancy according to US guidelines 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 T 4 during a normal pregnancy Conduct confirmatory thyroid hormone testing immediately 17 Stagnaro-Green A et al. Thyroid 2011;21:1081-125
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 prepregnancy, pregnancy and lactation period 18
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