Published Online December 23, 2010 Thyroid function in pregnancy John H. Lazarus * Centre for Endocrine and Diabetes Sciences, Cardiff University School of Medicine, University Hospital of Wales, Heath Park, Cardiff CF14 4XN, UK Introduction *Correspondence address. Centre for Endocrine and Diabetes Sciences, Cardiff University School of Medicine, University Hospital of Wales, Heath Park, Cardiff CF14 4XN, UK. E-mail: lazarus@cf.ac.uk Advances in understanding the physiology of thyroid function in normal pregnancy have highlighted the importance of the consequences of abnormal function on obstetric outcome and foetal well-being. Pubmed search was done using the terms thyroid and pregnancy. Areas of agreement are the following: gestational normative reference ranges for thyroid function tests are required for proper interpretation of any abnormalities. Measurement of thyroid-stimulating antibodies and antithyroid peroxidase antibodies is useful for diagnosis of thyroid disease in pregnancy. Treatment of Graves hyperthyroidism should be done with propylthiouracil for first trimester only, then carbimazole or methimazole. Patients on levothyroxine require an increase in dosage during gestation. Areas of controversy are the following: total thyroxine (TT4) versus Free T4 (FT4) assays in pregnancy. Screening for thyroid function in early gestation: should it be routinely performed on everyone? What tests are appropriate? Growing points are the following: physiology of thyroxine delivery to the foetus. Establishment of gestational thyroid hormone reference ranges. Evaluation of strategies to screen thyroid function in early pregnancy. Areas timely for developing research are the following: placental thyroid hormone physiology, thyroid hormone therapy and screening thyroid function. Keywords: thyroid function testing/hyperthyroid/hypothyroid/screening/ neurodevelopment Accepted: November 29, 2010 During the last 20 years, it has been appreciated that thyroid physiology changes significantly during gestation. 1 Advances in the assessment of thyroid function also have indicated that interpretation of thyroid function tests depend on the stage of pregnancy. Thyroid disorders are prevalent in women of child-bearing age and for this reason commonly present in pregnancy and the puerperium. 2 Uncorrected thyroid dysfunction in pregnancy has adverse effects on foetal and maternal well-being. The deleterious effects of thyroid dysfunction also British Medical Bulletin 2011; 97: 137 148 DOI:10.1093/bmb/ldq039 & The Author 2010. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
J. H. Lazarus extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. This review will focus on thyroid function in pregnancy followed by a discussion of thyroid dysfunction and its effects. Thyroid physiology and function in normal pregnancy Pregnancy has an appreciable effect on thyroid economy. 1 There is an increased excretion of iodine in the urine accounting for the increase in thyroid volume in areas of moderate and severe deficiency but not in iodine-sufficient regions. Iodine deficiency during pregnancy is associated with maternal goitre and reduced maternal thyoxine (T4) level, which is seen in areas of endemic cretinism. 3 A recommended daily iodine intake of 250 mg/day (suggested by a WHO consultation) represents an increase from the previous figure of 200 mg/day. In the pregnant woman, a median urinary iodine (UI) of 150 mg/l is regarded as insufficient, an excretion of 150 249 as adequate, that of 250 499 as more than adequate and 500 as excessive. 4 Thyroid hormone transport proteins particularly thyroxine-binding globulin (TBG) increase due to enhanced hepatic synthesis and a reduced degradation rate due to oligosaccharide modification. Serum concentration of thyroid hormones has been reported to be decreased, increased or unchanged during gestation by different groups depending on the assays used. Assays employing total T4 show a result approximately 1.5 times the non-pregnant value. There is general consensus that there is a transient rise in FT4 in the first trimester due to the relatively high circulating human chorionic gonadotrophin (hcg) concentration and a decrease of FT4 in the second and third trimester albeit within the normal reference range. 5 Changes in free triiodothyronine (FT3) concentration are also seen in which they broadly parallel the FT4, again within the normal range. The precise reason for the decline in free thyroid hormones is not clear but the interaction of thyroidstimulating hormone (TSH), oestrogen and thyroid-binding proteins is of importance. 1 In iodine deficient areas, hypothyroxinaemia with preferential T3 secretion may occur accompanied by a rise in median TSH and serum thyroglobulin (Fig. 1). It is probable that the changes in thyroid hormone during gestation relate to the necessity of delivering thyroxine to the foetal cells, particularly neuronal cells. Adequate concentrations of T4 are essential for neural development and this T4 can only be maternally derived from, at least during the first trimester. The placenta plays an important role in T4 transport, although details are still unclear. 138 British Medical Bulletin 2011;97
Thyroid function in pregnancy Fig. 1 Gestational variation in thyroid function in normal women. Data from 606 normal pregnancies showing the rise in TBG (top panel) accompanied by the changes in FT4 and FT3 concentrations throughout gestation in a mildly iodine deficient area (Brussels). The lower 2 panels show the relationship between serum TSH and hcg as a function of gestational age and the relation between FT4 and hcg in the first half of gestation. Adapted from Glinoer, DG (1997) 1 with permission. The placenta secretes hcg, a glycoprotein hormone sharing a common alpha subunit with TSH but having a unique beta subunit, which confers specificity. hcg, or a molecular variant, acts as a TSH agonist so that elevated levels contribute to the cause of gestational transient hyperthyroxinaemia seen in about 0.3% of pregnancies. Hyperemesis gravidarum, which sometimes requires hospitalization British Medical Bulletin 2011;97 139
J. H. Lazarus Fig. 1 Continued. because of the development of dehydration and ketosis, may be associated with hyperthyroidism due to excess hcg stimulation and hyperthyroidism is also seen in some cases of hydatiform mole where excess hcg is secreted. Thyroid function tests in pregnancy It is essential therefore to have reliable accurate tests of thyroid function in pregnancy as maternal thyroid dysfunction may affect maternal health, foetal health and obstetric outcome. Gestational thyroid physiology affects thyroid tests (Table 1) and it is becoming clear that normative gestational related reference ranges for thyroid hormones are required for diagnosis. 6 140 British Medical Bulletin 2011;97
Thyroid function in pregnancy Table 1 Physiologic changes in pregnancy that influence thyroid function tests from Brent 1997 5. Physiologic change Thyroid function test change Thyroid binding globulin (TBG) Serum total T4 and T3 concentration First trimester hcg elevation Free T4 and TSH Plasma volume T4 and T3 pool size Type III 5-deiodinase (inner ring deiodination) due to increased hormone placental mass T4 and T3 degradation resulting in requirement for increased production Thyroid enlargement (in some women) Serum thyroglobulin Iodine clearance Hormone production in iodine deficient areas Circulating T4 and T3 are at equilibrium with free- and proteinbound hormones. The majority of thyroid hormones (.99%) are bound to transport proteins, mainly to TBG and to a lesser extent to transthyretin and albumin. Protein binding may prevent thyroid hormones from entering cells to exert their biological effects and also provide a storage reservoir. In contrast, the free hormones are present at much lower concentrations ( picomolar compared with the nanomolar concentrations of total hormones) and are biologically active. Due to their increased serum concentrations, it has been technically easier to develop assays for total thyroid hormones and these are more accurate and valid than free hormone assays. 7 However, the rise in TBG causes total T4 to increase to 1.5 times the concentration typical in the non-pregnant individual. Total T4 assays generally agree quite well resulting in better-defined reference intervals in adults. Due to the changes in serum concentrations in pregnancy gestation-specific reference intervals for total thyroid hormones need to be defined and used. However, in most clinical laboratories total T4 testing has been replaced with free hormone assays. In general, commercial FT4 immunoassays are affected to variable degrees by the physiological increase in the TBG that occur in pregnancy. For this reason, there is significant method-dependant variation in FT4 measurement in pregnancy. Therefore, it is necessary to use method- and gestation-specific reference intervals for the interpretation of various laboratory results during pregnancy. 6 Furthermore, it is becoming increasingly recognized that iodine status of the reference population, as well as the background thyroid autoimmunity should be taken into account and that the reference population be iodine sufficient. 8 Serum TSH concentrations usually provide the first clinical indicator for thyroid dysfunction in the non-pregnant patient. Due to the loglinear relationship between TSH and FT4, very small changes in T4 concentrations will result in very large changes in serum TSH. However, in early gestation, TSH is suppressed by 20 50% by week 10 due to the steep increase in hcg concentrations (Fig. 1) and its British Medical Bulletin 2011;97 141
J. H. Lazarus measurement at this time does not provide a good indicator for either the diagnosis or the control of treatment of thyroid dysfunction. 9 Therefore, it is essential to rely on T4 and T3 (either bound or free) to assess thyroid status in early gestation, although TSH will be significantly elevated in overt hypothyroidism. Later in gestation (from about 16 weeks on) TSH is more reflective of thyroid status. Although the measurement of thyroid antibodies (thyroid peroxidize antibodies, TPOAbs and TSH receptor antibodies, TSHRAbs) does not give any indication of thyroid status, their presence does have important implications for the pregnancy. TPO antibodies are a marker for an increased risk of infertility, miscarriage and preterm delivery. 10 TPOAbs are found in around 10% of women in early pregnancy and are also associated with decreased thyroid functional reserve during gestation with possible development of hypothyroidism. 11 Their presence at 32 weeks gestation has also resulted in a significant IQ decrement in children even when the mothers were euthyroid. 12 It should also be remembered that the finding of TPOAbs in early pregnancy imparts a 50% risk for the development of postpartum thyroid dysfunction and the whole spectrum of postpartum thyroiditis. 13 TSH receptor antibodies are present only rarely in gestation (,1%) but do signify the presence of Graves disease. 14 Changes in thyroid function and thyroid antibodies during gestation must be viewed against the backdrop of the immune changes that occur during and immediately after pregnancy. 15 It is beyond the scope of this review to discuss these in detail. (For recent review see Weetman 16 ). Important facts to note include the presence of a Th2 state during pregnancy switching abruptly to Th1 at delivery. These changes as well as the development of postpartum thyroiditis are thought to be related to the actions of T regulatory cells (phenotypically CD4 þ CD25þ) in maintaining peripheral tolerance thus preventing autoimmune disease. Clinically, many autoimmune diseases including Graves disease show a remission during pregnancy only to relapse postpartum. Thyroid dysfunction in pregnancy Hyperthyroidism Hyperthyroidism occurs in 2 /1000 pregnancies, the commonest cause (85%) being Graves hyperthyroidism, due to thyroid stimulation by thyrotropin receptor antibodies (TRabs). 14 Transient gestational thyrotoxicosis (due to thyroid stimulation by hcg) seen in the first trimester, is more common in Asians than Europeans. 142 British Medical Bulletin 2011;97
Thyroid function in pregnancy The Th2 status of pregnancy may be the reason why there is usually an amelioration of the severity of Graves hyperthyroidism (and other autoimmune diseases) after the first trimester: deterioration in the first trimester may be due to increasing TRabs together with high levels of hcg. It is critical to interpret thyroid function tests correctly so as not to miss the diagnosis as there are significant maternal complications including miscarriage, placenta abruptio and preterm delivery and preeclampsia. One to 5% of neonates of mothers with Graves disease have hyperthyroidism due to the transplacental passage of maternal stimulating TRAbs (even though the mother may be euthyroid and has received previous treatment for Graves disease). Neonatal hyperthyroidism may also be due to an activating mutation of the TSH receptor dominantly inherited from the mother. Transient neonatal central hypothyroidism is due to poorly controlled Graves disease leading to suppression of the foetal pituitary thyroid axis due to placental transfer of T4. 17 Ideally a woman who is known to have hyperthyroidism should seek pre-pregnancy advice; appropriate education should allay fears that are commonly present in these women. She should be referred for specialist care for frequent checking of her thyroid status, thyroid antibody evaluation and close monitoring of her medication needs. 18 At all stages of pregnancy, the use of antithyroid drugs (ATDs) is the preferred treatment option. Radioiodine is contra-indicated and surgery requires pretreatment with antithyroid drugs to render the patient euthyroid. Important aspects of management are outlined in Table 2. The thionamide drugs carbimazole (CMI), methimazole (MMI) and propylthiouracil (PTU) are all effective in inhibiting thyroidal biosynthesis of thyroxine during pregnancy. PTU is the preferred drug in the Table 2 Management of Graves hyperthyroidism in pregnancy. Confirm diagnosis Discuss treatment with patient effect on patient effect on foetus breast feeding Start propylthiouracil use for first trimester only Render patient euthyroid continue with low dose carbimazole or MMI up to and during labour Monitor thyroid function regularly throughout gestation (4 6 weeks) Adjust ATD if necessary Serial ultrasonography of the foetus Check TRAbs at 30 36 weeks Inform paediatrician Review postpartum check for exacerbation Check infant for thyroid dysfunction if indicated British Medical Bulletin 2011;97 143
J. H. Lazarus Hypothyroidism first trimester pregnancy due to the possibility (albeit rare) of teratogenic effects of carbimazole and MMI (aplasia cutis and MMI embryopathy). The latter malformation may be extremely severe requiring surgical management. In women already receiving CMI before conception they should also be switched to PTU either before the planned gestation or as soon as possible on confirmation of pregnancy. However, there are recent data suggesting an increase in hepatotoxicity with PTU 19 so CMI or MMI should be given in the second and third trimesters. Maternal FT4 levels should be kept in the upper third of the normal non-pregnant reference range to avoid foetal hypothyroidism, as with this management serum-free T4 levels are normal in more than 90% of neonates. Although these patients may have received antithyroid drugs, surgery or radioiodine therapy and be euthyroid on or off thyroxine therapy, neonatal hyperthyroidism may still occur. TRAbs should be measured early in pregnancy in a euthyroid pregnant women previously treated by either surgery or radioiodine 20 TRAb antibodies should be measured again in the last trimester (at about 32 weeks) and if positive the neonate needs to be checked for hyperthyroidism following delivery. In contrast to hyperthyroidism, hypothyroidism is quite common in pregnancy. 21 The incidence of subclinical hypothyroidism (raised TSH and normal or low normal T4) is at least 2.5% and these women have no clinical features and are often asymptomatic, but 50 60% will have evidence of autoimmune thyroid disease ( positive TPOAbs and or thyroglobulin antibodies, TgAbs) in iodine-sufficient areas. It should be noted however that endemic iodine deficiency is the most common cause of hypothyroidism seen in pregnant women worldwide. Overt hypothyroidism occurs in only about 5% of all women who have a high TSH. To make the diagnosis of hypothyroidism in the first trimester, it is necessary to employ a gestation-related normative reference range for TSH (as this will be reduced by hcg at this time). For example, the upper limit for TSH in the non-pregnant woman (commonly 4.5 or 5 miu/l) may be reduced to 3.5 miu/l. During the last decade, it has become apparent that untreated maternal hypothyroidism and subclinical hypothyroidism in pregnancy is associated with adverse foetal and obstetric outcomes, 22,23 which can be ameliorated by adequate levo-thyroxine therapy. 24 These events include miscarriages, anaemia in pregnancy, preeclampsia, abruptio placenta and post-partum haemorrhage while premature birth, low birth weight and increased neonatal respiratory distress have been 144 British Medical Bulletin 2011;97
Thyroid function in pregnancy Table 3 Aspects of thyroxine treatment of hypothyroidism in pregnancy (adapted from Abalovich et al. 40 ). Preconception: optimise therapy in patients with pre-existing disease On confirmation of pregnancy, increase dose by 30 50% of preconception dose Check thyroid function early in first trimester Aim for TSH,2.5 mu/l in the first trimester and,3 mu/l in later pregnancy Monitor thyroid function 4 6 weeks and further adjust dose Higher dose requirement in post-ablative and post-surgical hypothyroidism After delivery reduce thyroxine to preconception dose Recheck thyroid function at 6 weeks postpartum Note drug interactions: (a) Drugs which impair thyroxine absorption: iron supplements, cholestyramine, calcium carbonate, soy milk (b) Drugs which increase thyroxine clearance: carbamazepine, rifampicin, valproate described in babies born to mothers with hypothyroidism. 25 There is a greater prevalence of subclinical hypothyroidism in women with delivery before 32 weeks and there is even an association between thyroid autoimmunity and adverse obstetric outcome, which is independent of thyroid function. 26 Higher maternal TSH levels even within the normal reference range are associated with an increased risk of miscarriages, foetal and neonatal distress 27 as well as preterm delivery. 28 Of equal or even greater importance than the above is the detrimental effect of gestational maternal hypothyroidism on foetal brain development. The availability of thyroxine to the developing foetal neurones is vital for their maturation and proper function. 29 Either due to iodine deficiency or autoimmune thyroid disease reduction of circulating maternal thyroxine has been shown to result in lower IQ in infants and young children in retrospective 30 and prospective 31 studies. Isolated hypothyroxinaemia (low FT4 and normal TSH) has been found not to be associated with adverse perinatal outcomes, 32 although other studies have shown it to be associated with reduced motor and intelligence performance in neonates 33 and in children aged 25 30 months in a Chinese population. 34 The strength of evidence relating maternal hypothyroidism to low IQ in children suggests strongly that screening thyroid function in early gestation with L-thyroxine intervention in appropriate women would be beneficial. There is evidence that such a strategy would be costeffective 35,36 but at present there are no prospective controlled trials of this strategy assessing child IQ. Preliminary results from a prospective randomized trial of L-T4 treatment in women screened prior to 16 weeks gestation (compared with control women not screened and therefore not treated with L-T4), the CATS study, are now available. The mean IQ of the two groups of children (screen and control) was not different. However, an on-treatment analysis showed that the number of children with IQ,85 born to women with subclinical British Medical Bulletin 2011;97 145
J. H. Lazarus hypothyroidism who were considered to have been compliant with their T4 treatment was significantly less (9%) than in the control group (15%). Conclusion There is agreement that pregnancy imposes a stress on the thyroid which is greater in areas of iodine deficiency. Changes in thyroid function characterized by a fall in TSH and a rise in total and free T4 levels associated with the rise in hcg are well established. The variation in assay methodology indicates the necessity of establishing normative gestational-related reference ranges for thyroid hormones. Hyperthyroidism in pregnancy, usually due to Graves disease, is uncommon but has deleterious effects on mother and foetus and requires therapy. Thionamide antithyroid drug therapy (propylthiouracil in the first trimester then carbimazole/mmi) is the treatment of choice. Hypothyroidism, usually subclinical, is common and should be treated with L-thyroxine to reduce obstetric and foetal complications. Women already receiving thyroxine require an increase in dose during gestation 37 (Table 3). There is current controversy relating to the validity of free thyroxine assays in pregnancy as measured by kits. Controversy also exists relating to the advisability of screening all women in early pregnancy for thyroid dysfunction. Current guidelines recommend a targeted approach 38 but studies have demonstrated that such a strategy may exclude 30 50% of women with significant thyroid dysfunction. 39,40 As foetal brain development requires adequate thyroxine delivery to foetal neurones, it seems reasonable to treat mothers with hypothyroidism with thyroxine to prevent IQ decrement as well as for obstetric reasons. However, preliminary results from the recently completed CATS study suggest caution and a degree of uncertainty relating to this approach. There is a need for more data concerning transfer of thyroid hormone from mother to foetus. The role of the placenta in this process is unclear at present. Correction of worldwide iodine deficiency continues to be required and monitored. Further prospective trials of screening thyroid function in pregnancy with measurable developmental outcomes are required. Funding Supported by The Wellcome Trust Grant number 065143/A/01/2. 146 British Medical Bulletin 2011;97
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