Historically, PTU has been the drug of choice when treating Graves' disease during pregnancy in the United States. Throughout the rest of the world, methimazole and carbimazole, are widely used to treat hyperthyroidism in pregnant women (Mandel, 2001; Dwarakanath, 1999). Methimazole has been linked to at least 25 reported cases of aplasia cutis, as well as at least 22 cases of esophageal or choanal atresia or a combination of both (Mestman, 2004; Mandel, 2001; Ferraris 2003; Hamburger, 1992; Van Dijke, 1987; Karlson, 2002; Seoud,2003; Kannan, 2008; Karg, 2004). Methimazole has been described as "methimazole embryopathy" in children exposed to methimazole during the first trimester of pregnancy, especially during the first 7 gestational weeks (Karlsson, 2002; Clementi, 1999). The embryopathy includes congenital anomalies such as choanal or esophageal atresia or aplasia cutis and developmental delay, hearing loss, and dysmorphic facial features (Chan, 2007).

An evaluation of 49,091 live births estimated the incidence of aplasia cutis in the general population to be 0.03% or 0.05% of congenital skin defects (Van Dijke, 1987). DiGianantonio and colleagues prospectively compared 241 women exposed to methimazole during pregnancy to 1,089 pregnant controls. No increased incidence of spontaneous or induced abortions or major congenital anomalies was reported in the methimazole cohort (DiGianantonio, 2001). Although a possible association between methimazole exposure during pregnancy and fetal congenital defects may exist, it has not been proven and may be secondary to hyperthyroidism (Briggs, 2011).

At least 7cases of congenital anomalies have been reported in newborns exposed to PTU. A causal relationship between PTU exposure and congenital anomalies has not been found (Briggs, 2011). The Israeli Teratology Information Service reported that the rate of major anomalies was comparable between PTU-exposed pregnancies and controls (Rosenfeld, 2009). At least 47 reports have been published describing PTU-related hepatic impairment in adults and children, approximately 0.1-0.5% in adults (Cooper, 1999; Cooper, 2009; Kontoleon, 2002; Patil-Sisodia, 2010). However, only one case has been reported of neonatal hepatitis secondary to transplacental propylthiouracil (Hayashida, 1990). Therapy with PTU should be discontinued since 25% of affected patients may progress to fulminant, fatal hepatic failure (Kontoleon, 2002; Patil-Sisodia, 2010). The incidence of PTU hepatic failure does not correlate to PTU dosage or duration or patient age (Patil-Sisodia, 2010).

The United States Food and Drug Administration classifies PTU and methimazole as Category D because of the potential for fetal hypothyroidism, rather than the potential teratogenicity. The American College of Obstetricians and Gynecologists (ACOG) recommends that either PTU or methimazole may be used to treat pregnant women with hyperthyroidism.

The "block and replace" regimen that adds levothyroxine with an antithyroid drug is not recommended in pregnant women (Marx, 2009). It was originally thought that the placental transfer of levothyroxine would prevent fetal hypothyroidism. Levothyroxine and methimazole administered concomitantly to pregnant women with Graves' disease has shown to reduce the incidence of postpartum hyperthyroidism (Hashizume, 1992). However, the necessary dose of the antithyroid drug is much higher when given with levothyroxine that fetal goiter and fetal hypothyroidism may still occur. Furthermore, the risk of fetal hypothyroidism is increased because the antithyroid medications but not levothyroxine cross the placenta (Rosenfeld, 2009).

#### **<IP_ADDRESS> Clinical trials**

140 A New Look at Hypothyroidism

Historically, PTU has been the drug of choice when treating Graves' disease during pregnancy in the United States. Throughout the rest of the world, methimazole and carbimazole, are widely used to treat hyperthyroidism in pregnant women (Mandel, 2001; Dwarakanath, 1999). Methimazole has been linked to at least 25 reported cases of aplasia cutis, as well as at least 22 cases of esophageal or choanal atresia or a combination of both (Mestman, 2004; Mandel, 2001; Ferraris 2003; Hamburger, 1992; Van Dijke, 1987; Karlson, 2002; Seoud,2003; Kannan, 2008; Karg, 2004). Methimazole has been described as "methimazole embryopathy" in children exposed to methimazole during the first trimester of pregnancy, especially during the first 7 gestational weeks (Karlsson, 2002; Clementi, 1999). The embryopathy includes congenital anomalies such as choanal or esophageal atresia or aplasia cutis and developmental delay,

An evaluation of 49,091 live births estimated the incidence of aplasia cutis in the general population to be 0.03% or 0.05% of congenital skin defects (Van Dijke, 1987). DiGianantonio and colleagues prospectively compared 241 women exposed to methimazole during pregnancy to 1,089 pregnant controls. No increased incidence of spontaneous or induced abortions or major congenital anomalies was reported in the methimazole cohort (DiGianantonio, 2001). Although a possible association between methimazole exposure during pregnancy and fetal congenital defects may exist, it has not been proven and may be

At least 7cases of congenital anomalies have been reported in newborns exposed to PTU. A causal relationship between PTU exposure and congenital anomalies has not been found (Briggs, 2011). The Israeli Teratology Information Service reported that the rate of major anomalies was comparable between PTU-exposed pregnancies and controls (Rosenfeld, 2009). At least 47 reports have been published describing PTU-related hepatic impairment in adults and children, approximately 0.1-0.5% in adults (Cooper, 1999; Cooper, 2009; Kontoleon, 2002; Patil-Sisodia, 2010). However, only one case has been reported of neonatal hepatitis secondary to transplacental propylthiouracil (Hayashida, 1990). Therapy with PTU should be discontinued since 25% of affected patients may progress to fulminant, fatal hepatic failure (Kontoleon, 2002; Patil-Sisodia, 2010). The incidence of PTU hepatic failure

The United States Food and Drug Administration classifies PTU and methimazole as Category D because of the potential for fetal hypothyroidism, rather than the potential teratogenicity. The American College of Obstetricians and Gynecologists (ACOG) recommends that either

The "block and replace" regimen that adds levothyroxine with an antithyroid drug is not recommended in pregnant women (Marx, 2009). It was originally thought that the placental transfer of levothyroxine would prevent fetal hypothyroidism. Levothyroxine and methimazole administered concomitantly to pregnant women with Graves' disease has shown to reduce the incidence of postpartum hyperthyroidism (Hashizume, 1992). However, the necessary dose of the antithyroid drug is much higher when given with levothyroxine that fetal goiter and fetal hypothyroidism may still occur. Furthermore, the risk of fetal hypothyroidism is increased because the antithyroid medications but not

does not correlate to PTU dosage or duration or patient age (Patil-Sisodia, 2010).

PTU or methimazole may be used to treat pregnant women with hyperthyroidism.

hearing loss, and dysmorphic facial features (Chan, 2007).

secondary to hyperthyroidism (Briggs, 2011).

levothyroxine cross the placenta (Rosenfeld, 2009).

**<IP_ADDRESS> Teratogenicity**

Clinical studies support that fetal thyroid function outcomes are similar between the two drugs (Mortimer, 1997; Marchant, 1977; Momotani, 1997). A retrospective chart review of 135 patients with a history or diagnosis of hyperthyroidism at a high risk obstetrics clinic over a 16 year time period (1974 to 1990) compared the use of PTU and methimazole to treat hyperthyroidism during pregnancy (Wing, 1994). Of the 135 patients, 99 (73.3%) received PTU and 36 (26.7%) received methimazole. Selection of the treatment agent was based solely on physician preference. Six of the patients received both PTU and methimazole and were therefore excluded from analysis.

Diagnosis of hyperthyroidism was based on history, physical exam, thyroid-stimulating hormone, free thyroxine index, and free triiodothyronine index. The time required to normalize free FT4 levels and the incidence of congenital malformations or fetal hypothyroidism were evaluated. Maternal and fetal outcomes were obtained via retrospective chart review from clinic, labor, delivery, and postpartum records. Baseline characteristics for the two treatment groups were similar with respect to age, ethnicity, and parity.

Maternal results showed that gestational age had no effect on the time to free FT4 normalization. The median time to normalization was 7 weeks for the methimazole-treated group and 8 weeks for the PTU-treated group (p=0.34). The Cox proportional hazard compared the time of normalization between the two groups after adjusting for the initial measurements with no statistical difference between the PTU-treated group and the methimazole-treated group (p=0.52). Of the 135 pregnancies, four infants (3%) were born with congenital anomalies to mothers treated with either PTU or methimazole. Of these four infants, three (3%) of the fetal anomalies occurred in the 99 women who were treated with PTU and one (2.7%) occurred in the 36 women treated with methimazole. Fetal anomalies reported were ventricular septal defect, patent ductus arteriosus, and severe pulmonic stenosis in the infants of the PTU-treated mothers, and congenital inguinal hernia in the infant of the methimazole-treated mother. No cases of aplasia cutis were reported in either group. Congenital hypothyroidism occurred in one infant of a PTU-treated mother. The authors concluded that the incidence of congenital anomalies were consistent with the national average of 2% to 5% in the general population. The authors concluded that both PTU and methimazole were equally safe and effective in the treatment of hyperthyroidism during pregnancy (Wing, 1994). Potential limitations to the study were mostly due to the retrospective design; unrandomized, unblinded, and non-placebo controlled. Selection bias in medication may have occurred as the choice of medication was based on physician preference. Also, small sample size resulted in inadequate power to evaluate the equivalence of the two medications.

Momotani et al. evaluated the effect of maternal ingestion of PTU and methimazole on fetal thyroid status using cord sera at delivery (Momotani, 1997). The authors identified 249 pregnant women with Graves' disease who received either PTU or methimazole during their pregnancy. Of these 249 women, 77 (30.9%) had received at least four weeks of therapy, 34 (44.2%) with PTU and 43 (55.8%) with methimazole. Controls consisted of 32 healthy women with no history of thyroid disease and who delivered at term.

Treatment of Graves' Disease During Pregnancy 143

used to treat pregnant women with hyperthyroidism. However, the Endocrine Society recommends PTU as a first line drug, especially during the first trimester (Abalovich, 2007). Clinical data shows that PTU and methimazole are equally efficacious in pregnant women with hyperthyroidism (Wing, 1994; Momotani, 1997). However, the possible association between methimazole and fetal anomalies such as aplasia cutis, esophageal atresia, and choanal atresia may present methimazole a less desirable first line treatment option than PTU. Although a causal relationship between methimazole and these fetal anomalies has not been established in clinical trials, the possibility of a relationship still exists. Therefore, in the absence of a compelling indication for the use of methimazole, PTU should still be considered as the first line agent in the treatment of Graves' disease during pregnancy. However, methimazole should be considered a viable second choice if the patient is intolerant to PTU, has an allergic reaction to PTU, or fails to become euthyroid on PTU.

AACE Thyroid Task Force. (2002). American Association of Clinical Endocrinologists

American Academy of Pediatricians. (2001). Committee on Drugs. *American Academy of*

American College of Obstetricians and Gynecologists. (2002). Thyroid disease in pregnancy.

Atkins P, Cohen SB, & Phillips BJ. (2000). Drug therapy for hyperthyroidism in pregnancy.

Azizi F, Khamseh ME, Bahreynian M, & Hedayati. (2002). Thyroid function and intellectual

Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall IR,

Barbero P, Valdez R, Rodriguez H, Tiscornia C, Mansilla E, Allons A, Coll S, & Liascovich R.

methimazole: a case-control study. *Am J Med Genet* 2008;146A:2390-2395. Briggs GG, Freeman RK, Yaffe SJ, eds. (2011). *Drugs in pregnancy and lactation*, 9th ed.

Casey BM, & Leveno KJ. (2006). Thyroid disease in pregnancy. *Obstet Gynecol* 2006;108:1283-

Chan GW, & Mandel SJ. (2007). Therapy insight: management of Graves' disease during pregnancy. *Nature Clinical Practice Endocrin Metab* 2007;3(6):470-478.

Philadelphia: Lippincott Williams and Wilkins, 2011.

medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. *Endocr Pract* 2002 Nov-Dec;8(6):457-69. Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, Mandel S, &

Stagnaro-Green A. (2007). Management of thyroid dysfunction during pregnancy and postpartum: an endocrine society clinical practice guideline. *J Clin Endocrinol*

ACOG Practice Bulletin No. 37. Clinical management guidelines for obstetrician-

development of children of mothers taking methimazole during pregnancy*. J*

Montori VM, Rivkees SA, Ross DS, Sosa JA, & Stan MN. (2011). Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists.*Thyroid*

(2008). Choanal atresia associated with maternal hyperthyroidism treated with

**4. References**

*Metab* 2007;92(8):S1-S47.

*Pediatricians* 2001;108;776-89.

*Drug Safety* 2000;23:229-244.

2011:21:593-646

92.

*Endocrinol Invest* 2002;25:586-589.

gynecologists. *Obstet Gynecol* 2002;100:387-96.

Serum samples from mother and fetus were assayed for free FT4 and TSH. No statistical difference was observed in mean fetal free FT4 or fetal TSH between the PTU and methimazole treated groups. Low fetal free FT4 was seen in 6% of the PTU group and 7% of the methimazole group. High fetal TSH rates were 21% in the PTU group and 14% in the methimazole group. The relationship between maternal dose and fetal thyroid status was not significant; low doses of PTU were associated with high TSH in 21% of infants and low doses of methimazole were associated with high TSH in 14% of infants. The authors concluded that the two agents were similar regarding the effects on fetal thyroid status, and the selection of PTU over methimazole to treat hyperthyroidism during pregnancy was not justified (Momotani, 1997). The trial appeared to be well designed and utilized a direct measure of fetal thyroid status at birth. Potential bias may have existed as medication selection was based solely on provider preference. The selection process was not explained regarding how pregnant women with Graves' disease and those who served as controls were identified.

Azizi et al. evaluated the methimazole's effect on intellectual development of children whose mothers received methimazole during pregnancy but not during lactation (Azizi, 2002). The authors identified 23 children, ages 3 to 11 years, of mothers who were treated with methimazole during pregnancy and 30 children, ages 3 to 11 years, of mothers who were not treated with methimazole during pregnancy. All mothers delivered at term and there were no congenital malformations in either group. Methimazole-exposed mothers received methimazole doses up to 20 mg per day. All neonates were euthyroid at the time of delivery.

No difference between the methimazole-treated group and the control in serum T3, T4, or TSH concentrations was observed. Physical characteristics such as weight and height were similar in both groups. A psychologist blinded to methimazole exposure used the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) to detect a difference in verbal and performance IQ between the two groups. No difference in verbal or performance IQ between the two groups of children was shown. Total IQ for the methimazole-treated group was 11711; IQ for the control group was 11314. The authors concluded that no detrimental effects on the physical or intellectual development occurred in those children exposed to methimazole during pregnancy (Azizi, 2002). The main strength of this study was the single blinded psychologist evaluation of child intellect using the WPPSI exam. Unfortunately, the WPPSI is an intelligence test designed for children ages 2 years 6 months to 7 years 3 months and the study population included children 3-11 years of age. Other limitations to this study were a small sample size and low exposure dose of methimazole.

#### **3. Conclusion**

The selection of PTU over methimazole as the drug of choice to treat Graves' disease during pregnancy should not be based on misleading statements in the literature that PTU has less placental transfer than methimazole, that PTU leads to less fetal hypothyroidism, or that exposure to methimazole during pregnancy leads to a decreased intellectual function in children. The United States Food and Drug Administration classifies both PTU and methimazole as a Category D because of the potential for fetal hypothyroidism, rather than potential teratogenicity. The ACOG recommends that either PTU or methimazole may be used to treat pregnant women with hyperthyroidism. However, the Endocrine Society recommends PTU as a first line drug, especially during the first trimester (Abalovich, 2007). Clinical data shows that PTU and methimazole are equally efficacious in pregnant women with hyperthyroidism (Wing, 1994; Momotani, 1997). However, the possible association between methimazole and fetal anomalies such as aplasia cutis, esophageal atresia, and choanal atresia may present methimazole a less desirable first line treatment option than PTU. Although a causal relationship between methimazole and these fetal anomalies has not been established in clinical trials, the possibility of a relationship still exists. Therefore, in the absence of a compelling indication for the use of methimazole, PTU should still be considered as the first line agent in the treatment of Graves' disease during pregnancy. However, methimazole should be considered a viable second choice if the patient is intolerant to PTU, has an allergic reaction to PTU, or fails to become euthyroid on PTU.

#### **4. References**

142 A New Look at Hypothyroidism

Serum samples from mother and fetus were assayed for free FT4 and TSH. No statistical difference was observed in mean fetal free FT4 or fetal TSH between the PTU and methimazole treated groups. Low fetal free FT4 was seen in 6% of the PTU group and 7% of the methimazole group. High fetal TSH rates were 21% in the PTU group and 14% in the methimazole group. The relationship between maternal dose and fetal thyroid status was not significant; low doses of PTU were associated with high TSH in 21% of infants and low doses of methimazole were associated with high TSH in 14% of infants. The authors concluded that the two agents were similar regarding the effects on fetal thyroid status, and the selection of PTU over methimazole to treat hyperthyroidism during pregnancy was not justified (Momotani, 1997). The trial appeared to be well designed and utilized a direct measure of fetal thyroid status at birth. Potential bias may have existed as medication selection was based solely on provider preference. The selection process was not explained regarding how pregnant women with Graves' disease and those who served as controls

Azizi et al. evaluated the methimazole's effect on intellectual development of children whose mothers received methimazole during pregnancy but not during lactation (Azizi, 2002). The authors identified 23 children, ages 3 to 11 years, of mothers who were treated with methimazole during pregnancy and 30 children, ages 3 to 11 years, of mothers who were not treated with methimazole during pregnancy. All mothers delivered at term and there were no congenital malformations in either group. Methimazole-exposed mothers received methimazole doses up to 20 mg per day. All neonates were euthyroid at the time of

No difference between the methimazole-treated group and the control in serum T3, T4, or TSH concentrations was observed. Physical characteristics such as weight and height were similar in both groups. A psychologist blinded to methimazole exposure used the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) to detect a difference in verbal and performance IQ between the two groups. No difference in verbal or performance IQ between the two groups of children was shown. Total IQ for the methimazole-treated group was 11711; IQ for the control group was 11314. The authors concluded that no detrimental effects on the physical or intellectual development occurred in those children exposed to methimazole during pregnancy (Azizi, 2002). The main strength of this study was the single blinded psychologist evaluation of child intellect using the WPPSI exam. Unfortunately, the WPPSI is an intelligence test designed for children ages 2 years 6 months to 7 years 3 months and the study population included children 3-11 years of age. Other limitations to

The selection of PTU over methimazole as the drug of choice to treat Graves' disease during pregnancy should not be based on misleading statements in the literature that PTU has less placental transfer than methimazole, that PTU leads to less fetal hypothyroidism, or that exposure to methimazole during pregnancy leads to a decreased intellectual function in children. The United States Food and Drug Administration classifies both PTU and methimazole as a Category D because of the potential for fetal hypothyroidism, rather than potential teratogenicity. The ACOG recommends that either PTU or methimazole may be

this study were a small sample size and low exposure dose of methimazole.

were identified.

delivery.

**3. Conclusion**

Treatment of Graves' Disease During Pregnancy 145

Kannan L, Mishra S, Agarwal R, Kartikeyan V, Gupta N, & Kabra M. (2008). Carbimazole

report and review of the literature. *Birth Defects Research* 2008;82:649-651. Karabinas CD, & Tolis GJ. Thyroid disorders and pregnancy. *J Obstet and Gynaecol*

Karg E, Bereg E, Gaspar L, Katona M, & Turi S. (2004). Aplasia cutis congenital after methimazole exposure in utero. *Pediatr Dermatol* 2004;21(4):491-494. Karlson FA, Axelsson O, & Melhus H. (2002). Severe embryopathy and exposure to methimazole in early pregnancy. *J Clin Endocrinol Metab* 2002;87:947-948. Kontoleon P, Ilias I, Koutras DA, Kontogiannis D, & Papapetrou PD. (2002). Successful

Laurberg P, Bournaud C. Karmisholt J, & Orgiazzi J. (2009). Management of Graves'

Lazarus JH. (2005). Thyroid disorders associated with pregnancy: etiology, diagnosis, and

Mandel SJ, & Cooper DS. (2001). The use of antithyroid drugs in pregnancy and lactation. *J*

Marchant B, Brownlie BE, Hart DM, Horton PW, & Alexander WD. (1977). The placental

Marx H, Amin P, & Lazarus JH. (1997). Hyperthyroidism and pregnancy. *BMJ* 2008;336:663-

Masiukiewicz US, & Burrow GN. (1999). Hyperthyroidism in pregnancy: diagnosis and

Mestman JH. (2004). Hyperthyroidism in pregnancy. *Best Pract Res Clin Endocrinol Metab*

Mestman JH. (1998). Hyperthyroidism in pregnancy. *Endocrinol Metab Clin North Am*

Miehle K, & Paschke R. (2003). Therapy of hyperthyroidism. *Exp Clin Endocrinol Diabetes*

Millar LK, Wing DA, Leung AS, Koonings PP, Montoro MN, & Mestman JH. (1994). Low

Momotani N, Yoshimura J, Ishikawa N, & Ito K. (1997). Effects of propylthiouracil and

Morreale de Escobar G, Obregon MJ, & Escobar del Rey F. (2000). Is neuropsychological

Mortimer RH, Cannell GR, Addison RS, Johnson LP, Roberts MS, & Bernus I. (1997).

hypothyroxinemia? *J Clin Endocrinol Metab* 2000;85:3975-87

placental lobule. *J Clin Endocrinol Metab* 1997;82:3099-3102.

birth weight and pre-eclampsia in pregnancies complicated by hyperthyroidism.

methimazole of fetal thyroid status in mothers with graves' hyperthyroidism. *J Clin*

development related to maternal hypothyroidism or to maternal

Methimazole and propylthoiuracil equally cross the perfused human term

transfer of propylthiouracil, methimazole and carbimazole. *J Clin Endocrinol Metab*

management. *Treat Endocrinol* 2005;4(1):31-41.

*Clin Endocrinol Metab* 2001;86:2354-2359.

treatment. *Thyroid* 1999;9:647-652.

1998;18:509-515.

305.

2009;160:1-8.

1977;45:1187-93.

2004;18:267-288.

1998;27:127-149.

2003;111:305-318.

*Obstet Gynecol* 1994;84:946-9.

*Endocrinol Metab* 1997;82:3633-3636.

7.

embryopathy-bilateral choanal atresia and patent vitello-intestinal duct: a case

treatment with carbimazole of a hyperthyroid pregnancy with hepatic impairment after propylthiouracil administration: a case report. *Clin Exp Obst Gyn* 2002;29:304-

hyperthyroidism in pregnancy : focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy. *Euro J Endocrinol*

Clark SM, Saade GR, Snodgrass WR, & Hankins GDV. (2006). Pharmacokinetics and

Clementi M, Di Gianantonio E, Pelo E, Mammi I, Basile RT, & Tenconi R. (1999).

Cooper DS. (1987). Antithyroid drugs: to breast-feed or not to breastfeed. *Am J Obstet*

Cooper DS. (2009). Putting propylthiouracil in perspective*. J Clin Endocrinol Metab*

Di Gianantonio E, Schaefer C, Mastroiacovo P, Cournot M, Benedicenti F, Reuvers M,

Ferraris S, Valenzise M, Lerone M, Divizia MT, Rosaia L, & Blaid D. (2003). Malformations

Fitzpatrick DL, & Russel MA. (2010). Diagnosis and management of thyroid disease in

Galorfre JC, & Davies TF. (2009). Autoimmune thyroid disease in pregnancy: a review. *J*

Garcia-Mayor RV, & Larranaga A. (2010). Treatment of Graves' hyperthyroidism with

Glinoer D. (2003). Management of hypo- and hyperthyroidism during pregnancy. *Growth*

Hamburger JI. (1992). Diagnosis and management of graves' disease in pregnancy. *Thyroid*

Hashizume K, Ichikawa K, Nishii Y, Kobayashi M, Sakurai A, Miyamoto T, Suzuki S,

Inoue M, Arata N, Koren G, & It S. ( 2009). Hyperthyroidism during pregnancy. *Can Fam*

Jonklaas J & Talbert RL. (2011). Thyroid Disorders. In : DiPiro JT, Talbert RL, Yee GC,

Kang AY, Baek YH, Sohn YJ, Lee SK, Son CH, Kim KH, & Yang DK. (2006). Diffuse alveolar

Takeda T. (1992). Effect of administration of thyroxine on the risk of postpartum recurrence of hyperthyroid Graves' disease. *J Clin Endocrinol Metab* 1992;75:6-10. Hayashida CY. (1990). Neonatal hepatitis and lymphocyte sensitization by placental

Matzke GR, Wells BG, Posey LM, eds. *Pharmacotherapy: A Pathophysiological*

hemorrhage associated with antineutrophil cytoplasmic antibody levels in a pregnant woman taking propylthiouracil. *Korean J Intern Med* 2006;21:240-243.

thionamides-derived drugs: review. *Med Chem* 2010;6(4):239-246.

transfer of propylthiouracil. *J Endocrinol Invest* 1990;13:937-41.

effects of prenatal methimazole exposure. *Teratology* 2001;64:262-266. Dwarakanath CS, Ammini AC, Kriplani A, Shah P, & Paul VK. (1999). Graves' disease during pregnancy- results of antithyroid drug therapy. *Singapore Med J* 1999;40:70. Ecker JL, & Musci TJ. (2000). Thyroid function and disease in pregnancy. *Curr Probl Obstet*

Cooper DS. (2005). Antithyroid Drugs. *N Eng J Med* 2005;352:905-17.

pregnancy. *Obstet Gynecol Clin N Am* 2010;37:173-93.

Gorman CA. (1999). Radioiodine and pregnancy. *Thyroid* 1999;9:721-6.

*Approach. 8*th ed. New York, NY: McGraw-Hill, 2011.

483.

1999;83:43-46.

*Gynecol* 1987;157:234-5.

2009;94(6):1881-1882.

*Gynecol Fertil* 2000;23:109-122.

*Mol Teratol* 2003;67:989-992.

*Women's Health* 2009;18(11):1847-56.

*Horm IGF Res* 2003;13:S45-S54.

1992;3:219-224.

*Phys* 2009;55:701-703.

pharmacotherapy of thionamides in pregnancy. *Ther Drug Monit* 2006;28(4):477-

Methimazole embryopathy: delineation of the phenotype. *Am J Med Genet*

Occupati V, Robert E, Bellemin B, Addis A, Arnon J, & Clementi M. (2001). Adverse

following methimazole exposure in utero: an open issue. *Birth Defects Res A Clin*

**8**

**Universal Screening for Thyroid Disorders in**

Eliska Potlukova1, Jan Jiskra1, Zdenek Telicka1, Drahomira Springer2 and Zdenka Limanova1

*2Institute of Clinical Biochemistry and Laboratory Diagnostics,*

*Charles University in Prague, Czech Republic*

*General University Hospital, Prague,*

 *Czech Republic*

**Pregnancy: Experience of the Czech Republic**

*13rd Department of Medicine, General University Hospital and 1st Faculty of Medicine,*

The role of the thyroid gland in pregnancy and the impact of thyroid disorders on the course of pregnancy and development of the offspring have drawn a considerable interest in the recent years, both in the medical and in the general society. About 10% of pregnant women are positive for autoantibodies against thyroperoxidase (TPOAb) (Glinoer 2007, Lazarus and Kokandi 2000, Springer 2009) and between 2 and 4% suffer subclinical or overt hypothyroidism (Casey 2005; Vaidya 2007, Springer 2009). Dysfunction of the maternal thyroid in pregnancy adversely affects the course of pregnancy and the psychomotor development of the offspring (Haddow 1999, Morreale de Escobar 2004). According to recent findings, even the mere positivity of TPOAb without concomitant thyroid dysfunction in pregnant women may have a negative impact on the psychomotor development of the child (Li 2010). Furthermore, up to one half of the TPOAb-positive (TPOAb+) pregnant women develop postpartum thyroiditis (PPT) which can lead to persistent hypothyroidism in about one third of women (Lazarus and Premawardhana 2008). According to recent findings of Stagnaro-Green, this proportion may be even much higher and persistent hypothyroidism may affect up to one-half of women with history of PPT (Stagnaro-Green 2011b). If unrecognised and untreated, late postpartum thyroid dysfunction, in most cases subclinical (SH) or overt hypothyroidism (OH) may have a longterm negative effect not only on the mother´s health, but also on the next pregnancies.

Since 2006, repeated attempts to implement a universal screening programme for thyroid disorders in the first trimester of pregnancy have been made in the Czech Republic. Moreover, the Czech Endocrine Society initiated a wide informational campaign concerning the importance of correct thyroid function in pregnancy in the media, including TV discussions, seminars and lectures for both the general population and the health professionals. Members of the Czech Endocrine Society together with colleagues from the Czech Society of Biochemistry have initiated several studies focused on various aspects of thyroid disorders among Czech pregnant women. In this review article, we present an

overview of the data obtained in the recent years.

**1. Introduction**

### **Universal Screening for Thyroid Disorders in Pregnancy: Experience of the Czech Republic**

Eliska Potlukova1, Jan Jiskra1, Zdenek Telicka1, Drahomira Springer2 and Zdenka Limanova1 *13rd Department of Medicine, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Czech Republic 2Institute of Clinical Biochemistry and Laboratory Diagnostics, General University Hospital, Prague, Czech Republic*

#### **1. Introduction**

146 A New Look at Hypothyroidism

Patil-Sisodia K, & Mestman JH. (2007). Graves hyperthyroidism and pregnancy: a clinical

Rashid M, & Rashid MH. Obstetric management of thyroid disease. *Obstet Gynecol*

Rosenfeld H, Ornoy A, Schechtman S, & Diav-Citrin O. (2009). Pregnancy outcome, thyroid

Seoud M, Nassar A, Usta I, Mansour M, Salti I, & Younes K. (2003). Gastrointestinal

Van Dijke CP, Heydendael RJ, & De Kleine MJ. (1987). Methimazole, carbimazole, and

Wing DA, Millar LK, Koonings PP, Montoro MN, & Mestman JH. (1994). A comparison of

dysfunction and fetal goiter after in utero exposure to propylthiouracil: a controlled

malformations in two infants born to women with hyperthyroidism untreated in

propylthiouracil versus methimazole in the treatment of hyperthyroidism in

update. *Endocr Pract* 2010;16(1):118-129.

the first trimester. *J Perinat* 2003;20:59-62.

pregnancy. *Am J Obstet Gynaecol* 1994;170:90-5.

cohort study. *Br J Clin Pharmacol* 2009;68(4):609-617.

congenital skin Defects. *Ann Intern Med* 1987;106:60-61. Weetman AP. (2000). Graves' Disease. *N Eng J Med* 2000;343:1236-1248.

2007;62(10):680-688.

The role of the thyroid gland in pregnancy and the impact of thyroid disorders on the course of pregnancy and development of the offspring have drawn a considerable interest in the recent years, both in the medical and in the general society. About 10% of pregnant women are positive for autoantibodies against thyroperoxidase (TPOAb) (Glinoer 2007, Lazarus and Kokandi 2000, Springer 2009) and between 2 and 4% suffer subclinical or overt hypothyroidism (Casey 2005; Vaidya 2007, Springer 2009). Dysfunction of the maternal thyroid in pregnancy adversely affects the course of pregnancy and the psychomotor development of the offspring (Haddow 1999, Morreale de Escobar 2004). According to recent findings, even the mere positivity of TPOAb without concomitant thyroid dysfunction in pregnant women may have a negative impact on the psychomotor development of the child (Li 2010). Furthermore, up to one half of the TPOAb-positive (TPOAb+) pregnant women develop postpartum thyroiditis (PPT) which can lead to persistent hypothyroidism in about one third of women (Lazarus and Premawardhana 2008). According to recent findings of Stagnaro-Green, this proportion may be even much higher and persistent hypothyroidism may affect up to one-half of women with history of PPT (Stagnaro-Green 2011b). If unrecognised and untreated, late postpartum thyroid dysfunction, in most cases subclinical (SH) or overt hypothyroidism (OH) may have a longterm negative effect not only on the mother´s health, but also on the next pregnancies.

Since 2006, repeated attempts to implement a universal screening programme for thyroid disorders in the first trimester of pregnancy have been made in the Czech Republic. Moreover, the Czech Endocrine Society initiated a wide informational campaign concerning the importance of correct thyroid function in pregnancy in the media, including TV discussions, seminars and lectures for both the general population and the health professionals. Members of the Czech Endocrine Society together with colleagues from the Czech Society of Biochemistry have initiated several studies focused on various aspects of thyroid disorders among Czech pregnant women. In this review article, we present an overview of the data obtained in the recent years.

Universal Screening for Thyroid Disorders in Pregnancy: Experience of the Czech Republic 149

2004

2005

2006

Case-finding screening

Case-finding screening

screening

screening

screening

Universal screening

Authority Year Recommendation American Association of Clinical Endocrinologists 2002 Universal screening

American College of Obstetrics and Gynecology 2007 Case-finding

The Endocrine Society 2007 Case-finding

American Thyroid Association 2011 Case-finding

Table 1. Overview of recommendations for screening for thyropathy in pregnancy.

The main argument of the opponents to universal screening is the lack of randomised controlled trials demonstrating that treatment by LT4 of pregnant women with subclinical hypothyroidism increases the offspring´s IQ. Preliminary results of the first major study "The Control Antenatal Thyroid Screening Study" presented on ITC in Paris 2010 were rather disappointing (Lazarus 2010). The authors found only a non-significant difference in the prevalence of three-year-old children with IQ<85 of women unscreened vs. mothers screened and treated in case of SH in pregnancy (15% vs. 11.5%, p=0.09). However, the major drawback of this study is that pregnant women up to the 16th gestation week were included. Thus, we may suspect that in some women the treatment started too late, after the crucial changes in the embryonic/foetal brain have occurred. Another multicenter randomized placebo-controlled clinical trial is at present being conducted by the Maternal Fetal Medicine Unit of the National Institutes of Health in the USA. The primary outcome will be child IQ at 5 years of age. Results of this study should be available in 2015 and they may give a final answer to the question of universal screening for thyroid disorders in

Due to the above-mentioned facts, the latest guidelines of the American Thyroid Association (ATA) recommend a case-finding screening targeted at women at high-risk for hypothyroidism in pregnancy (Stagnaro-Green 2011a). The new guidelines introduce age over 30 years and body-mass index over 40 kg/m2 among the risk factors. The other risk factors include: history of thyroid dysfunction or prior thyroid surgery, symptoms of thyroid dysfunction or the presence of goitre, TPOAb positivity, diabetes type 1 or other autoimmune diseases in history, history of miscarriage or preterm delivery, history of head of neck radiation, family history of thyroid dysfunction, use of amiodarone/lithium or recent administration of iodinated radiologic contrast, infertility and residence in an area of

Expert panel of American Thyroid Association, American Association of Clinical Endocrinologists and

Second panel of American Thyroid Association, American Association of Clinical Endocrinologists and

British Thyroid Association, Association of Clinical Biochemists, British Thyroid Foundation. UK guidelines for the Use of thyroid Function Tests

The Endocrine Society

The Endocrine Society

pregnancy.

**The case-finding screening strategy**

#### **Impact of thyroid dysfunction on pregnancy and foetal health**

The developing foetus is dependent upon the maternal thyroid hormone synthesis up to the 14th to 16th gestational weeks. Afterwards, its´ own thyroid gland starts to synthesise thyroid hormones, albeit in insufficient quantities. Thus, the first trimester of pregnancy is crucial in terms of adequate supply of maternal thyroid hormones to the embryo. Numerous retrospective and case-controlled studies confirmed detrimental effects of maternal overt hypothyroidism (OH) on the course of pregnancy and on foetal health.

Severe deficit of thyroid hormones leads to irreversible changes in foetal development. Impairment of neuronal differentiation leads to inadequate development of the central nervous system with resulting mental retardation. It may also lead to somatic defects including congenital cardiac defects and disrupted bone growth. These changes are most prominent in untreated congenital hypothyroidism (cretinism). Moderate thyroid hormone deficit may lead to less pronounced neurocognitive dysfunction. As Haddow et al. have shown in their well-cited study, children of untreated hypothyroid pregnant women had at age 7 to 9 years IQ below 85 points in 19% of cases in comparison with 5% of children of euthyroid or substituted mothers. The average IQ was 7 points lower in children of hypothyroid untreated mothers than in children of hypothyroid mothers substituted by levothyroxine (LT4) (Haddow 1999). Furthermore, iodine-deficient pregnant women are prone to hypothyroxinaemia. As Morreale de Escobar has shown, up to 70 % of children of iodine-deficient mothers may suffer from attention deficit hyperactive disorder (Morreale de Escobar 2004a,b).

Apart from neurocognitive foetal impairment, maternal untreated OH is associated with the risk of foetal loss in up to 60% (Abalovich 2002) and the risk of gestational hypertension in 22 % (Leung 1993), which was higher than in euthyroid women of women with subclinical hypothyroidism. According to Allan et al, women with OH have also an increased risk of foetal death (Allan 2000). Thus, it is of no doubt that untreated maternal OH may be detrimental for the maternal-foetal unit in the short-term and in the long-term sense.

#### **Pros and cons of universal screening for thyroid disorders in pregnancy**

Although maternal autoimmune thyroid disorders (AITD) fulfil many criteria used for identification of diseases subject to universal screening, this issue has been highly controversial. The main arguments for implementation of universal screening are the following: a) the impact of maternal hypothyroidism on the course of pregnancy and the health of offspring has been well described and the treatment is effective and simple; b) the prevalence of hypothyroidism in pregnancy is comparable with other universally screened diseases; c) the method of screening (laboratory measurement of thyroid parameters) is relatively simple and inexpensive – the financial costs depending on the choice of thyroid parameters screened; d) it is cost-effective (on condition that not only OH, but also SH decreases the offspring´s IQ (Dosiou 2008, Thung 2009); e) the risk-benefit ratio of the screening for each individual is acceptable. In the past, some authorities recommended universal screening but not the American Thyroid Association or the Association of American Obstetricians and Gynaecologists, who have consistently advocated a casefinding screening strategy focused on high-risk women (Abalovich 2007, Stagnaro-Green 2011) (Table 1).

The developing foetus is dependent upon the maternal thyroid hormone synthesis up to the 14th to 16th gestational weeks. Afterwards, its´ own thyroid gland starts to synthesise thyroid hormones, albeit in insufficient quantities. Thus, the first trimester of pregnancy is crucial in terms of adequate supply of maternal thyroid hormones to the embryo. Numerous retrospective and case-controlled studies confirmed detrimental effects of maternal overt

Severe deficit of thyroid hormones leads to irreversible changes in foetal development. Impairment of neuronal differentiation leads to inadequate development of the central nervous system with resulting mental retardation. It may also lead to somatic defects including congenital cardiac defects and disrupted bone growth. These changes are most prominent in untreated congenital hypothyroidism (cretinism). Moderate thyroid hormone deficit may lead to less pronounced neurocognitive dysfunction. As Haddow et al. have shown in their well-cited study, children of untreated hypothyroid pregnant women had at age 7 to 9 years IQ below 85 points in 19% of cases in comparison with 5% of children of euthyroid or substituted mothers. The average IQ was 7 points lower in children of hypothyroid untreated mothers than in children of hypothyroid mothers substituted by levothyroxine (LT4) (Haddow 1999). Furthermore, iodine-deficient pregnant women are prone to hypothyroxinaemia. As Morreale de Escobar has shown, up to 70 % of children of iodine-deficient mothers may suffer from attention deficit hyperactive disorder (Morreale de

Apart from neurocognitive foetal impairment, maternal untreated OH is associated with the risk of foetal loss in up to 60% (Abalovich 2002) and the risk of gestational hypertension in 22 % (Leung 1993), which was higher than in euthyroid women of women with subclinical hypothyroidism. According to Allan et al, women with OH have also an increased risk of foetal death (Allan 2000). Thus, it is of no doubt that untreated maternal OH may be

Although maternal autoimmune thyroid disorders (AITD) fulfil many criteria used for identification of diseases subject to universal screening, this issue has been highly controversial. The main arguments for implementation of universal screening are the following: a) the impact of maternal hypothyroidism on the course of pregnancy and the health of offspring has been well described and the treatment is effective and simple; b) the prevalence of hypothyroidism in pregnancy is comparable with other universally screened diseases; c) the method of screening (laboratory measurement of thyroid parameters) is relatively simple and inexpensive – the financial costs depending on the choice of thyroid parameters screened; d) it is cost-effective (on condition that not only OH, but also SH decreases the offspring´s IQ (Dosiou 2008, Thung 2009); e) the risk-benefit ratio of the screening for each individual is acceptable. In the past, some authorities recommended universal screening but not the American Thyroid Association or the Association of American Obstetricians and Gynaecologists, who have consistently advocated a casefinding screening strategy focused on high-risk women (Abalovich 2007, Stagnaro-Green

detrimental for the maternal-foetal unit in the short-term and in the long-term sense.

**Pros and cons of universal screening for thyroid disorders in pregnancy**

**Impact of thyroid dysfunction on pregnancy and foetal health**

hypothyroidism (OH) on the course of pregnancy and on foetal health.

Escobar 2004a,b).

2011) (Table 1).

Table 1. Overview of recommendations for screening for thyropathy in pregnancy.

The main argument of the opponents to universal screening is the lack of randomised controlled trials demonstrating that treatment by LT4 of pregnant women with subclinical hypothyroidism increases the offspring´s IQ. Preliminary results of the first major study "The Control Antenatal Thyroid Screening Study" presented on ITC in Paris 2010 were rather disappointing (Lazarus 2010). The authors found only a non-significant difference in the prevalence of three-year-old children with IQ<85 of women unscreened vs. mothers screened and treated in case of SH in pregnancy (15% vs. 11.5%, p=0.09). However, the major drawback of this study is that pregnant women up to the 16th gestation week were included. Thus, we may suspect that in some women the treatment started too late, after the crucial changes in the embryonic/foetal brain have occurred. Another multicenter randomized placebo-controlled clinical trial is at present being conducted by the Maternal Fetal Medicine Unit of the National Institutes of Health in the USA. The primary outcome will be child IQ at 5 years of age. Results of this study should be available in 2015 and they may give a final answer to the question of universal screening for thyroid disorders in pregnancy.

#### **The case-finding screening strategy**

Due to the above-mentioned facts, the latest guidelines of the American Thyroid Association (ATA) recommend a case-finding screening targeted at women at high-risk for hypothyroidism in pregnancy (Stagnaro-Green 2011a). The new guidelines introduce age over 30 years and body-mass index over 40 kg/m2 among the risk factors. The other risk factors include: history of thyroid dysfunction or prior thyroid surgery, symptoms of thyroid dysfunction or the presence of goitre, TPOAb positivity, diabetes type 1 or other autoimmune diseases in history, history of miscarriage or preterm delivery, history of head of neck radiation, family history of thyroid dysfunction, use of amiodarone/lithium or recent administration of iodinated radiologic contrast, infertility and residence in an area of

Universal Screening for Thyroid Disorders in Pregnancy: Experience of the Czech Republic 151

higher prevalence of hypothyroidism among Czech pregnant women; or our analytical method used for TSH measurements gives higher numbers than methods used by others. However, our analysis was performed using a well-established and widely used analyser (Advia Centaur, Siemens). Apparently, the cut-off at 2.5 mU/l would lead to large

Hypothyroidism was defined as TSH >3.67 mIU/l (overt with decreased FT4 and subclinical with TSH >3.67 mIU/l and normal FT4). Hyperthyroidism was defined as decreased TSH <0.06 mIU/l (overt with TSH <0.06 mIU/l and FT4 >23.0 pmol/l and subclinical with TSH<0.06 mIU/l and normal FT4.

Table 2. Results of universal screening for thyroid disorders among Czech pregnant women

selected 5520 1.280 0 411.874 0.048 0.147 3.713 4.796

Selected group: pregnant women with no history of thyroid disease, anti-TPO level lower than 60 kU/l

Table 3. Reference ranges for TSH in the 9th to 11th gestational weeks in Czech pregnant women.

**percentile**

4337 1.213 0 11.534 0.062 0.154 3.144 3.670

**5th percentile**

**95th percentile**

**97.5th percentile**

Number of women screened

numbers of pregnant women positive in screening.

in the 9th to 11th gestational weeks.

Non-

Selected group

**TSH mU/l N Median Minimum Maximum 2.5th**

and free bhCG lower than triple that of the median (56.6 mg/l).

Total 5520

Positive in screening (at least one parameter) 822 (14.89%) Hypothyroidism 299 (5.42 %) Overt hypothyroidism 49 (0.89 %) Subclinical hypothyroidism 250 (4.53 %) TPOAb+ hypothyroidism 144 (2.61 %) TPOAb- hypothyroidism 155 (2.81 %) Transient gestational hyperthyroidism 99 (1.8 %) Hyperthyroidism 141 (2.55 %) Overt hyperthyroidism 19 (0.34 %) Subclinical hyperthyroidism 122 (2.21 %) TPOAb+ hyperthyroidism 23 (0.42 %) TPOAb- hyperthyroidism 118 (2.14 %) TPOAb positivity (>143 kIU/l) 549 (9.95 %) Euthyroid TPOAb+ 376 (6.81 %) TPOAb+, normal TSH, decreased FT4 5 (0.09 %) TPOAb+, normal TSH, elevated FT4 1 (0.02 %)

known moderate to severe iodine insufficiency. Thus, according to ATA, the first physician dealing with newly pregnant women should consider 12 different risk factors. If any of them were positive, he should order a blood test for thyroid-stimulating hormone (TSH). In our opinion, this form of screening is likely to be neglected due to practical reasons. It has been shown that the case-finding approach may miss up to one half of pregnant women in comparison with universal screening (Vaidya 2007, Horacek 2010, Jiskra 2011a); and it may be difficult to implement in the routine practice (Vaidya 2002). Moreover, in our view, assessment of only TSH is insufficient due to the above-mentioned risks carried by isolated hypothyroxinemia and TPOAb positivity.

#### **2. Prevalence of thyroid disorders in pregnant Czech women**

The Czech Endocrine Society together with the Czech Society of Biochemistry has repeatedly attempted to implement universal screening for AITD in the first trimester of pregnancy. In order to gain data on thyroid disorders in Czech pregnant women, two large studies including nearly 8 000 consecutive pregnant women (Springer 2009, Limanova 2011), have been conducted in the Czech Republic in the last years.

The first study by Springer et al. was performed between 2006 and 2008 and examined 5520 consecutive asymptomatic pregnant women in the 9th-11th gestational week. The aim of this study was to evaluate the prevalence of thyroid disorders in pregnant Czech women and to identify optimal reference intervals in evaluation of maternal thyroid function during the first trimester of pregnancy. The screening consisted of laboratory assessment of serum thyroid stimulating hormone (TSH), free thyroxine (FT4, only in those with pathological TSH/TPOAb) and autoantibodies against thyroperoxidase (TPOAb). All measurements were performed by chemiluminometric immunoanalysis on an ADVIA Centaur system (Siemens, Healthcare Diagnostics Inc, Tarrytown, NY, USA) in one centre (Institute of Clinical Biochemistry and Laboratory Diagnostics, General University Hospital in Prague). Women with positive screening result were advised to visit an endocrinologist within a few days. Based on the results obtained, Springer et al. set normal limits for TSH and TPOAb in pregnancy as following: TSH 0.06-3.67 mU/l; TPOAb <143 kU/l; the study did not attempt to set new reference ranges for FT4. In this cohort of pregnant women, 822 (14.9%) had at least one of the parameters outside of the normal range. Suppressed TSH was found in 141 (2.55%) women, while 299 (5.42%) had TSH over the reference interval; elevation of TPOAb was present in 549 (9.95%) women (Jiskra 2011a). The data are shown in detail in Table 2.

Thus, in this study, there was a higher prevalence of pregnant women with TSH elevation (4.48%) as compared to other iodine-sufficient countries, where the prevalence of pregnant women with TSH elevation reaches 2-3% (Casey 2005; Allan 2000; Vaidya 2007). Obviously, these numbers depend on the TSH upper limit of reference range used. In the Czech studies, the cut-off at 3.67 mU/l was used (Springer 2009). This value was determined as the 97.5th percentile of TSH values of 4337 women in the first trimester of pregnancy with no history of thyroid disease, anti-TPO level lower than 60 kU/l (=negative) and free bhCG lower than triple that of the median (56.6 mg/l). It is interesting to note that the 97.5th percentile in unselected women was higher (Table 3). At present, world authorities recommend to use the upper cut-off at 2.5 mUl (Stagnaro-Green 2011). Therefore, for the Czech population, this cut-off lies either too low; or there is a

known moderate to severe iodine insufficiency. Thus, according to ATA, the first physician dealing with newly pregnant women should consider 12 different risk factors. If any of them were positive, he should order a blood test for thyroid-stimulating hormone (TSH). In our opinion, this form of screening is likely to be neglected due to practical reasons. It has been shown that the case-finding approach may miss up to one half of pregnant women in comparison with universal screening (Vaidya 2007, Horacek 2010, Jiskra 2011a); and it may be difficult to implement in the routine practice (Vaidya 2002). Moreover, in our view, assessment of only TSH is insufficient due to the above-mentioned risks carried by isolated

The Czech Endocrine Society together with the Czech Society of Biochemistry has repeatedly attempted to implement universal screening for AITD in the first trimester of pregnancy. In order to gain data on thyroid disorders in Czech pregnant women, two large studies including nearly 8 000 consecutive pregnant women (Springer 2009, Limanova

The first study by Springer et al. was performed between 2006 and 2008 and examined 5520 consecutive asymptomatic pregnant women in the 9th-11th gestational week. The aim of this study was to evaluate the prevalence of thyroid disorders in pregnant Czech women and to identify optimal reference intervals in evaluation of maternal thyroid function during the first trimester of pregnancy. The screening consisted of laboratory assessment of serum thyroid stimulating hormone (TSH), free thyroxine (FT4, only in those with pathological TSH/TPOAb) and autoantibodies against thyroperoxidase (TPOAb). All measurements were performed by chemiluminometric immunoanalysis on an ADVIA Centaur system (Siemens, Healthcare Diagnostics Inc, Tarrytown, NY, USA) in one centre (Institute of Clinical Biochemistry and Laboratory Diagnostics, General University Hospital in Prague). Women with positive screening result were advised to visit an endocrinologist within a few days. Based on the results obtained, Springer et al. set normal limits for TSH and TPOAb in pregnancy as following: TSH 0.06-3.67 mU/l; TPOAb <143 kU/l; the study did not attempt to set new reference ranges for FT4. In this cohort of pregnant women, 822 (14.9%) had at least one of the parameters outside of the normal range. Suppressed TSH was found in 141 (2.55%) women, while 299 (5.42%) had TSH over the reference interval; elevation of TPOAb was present in 549 (9.95%) women (Jiskra 2011a). The data are shown in detail in Table 2.

Thus, in this study, there was a higher prevalence of pregnant women with TSH elevation (4.48%) as compared to other iodine-sufficient countries, where the prevalence of pregnant women with TSH elevation reaches 2-3% (Casey 2005; Allan 2000; Vaidya 2007). Obviously, these numbers depend on the TSH upper limit of reference range used. In the Czech studies, the cut-off at 3.67 mU/l was used (Springer 2009). This value was determined as the 97.5th percentile of TSH values of 4337 women in the first trimester of pregnancy with no history of thyroid disease, anti-TPO level lower than 60 kU/l (=negative) and free bhCG lower than triple that of the median (56.6 mg/l). It is interesting to note that the 97.5th percentile in unselected women was higher (Table 3). At present, world authorities recommend to use the upper cut-off at 2.5 mUl (Stagnaro-Green 2011). Therefore, for the Czech population, this cut-off lies either too low; or there is a

**2. Prevalence of thyroid disorders in pregnant Czech women**

2011), have been conducted in the Czech Republic in the last years.

hypothyroxinemia and TPOAb positivity.

higher prevalence of hypothyroidism among Czech pregnant women; or our analytical method used for TSH measurements gives higher numbers than methods used by others. However, our analysis was performed using a well-established and widely used analyser (Advia Centaur, Siemens). Apparently, the cut-off at 2.5 mU/l would lead to large numbers of pregnant women positive in screening.

Hypothyroidism was defined as TSH >3.67 mIU/l (overt with decreased FT4 and subclinical with TSH >3.67 mIU/l and normal FT4). Hyperthyroidism was defined as decreased TSH <0.06 mIU/l (overt with TSH <0.06 mIU/l and FT4 >23.0 pmol/l and subclinical with TSH<0.06 mIU/l and normal FT4.

Table 2. Results of universal screening for thyroid disorders among Czech pregnant women in the 9th to 11th gestational weeks.

Selected group: pregnant women with no history of thyroid disease, anti-TPO level lower than 60 kU/l and free bhCG lower than triple that of the median (56.6 mg/l).

Table 3. Reference ranges for TSH in the 9th to 11th gestational weeks in Czech pregnant women.

Universal Screening for Thyroid Disorders in Pregnancy: Experience of the Czech Republic 153

in group of women aged 31-35 years) (Dvorakova 2006). Furthermore, the thyroid volume in pregnant women did not differ from controls. This is in contrast to the findings of both Fister and Vila, who showed an increased thyroid volume in pregnancy in iodine-sufficient (Fister 2009) and iodine-deficient areas (Vila 2008). The finding of small thyroids in pregnant Czech women is probably linked to the saturation with iodine. Iodine supplementation of salt has been introduced in Czechoslovakia in 1950. Therefore, the present pregnant women

In our study, we also found that only 49% of the TPOAb+ pregnant women had autoimmune pattern on TUS. This was significantly less than in non-pregnant TPOAb+ controls (74 %) (Fig.1). Apparently, alterations of immune system in pregnancy cause a different manifestation of autoimmunity in the thyroid tissue. Moreover, we found that the thyroid ultrasound pattern was associated with preterm delivery: TPOAb+ women without autoimmune pattern in TUS had significantly lower prevalence of preterm delivery than the TPOAb+ ones with autoimmune pattern (3.1 vs. 15.2 %). Therefore, autoimmune TUS image

Controls p=0.011 p<0.001

Pregnant women

are already the third generation who live in iodine-sufficient conditions.

in TPOAb+ pregnant women seems to be associated with preterm delivery.

**TPOAb>143 kU/l TPOAb>200 kU/l**

Fig. 1. Ultrasound autoimmune pattern in TPOAb-positive pregnant women and controls.

In the next study from 2011, we focused on the relationship between clinical history, laboratory findings and TUS pattern in positively screened pregnant women (Jiskra 2011b). In this study, 200 of the positively screened women from the cohort of Springer et al. were included (Springer 2009). We regarded women as high-risk if they had any of the following risk factors: family and/or personal history of thyroid disease (including presence of goitre and signs and symptoms suggestive for thyroid dysfunction), family and/or personal history for autoimmune disease, history of neck irradiation, previous miscarriages and preterm deliveries). After exclusion of transient gestational hyperthyroidism, only 74/159 (47 %) women were classified as high-risk for thyroid disease according to their history. There were no significant clinical and laboratory differences between the high- vs. low-risk women, except for higher proportion of FT4 < 75th percentile and a larger thyroid volume in the high-risk group. These finding were consistent with the results of Horacek et al. (Horacek 2010) who found that case-finding screening strategy would miss one half of the high-risk women.

**0**

**20**

**40**

**60**

**% with autoimmune pattern**

**80**

**100**

After two years of preparations, a joint "Pilot Project" of the Czech Society of Endocrinology, the Society of Clinical Biochemistry and the General Insurance Company of the Czech Republic started in 2009 (Limanova 2011). The Pilot Project was supported by the General Insurance Company. The aim of the Pilot Project was to ascertain the optimal combination and economic feasibility of diagnostic tests, the timing of the blood test and the possibility of connecting the test with genetic-disorder screening in the first trimester of pregnancy. The purpose of the study was also to provide information about cooperation among gynaecologists, laboratories and endocrinologists. In the Pilot Project, TSH, FT4 and TPOAb were measured in 2937 consecutive pregnant women from 13 Czech regions with good laboratory background and cooperative endocrinologists. Contrary to the previous study, measurements were performed in regional laboratories and the reference ranges differed according to each laboratory. In this cohort, 569 (19.4%) woman were screened as positive. Abnormalities of TSH were found in 11% of women: elevation in 7.8% and suppression in 3.2%. Only 15 (0.5%) women with TSH suppression were diagnosed with true hyperthyroidism. Hypothyroxinemia was found in 3.7% and TPOAb positivity in 262 (8.9%) women. One hundred fifty-eight women (5.37%) had positive TPOAb with normal thyroid function. Thus, in this second study, we found an even higher prevalence of abnormally high TSH among pregnant women than in the study of Springer et al. However, due to the different analytical methods, these results cannot be directly compared. Cooperation with gynaecologists wasn´t always optimal despite the fact that they were provided with all necessary information well in advance. On the other hand, laboratories analysed the samples promptly, and many of them took part in providing publicity and further information to other cooperating health care professionals. In conclusion, the Pilot Project study showed that implementation of universal screening for thyroid disorders in pregnancy would be feasible in the Czech Republic, although the general knowledge on importance of correct thyroid function in pregnancy needs to be improved among practical gynaecologists.

The attempts to implement a universal screening programme for AITD in pregnancy in the Czech Republic have suffered a major blow due to the world financial crisis starting in 2009. In the future years, we will probably have to concentrate on implementation of the casefinding approach years among the official risk factors.

#### **3. Ultrasound imaging and risk-assessment of positively screened pregnant women**

Most of the studies on AITD in pregnancy deal only with laboratory parameters and it is not clear whether the thyroid ultrasound (TUS) image is of any consequence for the clinical outcomes of the pregnancy. Studies concerning TUS in pregnancy are scarce, mostly aimed at the assessment of thyroid volume. Therefore, in one of our studies, we focused on the relationship between TUS, laboratory parameters and the outcome of pregnancy. Between 2006 and 2009, we performed thyroid ultrasound in 186 pregnant women positively screened for thyroid disorders in the first trimester of pregnancy; i.e. they had abnormal TSH and/or positivity for TPOAb (Jiskra 2011a). The control group consisted of 67 agecomparable non-pregnant women with pathological TSH and/or TPOAb levels. Unexpectedly, we found that these positively screened pregnant women had rather small thyroid glands with the median volume of 8.5 ml. This is smaller than in age-comparable non-selected non-pregnant Czech women in the study of Dvorakova et al. (median 11.8 mL

After two years of preparations, a joint "Pilot Project" of the Czech Society of Endocrinology, the Society of Clinical Biochemistry and the General Insurance Company of the Czech Republic started in 2009 (Limanova 2011). The Pilot Project was supported by the General Insurance Company. The aim of the Pilot Project was to ascertain the optimal combination and economic feasibility of diagnostic tests, the timing of the blood test and the possibility of connecting the test with genetic-disorder screening in the first trimester of pregnancy. The purpose of the study was also to provide information about cooperation among gynaecologists, laboratories and endocrinologists. In the Pilot Project, TSH, FT4 and TPOAb were measured in 2937 consecutive pregnant women from 13 Czech regions with good laboratory background and cooperative endocrinologists. Contrary to the previous study, measurements were performed in regional laboratories and the reference ranges differed according to each laboratory. In this cohort, 569 (19.4%) woman were screened as positive. Abnormalities of TSH were found in 11% of women: elevation in 7.8% and suppression in 3.2%. Only 15 (0.5%) women with TSH suppression were diagnosed with true hyperthyroidism. Hypothyroxinemia was found in 3.7% and TPOAb positivity in 262 (8.9%) women. One hundred fifty-eight women (5.37%) had positive TPOAb with normal thyroid function. Thus, in this second study, we found an even higher prevalence of abnormally high TSH among pregnant women than in the study of Springer et al. However, due to the different analytical methods, these results cannot be directly compared. Cooperation with gynaecologists wasn´t always optimal despite the fact that they were provided with all necessary information well in advance. On the other hand, laboratories analysed the samples promptly, and many of them took part in providing publicity and further information to other cooperating health care professionals. In conclusion, the Pilot Project study showed that implementation of universal screening for thyroid disorders in pregnancy would be feasible in the Czech Republic, although the general knowledge on importance of correct thyroid function

in pregnancy needs to be improved among practical gynaecologists.

finding approach years among the official risk factors.

**women**

The attempts to implement a universal screening programme for AITD in pregnancy in the Czech Republic have suffered a major blow due to the world financial crisis starting in 2009. In the future years, we will probably have to concentrate on implementation of the case-

**3. Ultrasound imaging and risk-assessment of positively screened pregnant**

Most of the studies on AITD in pregnancy deal only with laboratory parameters and it is not clear whether the thyroid ultrasound (TUS) image is of any consequence for the clinical outcomes of the pregnancy. Studies concerning TUS in pregnancy are scarce, mostly aimed at the assessment of thyroid volume. Therefore, in one of our studies, we focused on the relationship between TUS, laboratory parameters and the outcome of pregnancy. Between 2006 and 2009, we performed thyroid ultrasound in 186 pregnant women positively screened for thyroid disorders in the first trimester of pregnancy; i.e. they had abnormal TSH and/or positivity for TPOAb (Jiskra 2011a). The control group consisted of 67 agecomparable non-pregnant women with pathological TSH and/or TPOAb levels. Unexpectedly, we found that these positively screened pregnant women had rather small thyroid glands with the median volume of 8.5 ml. This is smaller than in age-comparable non-selected non-pregnant Czech women in the study of Dvorakova et al. (median 11.8 mL in group of women aged 31-35 years) (Dvorakova 2006). Furthermore, the thyroid volume in pregnant women did not differ from controls. This is in contrast to the findings of both Fister and Vila, who showed an increased thyroid volume in pregnancy in iodine-sufficient (Fister 2009) and iodine-deficient areas (Vila 2008). The finding of small thyroids in pregnant Czech women is probably linked to the saturation with iodine. Iodine supplementation of salt has been introduced in Czechoslovakia in 1950. Therefore, the present pregnant women are already the third generation who live in iodine-sufficient conditions.

In our study, we also found that only 49% of the TPOAb+ pregnant women had autoimmune pattern on TUS. This was significantly less than in non-pregnant TPOAb+ controls (74 %) (Fig.1). Apparently, alterations of immune system in pregnancy cause a different manifestation of autoimmunity in the thyroid tissue. Moreover, we found that the thyroid ultrasound pattern was associated with preterm delivery: TPOAb+ women without autoimmune pattern in TUS had significantly lower prevalence of preterm delivery than the TPOAb+ ones with autoimmune pattern (3.1 vs. 15.2 %). Therefore, autoimmune TUS image in TPOAb+ pregnant women seems to be associated with preterm delivery.

Fig. 1. Ultrasound autoimmune pattern in TPOAb-positive pregnant women and controls.

In the next study from 2011, we focused on the relationship between clinical history, laboratory findings and TUS pattern in positively screened pregnant women (Jiskra 2011b). In this study, 200 of the positively screened women from the cohort of Springer et al. were included (Springer 2009). We regarded women as high-risk if they had any of the following risk factors: family and/or personal history of thyroid disease (including presence of goitre and signs and symptoms suggestive for thyroid dysfunction), family and/or personal history for autoimmune disease, history of neck irradiation, previous miscarriages and preterm deliveries). After exclusion of transient gestational hyperthyroidism, only 74/159 (47 %) women were classified as high-risk for thyroid disease according to their history. There were no significant clinical and laboratory differences between the high- vs. low-risk women, except for higher proportion of FT4 < 75th percentile and a larger thyroid volume in the high-risk group. These finding were consistent with the results of Horacek et al. (Horacek 2010) who found that case-finding screening strategy would miss one half of the high-risk women.

Universal Screening for Thyroid Disorders in Pregnancy: Experience of the Czech Republic 155

**100** With risk factor

p=0.004 p= n.s.

Without risk factor

**FT4 in pregnancy FT4 at follow-up**

**30 40 50**

**FT4 (pmol/l)**

A B Fig. 3. **Postpartum development of the thyroid function in initially euthyroid TPOAb+ pregnant women.** A: Thyroid Stimulating Hormone (TSH); B: Free Thyroxine (FT4). Median time between delivery and follow-up was 17 months. Median values of TSH and FT4 are marked in grey. Reference intervals for non-pregnant women are marked by dotted lines.

Two studies have dealt with the cost-effectiveness of universal screening for thyroid disorders in pregnancy and both found it cost-effective under condition that subclinical hypothyroidism decreases IQ of the offspring (Dosiou 2008, Thung 2009). In order to roughly assess the financial aspects of the universal screening in the Czech conditions, we performed a simple statistical analysis of the financial costs of the Pilot Project (Telicka

**60** p=0.0004

**Old New Four selected**

Fig. 2. **Proportion of positively screened pregnant women with at least one risk factor for hypothyroidism.** Old: risk factors according to Guidelines of ATA 2007; New: risk factor according to Guidelines of ATA 2011; Four selected: age, personal and family history of

**Risk factors**

**0**

thyroid disease and the presence of goitre.

p=0.0015

**TSH in pregnancy TSH at follow-up**

**20**

**40**

**60**

**%**

**5. Financial analysis**

**TSH (mU/l)**

**80**

#### **4. Postpartum follow-up of positively screened women**

Between 2009 and 2010, we invited all 822 positively screened women from the first cohort of 5520 pregnant women screened (the cohort of Springer et al.) for follow-up (Potlukova et al. 2011, manuscript in preparation). In order to gain as complete a picture of their clinical state and history as possible, we asked them to fill in a detailed internet-based questionnaire concerning their personal, family and gynaecological history. Furthermore, we invited them for a blood test including analysis of TSH, FT4 and TPOAb. The two main aims of the study were: a) to assess the prevalence of high risk-profile women in this group; b) to evaluate the postpartum thyroid function in this group with regard to the adequacy of treatment.

Of the 822 women invited, 237 (28.8%) joined the study. This group of positively screened women differed from the one analysed in our other two recent studies (Jiskra 2011a, b). The median age of participating women was 31 years at the time of screening in pregnancy. The median interval between delivery and follow-up reached 21 months. The analysis of questionnaires brought a major finding: the use of the new guidelines of American Thyroid Association (Stagnaro-Green 2011) for identification of high-risk women substantially increased the proportion of high-risk women among the positively screened. The "old" risk factors could identify only two thirds of the positively screened women: personal and family history of thyroid disease (only first-degree relatives), diabetes mellitus type 1, other autoimmune diseases in personal history, infertility and history of spontaneous abortion. However, if the "new" risk factor, age>30 years (in our analysis, 31 years and more), was added to the classical ones, 85% of the women could be classified as "high-risk" (Fig.2). This is a surprisingly high number, especially in the view of previous studies (Jiskra 2011b, Horacek 2010, Vaidya 2002). However, this effect of age could be partially due to selection bias, as the majority of women who answered the questionnaire had good education and therefore they tended to later pregnancies. We also tried to identify the most important risk factors in order to simplify the decision process which women should be screened. We found that four risk factor could identify 82% of the high-risk women: age 31 and more, personal and family history of thyroid disease and the presence of goitre (Fig.2).

In our follow-up study, we further found that one third of initially euthyroid TPOAb+ pregnant women had TSH outside of normal range at follow-up. In comparison to pregnancy, median TSH (as well as FT4) significantly increased at follow-up (Fig. 3). Thirty-eight (33.6%) of 113 initially euthyroid TPOAb+ women had TSH outside of normal range at follow-up (median 17 months after delivery): 13 (11.5%) had TSH<0,37 mU/l; 18 (15.9%) had TSH >4,0 and <10.0 mU/l (all had normal FT4). Seven (6.2%) had TSH>10.0 mU/l with three having a hypothyroxinemia. It is important to note that many of these women were inadequately treated: all of the women with TSH suppression at follow-up were simply overdosed by LT4; and half of those with TSH elevation at followup were treated by too low doses of LT4. Thus, TPOAb positivity even with normal thyroid function in pregnancy carries a high risk of hypothyroidism one and half years postpartum. This is in line with results of Stagnaro-Green, who found that 50% of women with PPT were hypothyroid one year after delivery (Stagnaro-Green 2011). Our results also show that monitoring and treatment of women with AITD in the peripartal period is commonly inadequate.

Fig. 2. **Proportion of positively screened pregnant women with at least one risk factor for hypothyroidism.** Old: risk factors according to Guidelines of ATA 2007; New: risk factor according to Guidelines of ATA 2011; Four selected: age, personal and family history of thyroid disease and the presence of goitre.

Fig. 3. **Postpartum development of the thyroid function in initially euthyroid TPOAb+ pregnant women.** A: Thyroid Stimulating Hormone (TSH); B: Free Thyroxine (FT4). Median time between delivery and follow-up was 17 months. Median values of TSH and FT4 are marked in grey. Reference intervals for non-pregnant women are marked by dotted lines.

#### **5. Financial analysis**

154 A New Look at Hypothyroidism

Between 2009 and 2010, we invited all 822 positively screened women from the first cohort of 5520 pregnant women screened (the cohort of Springer et al.) for follow-up (Potlukova et al. 2011, manuscript in preparation). In order to gain as complete a picture of their clinical state and history as possible, we asked them to fill in a detailed internet-based questionnaire concerning their personal, family and gynaecological history. Furthermore, we invited them for a blood test including analysis of TSH, FT4 and TPOAb. The two main aims of the study were: a) to assess the prevalence of high risk-profile women in this group; b) to evaluate the

postpartum thyroid function in this group with regard to the adequacy of treatment.

Of the 822 women invited, 237 (28.8%) joined the study. This group of positively screened women differed from the one analysed in our other two recent studies (Jiskra 2011a, b). The median age of participating women was 31 years at the time of screening in pregnancy. The median interval between delivery and follow-up reached 21 months. The analysis of questionnaires brought a major finding: the use of the new guidelines of American Thyroid Association (Stagnaro-Green 2011) for identification of high-risk women substantially increased the proportion of high-risk women among the positively screened. The "old" risk factors could identify only two thirds of the positively screened women: personal and family history of thyroid disease (only first-degree relatives), diabetes mellitus type 1, other autoimmune diseases in personal history, infertility and history of spontaneous abortion. However, if the "new" risk factor, age>30 years (in our analysis, 31 years and more), was added to the classical ones, 85% of the women could be classified as "high-risk" (Fig.2). This is a surprisingly high number, especially in the view of previous studies (Jiskra 2011b, Horacek 2010, Vaidya 2002). However, this effect of age could be partially due to selection bias, as the majority of women who answered the questionnaire had good education and therefore they tended to later pregnancies. We also tried to identify the most important risk factors in order to simplify the decision process which women should be screened. We found that four risk factor could identify 82% of the high-risk women: age 31 and more, personal and family history of thyroid disease and

In our follow-up study, we further found that one third of initially euthyroid TPOAb+ pregnant women had TSH outside of normal range at follow-up. In comparison to pregnancy, median TSH (as well as FT4) significantly increased at follow-up (Fig. 3). Thirty-eight (33.6%) of 113 initially euthyroid TPOAb+ women had TSH outside of normal range at follow-up (median 17 months after delivery): 13 (11.5%) had TSH<0,37 mU/l; 18 (15.9%) had TSH >4,0 and <10.0 mU/l (all had normal FT4). Seven (6.2%) had TSH>10.0 mU/l with three having a hypothyroxinemia. It is important to note that many of these women were inadequately treated: all of the women with TSH suppression at follow-up were simply overdosed by LT4; and half of those with TSH elevation at followup were treated by too low doses of LT4. Thus, TPOAb positivity even with normal thyroid function in pregnancy carries a high risk of hypothyroidism one and half years postpartum. This is in line with results of Stagnaro-Green, who found that 50% of women with PPT were hypothyroid one year after delivery (Stagnaro-Green 2011). Our results also show that monitoring and treatment of women with AITD in the peripartal period is

**4. Postpartum follow-up of positively screened women**

the presence of goitre (Fig.2).

commonly inadequate.

Two studies have dealt with the cost-effectiveness of universal screening for thyroid disorders in pregnancy and both found it cost-effective under condition that subclinical hypothyroidism decreases IQ of the offspring (Dosiou 2008, Thung 2009). In order to roughly assess the financial aspects of the universal screening in the Czech conditions, we performed a simple statistical analysis of the financial costs of the Pilot Project (Telicka

Universal Screening for Thyroid Disorders in Pregnancy: Experience of the Czech Republic 157

Abalovich M, Gutierrez Z, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002;12:63-68 Abalovich M, Nobuyuki A, Barbour L, Cobin RH, De Groof LJ, Glinoer D, Mandel SJ,

Allan WC, Haddow JE, Palomaki GE, Williams JR, Mitchell ML, Hermos RJ, Faix JD, Klein

Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005; 105: 239-45 Dosiou C, Sanders GD, Araki SS, Crapo LM. Screening pregnant women for autoimmune thyroid disease: a cost-effectiveness analysis. Eur J Endocrinol 2008; 158: 841-851. Dvoraková M, Bílek R, Cerovská J, Hill M, Novák Z, Vavrejnová V, Vlcek P, Vrbíková J,

Czech Republic--determination of the norms. Vnitr Lek 2006; 52: 57-63. Fister P, Gaberscek S, Zaletel K, Krhin B, Gersak K, Hojker S (2009) Thyroid volume changes

Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from phsysiology to pathology. Endocr Rev 1997; 18: 404-33 Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gangon J et al. Maternal

Horacek J, Spitalnikova S, Dlabalova B, Malirova E, Vizda J, Svilias I, Cepkova I, McGrath C¸

Jiskra J, Bartakova J, Holinka S, Límanová Z , Springer D, Antosová M, Telicka Z and

Lazarus JH, Kokandi A. Thyroid disease in relation to pregnancy: a decade of change. Clin

Lazarus J. Outcome of the CATS study. Oral presentation at the International Thyroid Congress (ITC), Paris, France, 2010, September 11-16. Symposium no. 18 Lazarus JH, Premawardhana LDKE. Postpartum Thyroiditis. In: Contemporary

Leung AS, Millar LK, Koonings PP, Montoro M, Mestman JH. Perinatal outcome in

population screening. J Med Screen 2000; 7: 127-130

Eur J Obstet Gynecol Reprod Biol 2009 145: 45-48.

http://dx.doi.org/10.1055/s-0031-1284369

Humana Press Inc. New Jersey, USA, 2008: 177-92

hypothyroid pregnancies. Obstet Gynecol 1993; 81:349-353

Endocrinol (Oxf) 2000; 53: 265-78

development of the child. N Engl J Med 1999; 341: 549-55

Stagnaro-Geen A: Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrin Metab

RZ. Maternal thyroid deficiency and pregnancy complications: implications for

Zamrazil V. The volumes of the thyroid gland in adults aged 18-65 years in the

during pregnancy and after delivery in an iodine-sufficient Republic of Slovenia.

thyroid deficiency during pregnancy and subsequent neuropsychological

Maly J. Universal screening detects two-times more thyroid disorders in early pregnancy than targeted high-risk case finding. Eur J Endocrinol 2010;163: 645 – 650 Jiskra J, Bartakova J, Holinka S, Limanova Z, Springer D, Fait T, Antosova M, Telicka Z,

Potlukova E. Low concordance between positive antibodies to thyroperoxidase and thyroid ultrasound autoimmune pattern in pregnant women. Endocr J 2011; *in*

Potlukova E. Low prevalence of clinically high-risk women and pathological thyroid ultrasound among pregnant women positive in universal screening for thyroid disorders. Exp Clin Endocrinol Diabetes 2011; DOI

Endocrinology: Autoimmune Diseases in Endocrinology. AP Weetman (ed),

**8. References**

*press.*

2007; Aug;92(8 Suppl):S1-47

2010). The goal of this study was to find out the overall costs of the Pilot Project as compared to positively-screened tests and simulate the costs in the current situation when the screening is not paid by the insurances companies. Total costs of both TSH and TPOAb screening included in the Pilot Project were 1 373 218 CZK (15 280 €) for 2 651 tested women. The cost of one positive result in any tested parameter (TSH/TPOAb) amounted 2 243 CZK (91€) and the costs of one positive result for hypothyroidism was 1380 CZK (56€).

### **6. Conclusions**

We have shown that the prevalence of thyroid disorders is relatively high among the Czech pregnant women in comparison with other developed iodine-sufficient countries. About one tenth of pregnant women are TPOAb+ and more than 4% have subclinical or overt hypothyroidism in the first trimester of pregnancy. We have also shown that one third of initially euthyroid TPOAb+ pregnant women have TSH outside of normal range one and half years after delivery. This was due to postpartum thyroiditis and in many cases inadequate treatment. Thus, TPOAb positivity may endanger not only the current, but also the next pregnancies.

Based on the ultrasound findings in the positively screened women, we can furthermore conclude that pregnant TPOAb positive women have less pronounced TUS changes than non-pregnant controls. Thus, sonography may only be a part of a more complex diagnostic procedure in the screening for thyroid disorders in pregnancy. However, it seems that pregnant women with autoimmune pattern in thyroid ultrasound have an increased risk of preterm delivery.

Moreover, in our studies we confirmed that targeted case-finding screening programme based on the "old" risk factors (Abalovich 2007) would miss one-half of pregnant women with thyroid disease. Also, high- and low-risk pregnant women have similar clinical and laboratory characteristics. However, these findings change if "new" risk factors including age over 30 years (Stagnaro-Green 2011) are used for identification of high-risk women. Age over 30 years increases the proportion of positively screened pregnant women with at least one risk factor to 85%; however, this may be an effect of selection bias.

Finally, the financial analysis showed that the costs of the screening for thyroid dysfunction in pregnancy are not high enough to rend the financial issue a main obstacle in an implementation of universal screening. Both TSH and TPOAb should be included in any screening programme.

The awareness on the thyroid problematics in pregnancy has improved in the general population thanks to the activities of the Czech Society of Endocrinology in the recent; however, some health care professionals dealing with pregnant women show lack of interest in this topic. In conclusion, our data provide a contribution to the published guidelines for management of thyroid disease in pregnancy and present a basis for a world-wide discussion.

#### **7. Acknowledgements**

These studies were supported by the grants of the Czech Health Ministry IGA NS 10662-3 and 10595-3.

#### **8. References**

156 A New Look at Hypothyroidism

2010). The goal of this study was to find out the overall costs of the Pilot Project as compared to positively-screened tests and simulate the costs in the current situation when the screening is not paid by the insurances companies. Total costs of both TSH and TPOAb screening included in the Pilot Project were 1 373 218 CZK (15 280 €) for 2 651 tested women. The cost of one positive result in any tested parameter (TSH/TPOAb) amounted 2 243 CZK

We have shown that the prevalence of thyroid disorders is relatively high among the Czech pregnant women in comparison with other developed iodine-sufficient countries. About one tenth of pregnant women are TPOAb+ and more than 4% have subclinical or overt hypothyroidism in the first trimester of pregnancy. We have also shown that one third of initially euthyroid TPOAb+ pregnant women have TSH outside of normal range one and half years after delivery. This was due to postpartum thyroiditis and in many cases inadequate treatment. Thus, TPOAb positivity may endanger not only the current, but also

Based on the ultrasound findings in the positively screened women, we can furthermore conclude that pregnant TPOAb positive women have less pronounced TUS changes than non-pregnant controls. Thus, sonography may only be a part of a more complex diagnostic procedure in the screening for thyroid disorders in pregnancy. However, it seems that pregnant women with autoimmune pattern in thyroid ultrasound have an increased risk of

Moreover, in our studies we confirmed that targeted case-finding screening programme based on the "old" risk factors (Abalovich 2007) would miss one-half of pregnant women with thyroid disease. Also, high- and low-risk pregnant women have similar clinical and laboratory characteristics. However, these findings change if "new" risk factors including age over 30 years (Stagnaro-Green 2011) are used for identification of high-risk women. Age over 30 years increases the proportion of positively screened pregnant women with at least

Finally, the financial analysis showed that the costs of the screening for thyroid dysfunction in pregnancy are not high enough to rend the financial issue a main obstacle in an implementation of universal screening. Both TSH and TPOAb should be included in any

The awareness on the thyroid problematics in pregnancy has improved in the general population thanks to the activities of the Czech Society of Endocrinology in the recent; however, some health care professionals dealing with pregnant women show lack of interest in this topic. In conclusion, our data provide a contribution to the published guidelines for management of thyroid disease in pregnancy and present a basis for a world-wide discussion.

These studies were supported by the grants of the Czech Health Ministry IGA NS 10662-3

one risk factor to 85%; however, this may be an effect of selection bias.

(91€) and the costs of one positive result for hypothyroidism was 1380 CZK (56€).

**6. Conclusions**

the next pregnancies.

preterm delivery.

screening programme.

**7. Acknowledgements**

and 10595-3.

**9**

*Greece*

**Thyroid Function Following Treatment**

*1Dept. of Growth and Development, Children's Hosp. "P.A. Kyriakou"*

Elpis Vlachopapadopoulou1, Vassilios Papadakis2, Georgia Avgerinou2 and Sophia Polychronopoulou2

**of Childhood Acute Lymphoblastic Leukemia**

*2Dept. of Pediatric Hematology-Oncology,. "Agia Sofia" Children's Hosp Athens,*

Acute lymphoblastic leukemia (ALL) is the most frequently encountered malignancy in childhood. Peak incidence is in early childhood. There is male predominance with 1.2:1 male to female ratio (Pui et al., 2006). Current therapeutic modalities have succeeded in assuring high cure rates. Treatment protocols involve mainly chemotherapy according to patient and leukemia risk classification. Irradiation therapy can be used as central nervous system (CNS) prophylaxis or as therapy for CNS involvement, although the use of CNS irradiation is reduced (Pui et al., 2009). Furthermore, allogeneic bone marrow transplantation can be used for very high risk patients or patients not responding to the treatment protocols (Pui et al.,

Surveillance for long-term complications, following completion of chemotherapy is important, in order to prevent morbidity and to improve quality of life (Oeffinger et al., 2006). The vast majority of long-term sequelae are endocrine abnormalities involving the hypothalamic pituitary axis, the thyroid gland and the gonads. Growth hormone deficiency, precocious puberty, gonadal failure, hypothyroidism and thyroid cancer are the most likely

The prevalence of hypothyroidism was found to be higher among childhood cancer survivors than in the general population, in a nation-wide registry of Finland. They reported the prevalence of hypothyroidism among cancer survivors, by reporting the clinically diagnosed hypothyroid patients who were receiving levothyroxine replacement therapy. Direct radiotherapy of the thyroid gland was related to a higher prevalence of hypothyroidism. Furthermore, they reported that females were more susceptible to hypothyroidism than males following childhood cancer (Madanat, 2008). Hypothyroidism, either primary or central, can be manifested in survivors of childhood malignancies (Madanat et al., 2007, Rose et al., 2006). The retrospective study by Madanat et al., reported that impaired thyroid function occurred in patients with a history of brain tumor, Hodgkin's disease, leukemia/non Hodgkin's lymphoma (NHL) and others. Age at diagnosis did not have an effect on the occurrence or time frame of development of thyroid hypofunction.

long-term clinical presentations (Chemaitilly & Sklar, 2010).

**1. Introduction**

2006).

### **Thyroid Function Following Treatment of Childhood Acute Lymphoblastic Leukemia**

Elpis Vlachopapadopoulou1, Vassilios Papadakis2, Georgia Avgerinou2 and Sophia Polychronopoulou2 *1Dept. of Growth and Development, Children's Hosp. "P.A. Kyriakou" 2Dept. of Pediatric Hematology-Oncology,. "Agia Sofia" Children's Hosp Athens, Greece*

#### **1. Introduction**

158 A New Look at Hypothyroidism

Li Y, Shan Z, Teng W, Yu X, Li Y, Fan C, Teng X, Guo R, Wang H, Li J, Chen Y, Wang W,

Limanova Z, Springer D: Thyreopathy examination during pregnancy - results of pilot

Morreale de Escobar G, Obregon MJ, del Rey FE. Maternal thyroid hormones early in

Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Role of thyroid hormone during

Springer D, Zima T, Limanova Z. Reference intervals in evaluation of maternal thyroid function during the first trimester of pregnancy. Eur J Endocrinol. 2009;160(5):791-7. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Parce

Stagnaro-Green A, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Negro R. High rate of

thyroiditis in southern Italy. J Clin Endocrinol Metab 2011;96: 652-657 Telicka Z, Jiskra J, Springer D. Simple Method of Economical Analysis of Diagnosis

Informatics. 2010; online: http://ejbi.cz/articles/201012/59/1.html Thung SF, Funai EF, Grobman WA. The cost-effectiveness of universal screening in

thyroid disease in pregnancy: an audit. Clin Med 2002; 2: 599-600

early brain development: Eur J Endocrinol 2004; 151: U25–U37.

pregnancy and postpartum. Thyroid 2011; 21: 1-45.

finding? J Clin Endocrinol Metab 2007; 92: 203-7

at 25-30 motnhs. Clin Endocrinol (Oxf) 2010; 72: 825-829

project. Cas Lek ces. 2011; 150: 389-393.

2004; 18: 225-48

Chawinga M, Zhang L, Yang L, Zhao Y, Hua T. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children

pregnancy and foetal brain development. Best Pract Res Clin Endocrinol Metab

EN, Soldin OP, Sullivan S, Wiersinga W. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during

persistent hypothyroidism in a large-scale prospective study of postpartum

Procedure (Used in Screening of Thyroid Gland Diseases in Pregnant Women) during the first trimester of pregnancy. European Journal for Biomedical

pregnancy for subclinical hypothyroidism. Am J Obstet Gynecol 2009; 267.e1-267.e7

dysfunction in early pregnancy: Universal screening or targeted high-risk case

Domingo M. Iodine status and thyroid volume changes during pregnancy: results of a survey in Aran Valley (Catalan Pyrenees). J Endocrinol Invest 2008; 31: 851-855.

Vaidya B, Bilous M, Hutchinson RS, Connolly, V, Jones S, Kelly WF et al. Screening for

Vaidya B,Anthony S, Bilous M, Shields B, Drury J, Hutchison S et al. Detection of thyroid

Vila L, Legaz G, Barrionuevo C, Espinel ML, Casamitjana R, Muñoz J, Serra-Prat M, Puig-

Acute lymphoblastic leukemia (ALL) is the most frequently encountered malignancy in childhood. Peak incidence is in early childhood. There is male predominance with 1.2:1 male to female ratio (Pui et al., 2006). Current therapeutic modalities have succeeded in assuring high cure rates. Treatment protocols involve mainly chemotherapy according to patient and leukemia risk classification. Irradiation therapy can be used as central nervous system (CNS) prophylaxis or as therapy for CNS involvement, although the use of CNS irradiation is reduced (Pui et al., 2009). Furthermore, allogeneic bone marrow transplantation can be used for very high risk patients or patients not responding to the treatment protocols (Pui et al., 2006).

Surveillance for long-term complications, following completion of chemotherapy is important, in order to prevent morbidity and to improve quality of life (Oeffinger et al., 2006). The vast majority of long-term sequelae are endocrine abnormalities involving the hypothalamic pituitary axis, the thyroid gland and the gonads. Growth hormone deficiency, precocious puberty, gonadal failure, hypothyroidism and thyroid cancer are the most likely long-term clinical presentations (Chemaitilly & Sklar, 2010).

The prevalence of hypothyroidism was found to be higher among childhood cancer survivors than in the general population, in a nation-wide registry of Finland. They reported the prevalence of hypothyroidism among cancer survivors, by reporting the clinically diagnosed hypothyroid patients who were receiving levothyroxine replacement therapy. Direct radiotherapy of the thyroid gland was related to a higher prevalence of hypothyroidism. Furthermore, they reported that females were more susceptible to hypothyroidism than males following childhood cancer (Madanat, 2008). Hypothyroidism, either primary or central, can be manifested in survivors of childhood malignancies (Madanat et al., 2007, Rose et al., 2006). The retrospective study by Madanat et al., reported that impaired thyroid function occurred in patients with a history of brain tumor, Hodgkin's disease, leukemia/non Hodgkin's lymphoma (NHL) and others. Age at diagnosis did not have an effect on the occurrence or time frame of development of thyroid hypofunction.

Thyroid Function Following Treatment of Childhood Acute Lymphoblastic Leukemia 161

The patient population included and analyzed retrospectively in this study, consists of the patient cohort with newly diagnosed acute lymphoblastic leukemia (ALL), treated according to the ALL-BFM protocols (ALL-BFM-90 and ALL-BFM-95 Protocols) from April 1994 to December 2010, in the Department of Pediatric Hematology-Oncology, at Agia Sofia

Acute lymphoblastic leukemia was diagnosed by bone marrow morphology and phenotype. Patients were assigned to the high risk (HR) treatment group if they had an absolute blast count on peripheral blood of more than 1.0 k/ul on day +8 of induction, following prednisolone treatment (prednisolone poor responders), no remission by bone marrow morphology on day +33 following induction or if they were found to have translocations t(4;11) or t(9;22) by karyotype or FISH at diagnosis bone marrow specimens. The rest of the patients were assigned to the median risk (MR) treatment group. Thus, standard risk (SR)

Figure 1 illustrates the outline of protocol ALL-BFM-90 and ALL-BFM 95 (Katsimpardi et

Fig. 1. ALL-BFM-95 and ALL-BFM-90 treatment protocol outline. From K Katsimpardi et al,

Support Care Cancer (2006) 14: 277–284. DOI 10.1007/s00520-005-0884-6

patients were upgraded to the MR group (Schrapp et al., 2000, Moricke et al., 2008).

**2. Subjects and methods**

al., 2006).

Children's Hospital in Athens, Greece.

They found that radiotherapy combined with chemotherapy was associated with a higher risk for development of hypothyroidism, compared to chemotherapy alone (Madanat et al., 2007).

A recent report from the Japanese childhood cancer survivors program, reveals thyroid dysfunction in 18% of the patients, primary as well as central hypothyroidism. The vast majority of patients with primary hypothyroidism were irradiated to the neck area (Miyoshi et al., 2008).

Additional information derives from the registry of German patients, for the evaluation of side effects after radiation therapy in childhood and adolescence. The preliminary results of their report on the incidence of thyroid dysfunction come following a relatively short period of observation. The prevalence of thyroid dysfunction in patients treated for childhood ALL, is 11% which is much lower than the prevalence in patients treated for brain tumors. This is related to the lower dose of radiation given to the thyroid gland of ALL patients (Bőling et al., 2011).

Rose et al., reported on 62 patients with central hypothyroidism. Of those 10 patients (16%) had received chemotherapy only and none of these patients had hypothalamic tumors that would be clearly associated with endocrine dysfunction (Rose et al., 2006). Thus, they suggest that the occurrence of central hypothyroidism is more common than is thought, and they recommend a more vigilant and timely work-up in order to assure early identification and treatment of the hypothyroidism.

Thyroid dysfunction has been reported in survivors of childhood ALL in previous papers, but the incidence and the severity of thyroid dysfunction varies. ALL treatment protocols have evolved overtime, duration and intensity of the treatment, as well as medication combination and radiotherapy dose have changed. In a small group of Italian ALL patients, thyroid dysfunction was not appreciated during a 6 year follow-up period. However, a case of papillary thyroid cancer was identified (Neves Mascarenhas et al., 2006). In the paper published by Steffens et al, a retrospective analysis, primary hypothyroidism had occurred in patients treated for childhood ALL. The patients were divided in three groups, according to the therapeutic regime used: 1. chemotherapy only, 2. chemotherapy and cranial irradiation, and 3. combination of chemotherapy, cranial irradiation and bone marrow transplantation. Cases of hypothyroidism, as judged based on elevated serum TSH values were identified in all three groups but the higher incidence was appreciated in the latter group (Steffens M et al, 2008). Furthermore, there are reports of hypothyroidism in ALL patients, related to the use of craniospinal irradiation (Lando et al., 2001).

The papers presented, include pediatric patients diagnosed with ALL treated with different chemotherapeutic protocols with or without cranial irradiation and hemopoietic stem cell transplantation. The aim of the current retrospective study is to investigate a homogeneous group of children with ALL, treated with the same protocol (BFM). Patients with early death or relapse, as well as, patients who underwent hemopoietic stem cell transplantation in first remission were excluded from this analysis. Thyroid function was evaluated at diagnosis, at the end of chemotherapy, one to two years post chemotherapy completion and more than 3 years post treatment cessation. This study seeks to define the total prevalence of thyroid dysfunction in this homogeneously treated group of patients diagnosed with childhood acute lymphocytic leukemia.

### **2. Subjects and methods**

160 A New Look at Hypothyroidism

They found that radiotherapy combined with chemotherapy was associated with a higher risk for development of hypothyroidism, compared to chemotherapy alone (Madanat et

A recent report from the Japanese childhood cancer survivors program, reveals thyroid dysfunction in 18% of the patients, primary as well as central hypothyroidism. The vast majority of patients with primary hypothyroidism were irradiated to the neck area (Miyoshi

Additional information derives from the registry of German patients, for the evaluation of side effects after radiation therapy in childhood and adolescence. The preliminary results of their report on the incidence of thyroid dysfunction come following a relatively short period of observation. The prevalence of thyroid dysfunction in patients treated for childhood ALL, is 11% which is much lower than the prevalence in patients treated for brain tumors. This is related to the lower dose of radiation given to the thyroid gland of ALL patients (Bőling et

Rose et al., reported on 62 patients with central hypothyroidism. Of those 10 patients (16%) had received chemotherapy only and none of these patients had hypothalamic tumors that would be clearly associated with endocrine dysfunction (Rose et al., 2006). Thus, they suggest that the occurrence of central hypothyroidism is more common than is thought, and they recommend a more vigilant and timely work-up in order to assure early identification

Thyroid dysfunction has been reported in survivors of childhood ALL in previous papers, but the incidence and the severity of thyroid dysfunction varies. ALL treatment protocols have evolved overtime, duration and intensity of the treatment, as well as medication combination and radiotherapy dose have changed. In a small group of Italian ALL patients, thyroid dysfunction was not appreciated during a 6 year follow-up period. However, a case of papillary thyroid cancer was identified (Neves Mascarenhas et al., 2006). In the paper published by Steffens et al, a retrospective analysis, primary hypothyroidism had occurred in patients treated for childhood ALL. The patients were divided in three groups, according to the therapeutic regime used: 1. chemotherapy only, 2. chemotherapy and cranial irradiation, and 3. combination of chemotherapy, cranial irradiation and bone marrow transplantation. Cases of hypothyroidism, as judged based on elevated serum TSH values were identified in all three groups but the higher incidence was appreciated in the latter group (Steffens M et al, 2008). Furthermore, there are reports of hypothyroidism in ALL

The papers presented, include pediatric patients diagnosed with ALL treated with different chemotherapeutic protocols with or without cranial irradiation and hemopoietic stem cell transplantation. The aim of the current retrospective study is to investigate a homogeneous group of children with ALL, treated with the same protocol (BFM). Patients with early death or relapse, as well as, patients who underwent hemopoietic stem cell transplantation in first remission were excluded from this analysis. Thyroid function was evaluated at diagnosis, at the end of chemotherapy, one to two years post chemotherapy completion and more than 3 years post treatment cessation. This study seeks to define the total prevalence of thyroid dysfunction in this homogeneously treated group of patients diagnosed with childhood

patients, related to the use of craniospinal irradiation (Lando et al., 2001).

al., 2007).

et al., 2008).

al., 2011).

and treatment of the hypothyroidism.

acute lymphocytic leukemia.

The patient population included and analyzed retrospectively in this study, consists of the patient cohort with newly diagnosed acute lymphoblastic leukemia (ALL), treated according to the ALL-BFM protocols (ALL-BFM-90 and ALL-BFM-95 Protocols) from April 1994 to December 2010, in the Department of Pediatric Hematology-Oncology, at Agia Sofia Children's Hospital in Athens, Greece.

Acute lymphoblastic leukemia was diagnosed by bone marrow morphology and phenotype. Patients were assigned to the high risk (HR) treatment group if they had an absolute blast count on peripheral blood of more than 1.0 k/ul on day +8 of induction, following prednisolone treatment (prednisolone poor responders), no remission by bone marrow morphology on day +33 following induction or if they were found to have translocations t(4;11) or t(9;22) by karyotype or FISH at diagnosis bone marrow specimens. The rest of the patients were assigned to the median risk (MR) treatment group. Thus, standard risk (SR) patients were upgraded to the MR group (Schrapp et al., 2000, Moricke et al., 2008).

Figure 1 illustrates the outline of protocol ALL-BFM-90 and ALL-BFM 95 (Katsimpardi et al., 2006).

Fig. 1. ALL-BFM-95 and ALL-BFM-90 treatment protocol outline. From K Katsimpardi et al, Support Care Cancer (2006) 14: 277–284. DOI 10.1007/s00520-005-0884-6

Thyroid Function Following Treatment of Childhood Acute Lymphoblastic Leukemia 163

relapse and patients who underwent bone marrow transplantation in first remission

Two hundred twenty- three patients, were treated for newly diagnosed ALL according to the BFM Protocol (ALL-BFM-90 and ALL-BFM-95 Protocols) from April 1994 to December 2010. From them 18 have not yet completed the prescribed chemotherapy and 5 suffered early death from toxicity and thus they were excluded from analysis. Additionally, 32 patients were excluded from the analysis, of which 17 underwent stem cell transplantation in first remission and 15 patients due to early relapse. Thus, 168 patients were eligible for

The median age at diagnosis was 5.1 years (range, 1.0 to 16.7 years). Median duration of treatment and median age at completion of maintenance treatment was 3.2 years (range, 2.1 to 4.2 years) and 8.2 years (range, 4.0 to 19.6 years) respectively. A total of 26 patients

Subjects who were diagnosed between April 1994 and April 1996 were treated according to the ALL-BFM-90 protocol (26 Patients) and those who were diagnosed beyond April 1996 according to the ALL-BFM-95 treatment protocol (142 Patients). Patients were sub-grouped into two groups according to risk, 149 patients were characterized as medium -risk and 19 as high -risk. From the patients included in the HR group, 5 were treated with BFM-90 and 14

A retrospective analysis of patient data extracted from their charts was performed. Time points at which the data were grouped together were: a. Diagnosis b. End of treatment, c. One year and d. More than three years after completion of prescribed treatment. For patients relapsing after cessation of treatment, the data up to the time of relapse were eligible for

Data of thyroid function that was evaluated were: serum levels of the thyroid stimulating hormone (TSH), triiodo-thyronine (T3) and thyroxine (T4), anti-thyroidal antibody levels

Serum levels of TSH, T3 and T4 were measured with current high resolution commercially available assays. For the purpose of this study, thyroid dysfunction was defined as either a T4 value below or a TSH value exceeding the defined normal range. By this definition, thyroid dysfunction includes cases of clinical, subclinical and central

Out of the 168 eligible patients, 141 had at least one evaluation of thyroid function following completion of treatment. This cohort of patients evaluated consisted of 78 males and 63 female patients. Thirteen were treated according to the ALL-BFM 90 Protocol (all were assigned to MR treatment group) whilst 128 were treated according to the ALL-BFM 95 Protocol (115 MR, 13 HR treatment group). In regards to radiotherapy, 21 patients received cranial irradiation at a dose of 12 Gy, except for one earlier patient who received

according to the Protocol were excluded from the analysis.

analysis and the sex distribution was 93 males and 75 females.

with BFM-95 (patients who underwent transplantation were excluded).

and imaging of the thyroid gland by ultrasonography.

received cranial irradiation.

analysis.

hypothyroidism.

**3. Results**

16.8 Gy.

Synopsis of the treatment schedule and strategy follows. Overall, treatment consisted of an induction, consolidation, reinduction and maintenance phase. The induction phase (Figure 1, Protocol I) was based initially on four drugs (prednisolone, vincristine, L-asparaginase and daunorubicin). Later (second phase of Protocol I, induction), two courses of 1 gr/m2 of cyclophosphamide were administered at a 28-day interval, with 6-mercaptopurine p.o. and low dose aracytin i.v., for the interim time. This second part of the induction is omitted for all HR patients. The consolidation phase for MR patients (Figure 1, MA or MCA) was based on p.o. 6-mercaptopurine and 4 courses of high dose (5 gr/m2) methotrexate i.v. The reinduction phase for the MR patients was similar to the induction phase (Figure 1, Protocol II), but with dexamethasone, vincristine, L-asparaginase and doxorubicin, initially. One dose of cyclophosphamide at 1 gr/m2 with 14 days of 6-thioguanine and low dose i.v. aracytin followed (second phase of Protocol II).

Following only the initial phase of induction (Protocol IA), the high risk (HR) patient group received different, intensified treatment according to the protocol. Thus, patients treated according to the ALL-BFM-90 protocol received 9 blocks of treatment (in sequence: HR1, HR2, HR3 given in three series and no reinduction (ALL-BFM-90, Figure 1). Two of these HR blocks are based on high dose methotrexate (HR1, HR2) and one (HR3) is based on high dose aracytin. On the other hand, HR patients treated according to the ALL-BFM-95 protocol received 6 blocks of treatment (in sequence: HR1, HR2, HR3 given in two series). Then, reinduction with Protocol II followed, (ALL-BFM-95, Figure 1). Thus, Protocol II reinduction phase was common for MR and HR patients.

According to the protocols, all HR patients and all patients with T-precursor ALL received 12 Gy of cranial irradiation following the completion of the treatment that was described previously and prior to starting maintenance chemotherapy. MR patients were irradiated, as above, on the ALL-BFM-90 protocol but not on the ALL-BFM-95.

Allogeneic bone marrow transplantation (BMT) was recommended for a subset of HR patients, provided that a matched sibling donor was available.

Maintenance treatment consisted of 24 or 30 months in total for females and males respectively, of daily 6-mercaptopurine (50 mg/m2) p.o./weekly methotrexate (20 mg/m2) p.o. and monthly (28 day cycle) i.v. vincristine (1.5 mg/m2), together with a five-day p.o. prednisolone (40 mg/m2/day) pulse. Triple (methotrexate/ aracytin/ steroid, doses adjusted to age) intrathecal (IT) infusions every third pulse (84 days), were administered to patients not given CNS irradiation.

Overall, this ALL patient cohort has received more intensive treatment than the original ALL-BFM-90 and ALL-BFM 95 Protocol (Schrappe et al., 2000, Morriche et al., 2010). All SR group patients were treated according to the MR group (receiving additional 2 doses of anthracyclines) and maintenance treatment was increased in length (24 months for girls and 30 months for boys maintenance treatment in total) and was intensified with vincristine/ prednizolone monthly pulses and triple intrathecal infusions every third pulse. Detailed treatment schedule has been previously described. Details of the treatment schedule and patient outcome has been described before (Papadakis et al., 2003).

The purpose of this analysis is to evaluate the effect of ALL treatment on thyroidal function. Thus, in order to have a homogenously treated patient group, patients with early death or relapse and patients who underwent bone marrow transplantation in first remission according to the Protocol were excluded from the analysis.

Two hundred twenty- three patients, were treated for newly diagnosed ALL according to the BFM Protocol (ALL-BFM-90 and ALL-BFM-95 Protocols) from April 1994 to December 2010. From them 18 have not yet completed the prescribed chemotherapy and 5 suffered early death from toxicity and thus they were excluded from analysis. Additionally, 32 patients were excluded from the analysis, of which 17 underwent stem cell transplantation in first remission and 15 patients due to early relapse. Thus, 168 patients were eligible for analysis and the sex distribution was 93 males and 75 females.

The median age at diagnosis was 5.1 years (range, 1.0 to 16.7 years). Median duration of treatment and median age at completion of maintenance treatment was 3.2 years (range, 2.1 to 4.2 years) and 8.2 years (range, 4.0 to 19.6 years) respectively. A total of 26 patients received cranial irradiation.

Subjects who were diagnosed between April 1994 and April 1996 were treated according to the ALL-BFM-90 protocol (26 Patients) and those who were diagnosed beyond April 1996 according to the ALL-BFM-95 treatment protocol (142 Patients). Patients were sub-grouped into two groups according to risk, 149 patients were characterized as medium -risk and 19 as high -risk. From the patients included in the HR group, 5 were treated with BFM-90 and 14 with BFM-95 (patients who underwent transplantation were excluded).

A retrospective analysis of patient data extracted from their charts was performed. Time points at which the data were grouped together were: a. Diagnosis b. End of treatment, c. One year and d. More than three years after completion of prescribed treatment. For patients relapsing after cessation of treatment, the data up to the time of relapse were eligible for analysis.

Data of thyroid function that was evaluated were: serum levels of the thyroid stimulating hormone (TSH), triiodo-thyronine (T3) and thyroxine (T4), anti-thyroidal antibody levels and imaging of the thyroid gland by ultrasonography.

Serum levels of TSH, T3 and T4 were measured with current high resolution commercially available assays. For the purpose of this study, thyroid dysfunction was defined as either a T4 value below or a TSH value exceeding the defined normal range. By this definition, thyroid dysfunction includes cases of clinical, subclinical and central hypothyroidism.

#### **3. Results**

162 A New Look at Hypothyroidism

Synopsis of the treatment schedule and strategy follows. Overall, treatment consisted of an induction, consolidation, reinduction and maintenance phase. The induction phase (Figure 1, Protocol I) was based initially on four drugs (prednisolone, vincristine, L-asparaginase and daunorubicin). Later (second phase of Protocol I, induction), two courses of 1 gr/m2 of cyclophosphamide were administered at a 28-day interval, with 6-mercaptopurine p.o. and low dose aracytin i.v., for the interim time. This second part of the induction is omitted for all HR patients. The consolidation phase for MR patients (Figure 1, MA or MCA) was based on p.o. 6-mercaptopurine and 4 courses of high dose (5 gr/m2) methotrexate i.v. The reinduction phase for the MR patients was similar to the induction phase (Figure 1, Protocol II), but with dexamethasone, vincristine, L-asparaginase and doxorubicin, initially. One dose of cyclophosphamide at 1 gr/m2 with 14 days of 6-thioguanine and low dose i.v.

Following only the initial phase of induction (Protocol IA), the high risk (HR) patient group received different, intensified treatment according to the protocol. Thus, patients treated according to the ALL-BFM-90 protocol received 9 blocks of treatment (in sequence: HR1, HR2, HR3 given in three series and no reinduction (ALL-BFM-90, Figure 1). Two of these HR blocks are based on high dose methotrexate (HR1, HR2) and one (HR3) is based on high dose aracytin. On the other hand, HR patients treated according to the ALL-BFM-95 protocol received 6 blocks of treatment (in sequence: HR1, HR2, HR3 given in two series). Then, reinduction with Protocol II followed, (ALL-BFM-95, Figure 1). Thus, Protocol II

According to the protocols, all HR patients and all patients with T-precursor ALL received 12 Gy of cranial irradiation following the completion of the treatment that was described previously and prior to starting maintenance chemotherapy. MR patients were irradiated, as

Allogeneic bone marrow transplantation (BMT) was recommended for a subset of HR

Maintenance treatment consisted of 24 or 30 months in total for females and males respectively, of daily 6-mercaptopurine (50 mg/m2) p.o./weekly methotrexate (20 mg/m2) p.o. and monthly (28 day cycle) i.v. vincristine (1.5 mg/m2), together with a five-day p.o. prednisolone (40 mg/m2/day) pulse. Triple (methotrexate/ aracytin/ steroid, doses adjusted to age) intrathecal (IT) infusions every third pulse (84 days), were administered to

Overall, this ALL patient cohort has received more intensive treatment than the original ALL-BFM-90 and ALL-BFM 95 Protocol (Schrappe et al., 2000, Morriche et al., 2010). All SR group patients were treated according to the MR group (receiving additional 2 doses of anthracyclines) and maintenance treatment was increased in length (24 months for girls and 30 months for boys maintenance treatment in total) and was intensified with vincristine/ prednizolone monthly pulses and triple intrathecal infusions every third pulse. Detailed treatment schedule has been previously described. Details of the treatment schedule and

The purpose of this analysis is to evaluate the effect of ALL treatment on thyroidal function. Thus, in order to have a homogenously treated patient group, patients with early death or

aracytin followed (second phase of Protocol II).

reinduction phase was common for MR and HR patients.

above, on the ALL-BFM-90 protocol but not on the ALL-BFM-95.

patients, provided that a matched sibling donor was available.

patient outcome has been described before (Papadakis et al., 2003).

patients not given CNS irradiation.

Out of the 168 eligible patients, 141 had at least one evaluation of thyroid function following completion of treatment. This cohort of patients evaluated consisted of 78 males and 63 female patients. Thirteen were treated according to the ALL-BFM 90 Protocol (all were assigned to MR treatment group) whilst 128 were treated according to the ALL-BFM 95 Protocol (115 MR, 13 HR treatment group). In regards to radiotherapy, 21 patients received cranial irradiation at a dose of 12 Gy, except for one earlier patient who received 16.8 Gy.

Thyroid Function Following Treatment of Childhood Acute Lymphoblastic Leukemia 165

Additionally two patients (1 male and 1 female) had compensated hypothyroidism (elevated TSH values with T4 values within the normal range) which resolved spontaneously, as the patients did not receive substitution therapy, and repeat thyroid

Of interest is the case of a 7.3 years old girl who at diagnosis was found to have hypothyroidism as evidenced by elevated ΤSH (10.5 μIU/ml) and thyroid sonogram with echogenicity changes characteristic of thyroiditis Hashimoto. However, antithyroglobulin and anti-Thyroid peroxidase antibodies were negative. One month later and while on treatment with high dose steroids and chemotherapy, the T4 and TSH serum values of 11.7 (in μg/dl ) and 10,5 ( in μIU/ml) found at diagnosis were reduced to 3.9 and 0.7, respectively. This change was attributed to steroid administration. At the last follow up 6.5 years from diagnosis and 3.8 years after the end of treatment, she remains euthyroid (T4 6.19

Furthermore, one male patient, 13.6 years old, during the maintenance treatment phase of chemotherapy, was diagnosed with compensated hypothyroidism, during laboratory investigation for bilateral femoral neck necrosis. At initial evaluation he was found to have TSH values of 6.5 μIU/ml with normal values of T4 and T3. On a 4 month follow-up, TSH value had increased to 7.8 μIU/ml and he was started on substitution therapy with p.o. levothyroxine. He was found to have positive anti-thyroglobulin antibodies while thyroid gland ultrasonography depicted minor echogenicity changes. Thus, he was diagnosed with compensated hypothyroidism 2.3 years after commencement of leukemia treatment, due to thyroiditis Hashimoto, and he continues to be on replacement therapy. This patient is

Out of the 168 eligible patients, 25 have received cranial irradiation. Out of the 141 evaluable, analyzed patients, 24 had received cranial irradiation as prophylaxis. Even though CNS leukemia was not apparent at diagnosis, the patients either belonged to the high risk group or were diagnosed with T-cell ALL and were irradiated according to the protocol mandates. Radiotherapy dose was 12 Gy for 24 patients and 16.8 Gy in one of the ALL-BFM 90 patients. Thyroid function data was available in all 24 patients at some timepoint following initiation of treatment and in some patients with serial values. Thyroid function measurements were available at a median time of 7.8 years (range, 2.0 to 12.9 years) after initiation of treatment and at a median time of 4.6 years (range, -0.9 to 10.0 years) after completion of treatment. All patients had thyroid function within normal limits and no borderline values (median TSH value of 2.85 μIU/ml, range 1.1 to 4.1 μIU/ml). One patient had borderline low T4 with normal TSH, raising suspicion for hidden central hypothyroidism, but further evaluation with TRH or night TSH surge was not performed. At the same time, 5 of 5 patients with thyroid ultrasound evaluation, normal thyroid gland size and architecture was appreciated. The patient who had received 16.8 Gy of cranial irradiation, had normal function at one year following cessation of treatment and no further evaluation. All patients who were evaluated for thyroid function (in total, all 5 and 12 patients evaluated for thyroid function) at the end of treatment (5 patients) and one year

μg/dl, T3 124.8 ng/ml and TSH 1.98 μIU/ml) with minor changes on ultrasound.

function tests were normal.

excluded from further analysis.

**3.2 High risk patients who received cranial irradiation**

later (12 patients), were also found to have values within normal limits.

#### **3.1 Data at diagnosis of leukemia**

At the time of diagnosis, one 12.6 year old female patient, with known Down syndrome (trisomy 21), had been diagnosed with hypothyroidism and was already receiving T4 supplementation for years. This patient was excluded from further analysis.

Table 1. Patient Characteristics of the Eligible Patients. Abbreviations: MR, Median Risk; HR, High Risk; CT, Chemotherapy; RT, radiotherapy

Twenty -seven patients have thyroid function data at diagnosis. Of those patients, 19 out of 27 had values of thyroid hormones and TSH within normal range and with appropriate ratio. Another 6 patients (2 males and 4 females) had low T4 with corresponding low TSH value. Free T4 (FT4) was not measured. Those 6 patients are considered to have low thyroid function due to critical illness, that is acute lymphoblastic leukemia. The corresponding T4 (in μg/dl) and TSH (in μIU/ml) serum values were 5.2/3.0; 2.9/1.1; 3.0/2.5; 6.3/0.2 respectively. The nonthyroidal illness syndrome or euthyroid sick syndrome, describes a condition characterized by abnormal thyroid function tests encountered in patients with acute or chronic systemic illnesses. The laboratory parameters of this syndrome include low serum levels of T3 and high levels of reverse T3, with normal or low levels of T4 and normal or low TSH. Thyroid function usually returns to normal as, the acute illness resolves.

At the time of diagnosis, one 12.6 year old female patient, with known Down syndrome (trisomy 21), had been diagnosed with hypothyroidism and was already receiving T4

**TOTAL**

Male 78 55.3 Female 63 44.7

ALL-BFM 90 13 9.2 ALL-BFM 95 128 90.7

MR Group 128 90.7 HR Group 13 9.2 CT Only 117 83.0 CT + RT 24 17.0

Abbreviations: MR, Median Risk; HR, High Risk; CT, Chemotherapy; RT, radiotherapy

or low TSH. Thyroid function usually returns to normal as, the acute illness resolves.