Frontiers in Gynecological Endocrinology: Volume 1: From Symptoms to Therapies (ISGE Series)

16. Thyroid Disorders and Pregnancy: Diagnostic and Therapeutic Proposal

Andrzej Milewicz , Anna Brona2, Diana Jędrzejuk2 and Felicja Lwow1

(1)

Department of Health Promotion, Faculty of Physiotherapy, University School of Physical Education, Paderewskiego 35, Wroclaw, 51-612, Poland

(2)

Department of Endocrinology, Diabetology and Isotopes Therapy, Wrocław Medical University, Pasteura 4, Wrocław, 50-367, Poland

Andrzej Milewicz

Email: andrzej.milewicz@umed.wroc.pl

Thyroid function changes in pregnancy. Thyroid volume increases by 10 to 20–40 % (more in iodine deficiency regions). The total T4 and T3 production increases by about 50 % (with simultaneous requirements for iodine). TSH concentrations fall during pregnancy, especially in the first trimester, because hCG cross-reacts with TSH receptors on the thyroid gland. The lowest serum TSH level is observed in 10 week of pregnancy. At the same time (between 7 and 11 weeks gestation), serum hCG level is highest. Serum TSH level increases gradually throughout pregnancy.

In 10–20 % of pregnant women, in the first trimester, increased thyroid antibodies titer with normal TSH levels are found. In 16 % of them, TSH level will exceed 4.0 mlU/l by third trimester. 33–50 % of pregnant women with thyroid antibodies will develop postpartum thyroiditis. There are no indications for thyroid antibodies screening; however, TPO antibodies estimation should be considered in pregnant women in first trimester or those who are planning pregnancy.

During pregnancy, free thyroid hormones concentrations should be carefully interpreted. The tests based on antigen–antibody reaction may provide lower than real results, especially in second and third trimesters, because serum TBG concentrations rise and lead to increase in circulating total T4. Albumins concentrations decrease and dilution of serum is present. Free fatty acids concentrations rise. Rare effect of drugs administered during pregnancy (i.e., heparins) may be present. In some women in the advanced stages of pregnancy, free thyroxin level is observed to drop (by 10–30 %). In ambiguous cases, 150 % value of standard upper range of normal total thyroid hormones concentrations for nonpregnant women may be applied.

TSH screening should be regarded before and during pregnancy. TSH routine determination is indicated in women planning pregnancy. TSH routine determination is also indicated in women in 4th–8th week of pregnancy. TSH evaluation is recommended before conception in women taking medicines influencing concentration of thyroid hormones (metformin). It is advisable to define and apply referential TSH values, which are specific for pregnancy particular trimesters in the particular population and laboratory. If it is impossible, values not higher than 2.5 mlU/l should be adopted as standard TSH upper range.

TPO antibodies estimation is recommended in pregnant women or those planning pregnancy with concomitant autoimmune diseases, positive history of autoimmune diseases, TSH >2.5 mIU/l, thyroid ultrasound pointing at thyroid autoimmune disease regardless TSH result, positive history of miscarriages or preterm deliveries, after postpartum thyroiditis, and in those who are or were treated for infertility.

Determination of serum TRAb is recommended in hyperthyroid patients diagnosed for the first time during pregnancy. It is also recommended at the end of second trimester (before 22nd week of gestation) in the case of fetal or neonatal hyperthyroidism during previous gestations, current antithyroid drug therapy due to Graves’ disease, pregestation treatment (thyroidectomy or 131l treatment) due to Graves’ disease—including also euthyroid and hyperthyroid patients, previously increased TRAb titer and presence of fetal inexplicable tachycardia or fetal goiter detected on ultrasound.

Thyroid imaging is used in some situation. Thyroid ultrasound in pregnancy is indicated in the following cases: dispersed or nodular goiter or its suspect, abnormal results of hormonal tests or thyroid antibodies tests, and in pregnant women from thyroid cancer risk group. The examination should be performed in patients with increased TRAb titer or/and treated by antithyroid drugs. It should be performed for the first time in 18th–22nd week of gestation and preferably repeated every 4–6 weeks. Active or subsided Graves’ disease as well as antithyroid drugs treatment are indications for fetal thyroid ultrasound. It should be performed at the end of second trimester (18th–22nd week) and should be repeated every 4–6 weeks if there are any clinical indications.

16.1 Thyroid Disorders and Pregnancy

Hyperthyroidism and hypothyroidism are the main causes of thyroid disorders in pregnancy. Thyroid diseases affect up to 4 % of all pregnancies (0.1–0.4 % hyperthyroidism, 2–3 % hypothyroidism).

16.1.1 Hyperthyroidism

Graves’ disease is the most common cause of autoimmune hyperthyroidism in pregnancy. It affects 0.1–1.0 % of all pregnancies (of these 0.4 % clinical and 0.6 % subclinical). More frequent than Graves’ disease as the cause of thyrotoxicosis is the syndrome of gestational hyperthyroidism defined as “transient hyperthyroidism, limited to the first half of pregnancy characterized by elevated FT4 or adjusted TT4 and suppressed or undetectable serum TSH, in the absence of serum markers of thyroid autoimmunity”. It is diagnosed in about 1–3 % of pregnancies, depending on the geographic area and is secondary to elevated hCG levels. It may be associated with hyperemesis gravidarum. Other conditions associated with hCG-induced thyrotoxicosis include multiple gestation (TSH suppression is observed in 67 % of pregnant women with hCG concentration >200,000 IU/l, and in 100 % with hCG concentration >400,000 IU/l; since hCG concentrations are higher in multiple pregnancies than in singleton pregnancies, the downward shift in the TSH reference interval is greater in twin pregnancies than in singleton pregnancies), hydatidiform mole, or choriocarcinoma. In previously healthy pregnant woman, in whom TSH value is found below lower range of referential values, fT3 and fT4 evaluation is indicated, and TSH should be checked in second trimester. Treatment is not necessary. Thyroid ultrasound is required and in ambiguous cases. TRAb titer should be determined.

Multiple gestation patients with nonrestrained vomiting or gestational trophoblastic disease are especially predisposed to pregnancy induced thyrotoxicosis. In this group of patients, FT3, FT4, and TSH and even TRAb antibodies should be determined as well as thyroid ultrasound is indicated. Antithyroid drugs administration may be considered only when the symptoms of hyperthyroidism are very aggravated in mother. In most women, FT4 level normalizes in 15th week and TSH in 19th week. Incorrectly controlled hyperthyroidism may lead to: miscarriages, preterm deliveries, small birth weight, stillbirths, mother’s thyroid storm, and her congestive heart failure. Differentiation between gestational hyperthyroidism and other reasons for thyrotoxicosis is very critical as they require different procedures.

Diagnosis of hyperthyroidism during pregnancy creates sometimes some difficulties, because of nonspecific symptoms of hyperthyroidism: tachycardia, increased sweating, nervousness, tremor, and weight loss, which are typical symptoms for pregnant women without any thyroid disease. Specific symptoms of thyroid disease like goiter, thyroid ophthalmopathy, pretibial edema, lower TSH (depends on trimester of pregnancy; 0.01–0.3), proximal myopathy, weight loss in women without vomiting and with good appetite, and increased TRAb titer are necessary for diagnosis of hyperthyroidism in pregnant women.

Treatment of hyperthyroidism in pregnancy comprises antithyroid drugs and thyroidectomy. Antithyroid drugs [methimazole (MMI) and propylthiouracil (PTU)] are the drugs of first choice. The great concern with the use of antithyroid drugs are side effects—rare cases of embryopathy associated with MMI and the risk of acute hepatic failure associated with PTU. Starting doses are 5–15 mg for MMI, and 50–300 mg for PTU. PTU is postulated to be restricted to first trimester. Other exceptions to avoiding PTU are patients with MMI allergy and management of thyroid storm. Hepatotoxicity may occur at any time during PTU treatment. Monitoring hepatic enzymes during administration of PTU should be considered. In the second trimester, change for MMI is recommended. At the initial stage of treatment, follow-up should be continued every 2 weeks. After restoration of euthyroid state, control tests should be continued every 2–4 weeks. FT4 concentration should be maintained in the upper range of reference values characteristic for gestation. The “block and substitute” treatment (LT4 and antithyroid drug combination) is forbidden.

Thyroidectomy is indicated in second trimester only in the case of antithyroid drugs severe side effects, the necessity of high doses or/noncooperative patient with uncontrolled hyperthyroidism. Subclinical hyperthyroidism should not be treated. 131l treatment during breast feeding is absolutely forbidden. Cordocentesis for estimation of umbilical blood thyroid hormones concentration should be performed only in the case of inability to diagnose fetal thyroid disease on the basis of clinical history or when the result may influence the treatment.

Hyperthyroidism is associated with following adverse pregnancy outcomes: preeclampsia (OR 1.78), superimposed preeclampsia (OR 3.64), preterm birth (OR 1.81), and intensive care unit admission (OR 2.08). Fetal and neonatal risk related to mother’s hyperthyroidism are fetal hyperthyroidism, neonatal hyperthyroidism, fetal and neonatal hypothyroidism, and central (secondary) hypothyroidism.

There are no contraindications for breast feeding in hyperthyroid patients if MMI dose does not exceed 20 mg/day, and PTU 300 mg/day. The drugs should be taken after breast feeding and 3-h break should be preserved before the next one [14].

16.1.2 Hypothyroidism and Pregnancy

Clinical hypothyroidism is characterized by TSH >2.5 mlU/ml and decreased FT4 or TSH >10 mlU/ml independently of FT4 concentration. Subclinical hypothyroidism means TSH within the range 2.5–10 mlU/ml and normal value of FT4. Subclinical hypothyroidism is related to neurocognitive defects, increased risk of miscarriage and obstetric complications. In women with previously diagnosed hypothyroidism, in preconception period, TSH concentration value should be maintained at the level below 2.5 mlU/l, preferred value—at about 1.0 mlU/l (in order to reduce the risk of TSH elevation during the first trimester). After pregnancy confirmation, L-Thyroxin dose should be increased by 30–50 %. After change of L-Thyroxin dose, TSH concentration control is needed every 4 weeks. After delivery, pregestation L-Thyroxin dose should be adjusted and TSH should be checked after 4–6 weeks. There is no contraindication for breast feeding in patients treated with L-Thyroxin.

L-Thyroxin therapy is indicated for patients planning pregnancy with TSH concentration value between 2 and 2.5 mlU/l and standard upper range for the particular laboratory, especially when TPOAb titer is increased.

In the case of diagnosis of clinical hypothyroidism, normal TSH and free thyroid hormone concentration should be resumed. Subclinical hypothyroidism diagnosed during pregnancy should also be treated. There is no evidence for advantageous treatment of isolated hypothyroxinemia in second and third trimester of pregnancy. Adequate iodine prophylaxis should be administered. Hypothyroidism is associated with following adverse pregnancy outcomes: preeclampsia (OR 1.47), superimposed preeclampsia (OR 2.25), gestational diabetes (OR 1.57), preterm birth (OR 1.34), induction (OR 1.15), cesarean section, both preterm and after spontaneous labor (OR 1.31), and intensive care unit admission (OR 2.08) [14].

16.1.3 Thyroiditis and Pregnancy

Chronic autoimmune thyroiditis should be considered before pregnancy. In women planning pregnancy, in whom TSH exceeds the value of 2.5 mlU/l, TPOAb titer should be estimated. In women planning pregnancy, in whom TPOAb titer is elevated, TSH concentration should be monitored every 6 months.

Patients, especially predisposed to postpartum thyroiditis, are these with increased TPOAb titer and the history of postpartum thyroiditis or diabetes type 1. In this group, TSH measurement is indicated in 6 week, 3, 6, and 12 months after delivery. In thyrotoxic phase in the course of postpartum thyroiditis, antithyroid drugs administration should be avoided. In hypothyroid phase, L-Thyroxin should be administered and TSH concentration should be maintained <2.5 μlU/ml—preferable value is below 2.0 μlU/ml. After 1-year treatment with L-Thyroxin may be abandoned [14].

16.1.4 Nodular Goiter and Pregnancy

The prevalence of nodular goiter increases with gestations number (in iodine insufficiency areas). Increase of existing thyroid nodules size during pregnancy may occur. Pregnancy is the risk factor of new thyroid nodules formation. Indications for fine-needle aspiration in pregnant women are the same as in general population. Thyroid gland biopsy may be performed regardless of stage of pregnancy. In case of fine-needle aspiration sample is suspicious for thyroid cancer, there is no indication for L-Thyroxin treatment. Pregnant woman with nodular goiter should supplement their diet with standard prophylactic doses of iodine [14].

16.2 Thyroid Carcinoma and Pregnancy

Diagnosis of thyroid carcinoma in pregnancy requires fine-needle biopsy. In case of advanced carcinoma process, surgery should be considered irrespectively of gestational age. In other cases, surgical procedures may be postponed until postpartum period. Surgery for follicular (well-differentiated thyroid) carcinoma should be performed in postpartum period. In women treated pharmacologically during pregnancy (surgery for well-differentiated thyroid carcinoma deferred after postpartum), L-Thyroxin should be administered in order to maintain TSH concentration of 0.1–1.5 mlU/l. In women with previously treated thyroid cancer, the level of TSH suppression depends on preconception evidence of residual or recurrent disease [14].

16.3 Thyroid Function and Fertility

In patients preparing for assisted reproduction, temporary TSH increase is observed and it lasts till the end of 1st trimester—small doses of L-Thyroxin are proposed. There is no equivocal indication for L-Thyroxin use in euthyroid women (TSH below 2.5 mlU/l) with the presence of thyroid antibodies and miscarriages in medical history or/and treated for infertility in the past. In women suffering from endometriosis and/or ovarian dysfunction as well as in women preparing for treatment of infertility with the use of assisted reproduction technologies, thyroid function should be assessed and thyroid antibodies should be estimated [14].

16.4 Conclusions

Serum levels of TSH and FT3, FT4 depend on trimester of pregnancy. In hyperthyroidism (adenoma toxicum and Graves’ disease) in the first trimester PTU and in the second trimester MMI therapy is recommended. In hypothyroidism, L-Thyroxin treatment is recommended in dose adjusted to the severity of disease. Breast feeding is not contraindicated in women treated for hyper- or hypothyroidism (Fig. 16.1).

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Fig. 16.1

First trimester screen algorithm

References

1.

Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, Mandel SJ, Stagnaro-Green A (2007) Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 92:S1–S47PubMedCrossRef

2.

Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S, Wiersinga W, The American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum (2011) Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21:1081–1125PubMedCentralPubMedCrossRef

3.

Hubalewska-Dydejczyk A, Lewiński A, Milewicz A, Radowicki S, Poręba R, Karbownik-Lewińska M, Kostecka-Matyja M, Trofimiuk-Müldner M, Pach D, Zygmunt A, Bandurska-Stankiewicz E, Bar-Andziak E, Bednarczuk T, Buziak-Bereza M, Drews K, Gietka-Czernel M, Górska M, Jastrzębska H, Junik R, Nauman J, Niedziela M, Reroń A, Sowiński J, Sworczak K, Syrenicz A, Zgliczyński W (2011) Management of thyroid diseases during pregnancy. Endokrynol Pol 62:362–381PubMed

4.

De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, Eastman CJ, Lazarus JH, Luton D, Mandel SJ, Mestman J, Rovet J, Sullivan S (2012) Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 97:2543–2565PubMedCrossRef



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