Thiouracil, propylthiouracil, benzylthiouracil

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Andersen 2017 (control exposed to MMI/CMZ), 2017	Sweden 2006 - 2012	All live-born children in Sweden between 2006 and 2012	The child was defined as exposed to PTU in early pregnancy if the mother had at least one redeemed prescription of ATD less than six months before the estimated pregnancy start and before the 11th gestational week.	exposed to other treatment, sick The child was defined as exposed to MMI/CMZ in early pregnancy if the mother had at least one redeemed prescription of ATD less than six months before the estimated pregnancy start and before the 11th gestational week.	218 / 162	Subanalyze of live-born children exposed to PTU (n = 218) in early pregnancy. The study also analyzed live-born children exposed to MMI/CMZ (n = 162), to MMI/CMZ and PTU (n= 66) in early pregnancy. TOTAL : n =446.
Andersen 2017 (control unexposed, disease free), 2017	Sweden 2006 - 2012	All live-born children in Sweden between 2006 and 2012	The child was defined as exposed to PTU in early pregnancy if the mother had at least one redeemed prescription of ATD less than six months before the estimated pregnancy start and before the 11th gestational week.	unexposed, disease free Children born to mothers with no redeemed prescriptions of ATD or thyroid hormones from 2005 to 2014 and no diagnosis of hyperthyroidism registered from 2005 to 2014 in the Swedish National Patient Register.	218 / 682343	Subanalyze of live-born children exposed to PTU (n = 218) in early pregnancy. The study also analyzed live-born children exposed to MMI/CMZ (n = 162), to MMI/CMZ and PTU (n= 66) in early pregnancy. TOTAL : n =446.
Andersen 2017 (control unexposed, sick), 2017	Sweden 2006 - 2012	All live-born children in Sweden between 2006 and 2012	The child was defined as exposed to PTU in early pregnancy if the mother had at least one redeemed prescription of ATD less than six months before the estimated pregnancy start and before the 11th gestational week.	unexposed, sick Children born to mothers who were treated with ATD more than one year before or more than one year after pregnancy and received no treatment with thyroid hormone in pregnancy.	218 / 1551	Subanalyze of live-born children exposed to PTU (n = 218) in early pregnancy. The study also analyzed live-born children exposed to MMI/CMZ (n = 162), to MMI/CMZ and PTU (n= 66) in early pregnancy. TOTAL : n =446.
Andersen 2019 (control exposed to MMI/CMZ), 2019	Denmark 1997 - 2016	All children live-born in Denmark from January 1, 1997 to December 31, 2016 who were identified in the Danish Medical Birth Register (MBR) and had available information on gestational age at birth.	Use of PTU in early pregnancy (redeemed prescriptions of the drugs in the period ranging from six months prior to pregnancy start up to and including the 10th week of pregnancy)	exposed to other treatment, sick Use of MMI/CMZ in early pregnancy (redeemed prescriptions of the drugs in the period ranging from six months prior to pregnancy start up to and including the 10th week of pregnancy)	889 / 1574	Update of the previous study Andersen 2013 '(children born from 1996 to 2008) with this longer study (1997-2016).
Andersen 2019 (control unexposed, disease free), 2019	Denmark 1997 - 2016	All children live-born in Denmark from January 1, 1997 to December 31, 2016 who were identified in the Danish Medical Birth Register (MBR) and had available information on gestational age at birth.	Use of PTU in early pregnancy (redeemed prescriptions of the drugs in the period ranging from six months prior to pregnancy start up to and including the 10th week of pregnancy)	unexposed, disease free Children whose mother had no diagnosis of hyperthyroidism, no registration of thyroid surgery and no redeemed prescription of ATD or Levothyroxine before, during or after the pregnancy under study and up to December 31, 2017	889 / 1159181	Update of the previous study Andersen 2013 '(children born from 1996 to 2008) with this longer study (1997-2016).
Chen (Control exposed to MMI), 2011	Taiwan Jan 2005 - Dec 2005	All women in Taiwan who had live singleton births and used prenatal care services from 1 January 2005 to 31 December 2005	Women with hyperthyroidism diagnosis, who were prescribed PTU treatment during pregnancy for more than 30 days during pregnancy.	exposed to other treatment, sick Women with hyperthyroidism diagnosis, who were prescribed MMI treatment during pregnancy for more than 30 days during pregnancy.	630 / 73	Subanalyze of live-born children exposed to PTU (n = 630) during pregnancy. The study also analyzed live-born children exposed to MMI/CMZ (n = 73) ; to MMI/CMZ or PTU (n= 703) during pregnancy.
Chen (control unexposed, disease free), 2011	Taiwan Jan 2005 - Dec 2005	All women in Taiwan who had live singleton births and used prenatal care services from 1 January 2005 to 31 December 2005	Women with hyperthyroidism diagnosis, who were prescribed PTU treatment during pregnancy for more than 30 days during pregnancy.	unexposed, disease free The remaining women in the database, excluding women with a diagnosis of hyperthyroidism anytime during the period 1996-2006.	630 / 14150	Subanalyze of live-born children exposed to PTU (n = 630) during pregnancy. The study also analyzed live-born children exposed to MMI/CMZ (n = 73) ; to MMI/CMZ or PTU (n= 703) during pregnancy.
Chen (control unexposed, sick), 2011	Taiwan Jan 2005 - Dec 2005	All women in Taiwan who had live singleton births and used prenatal care services from 1 January 2005 to 31 December 2005	Women with hyperthyroidism diagnosis, who were prescribed PTU treatment during pregnancy for more than 30 days during pregnancy.	unexposed, sick Women with a diagnosis of hyperthyroidism not receiving antithyroid drug.	630 / 2127	Subanalyze of live-born children exposed to PTU (n = 630) during pregnancy. The study also analyzed live-born children exposed to MMI/CMZ (n = 73) ; to MMI/CMZ or PTU (n= 703) during pregnancy.
Davis, 1989	USA 1974 - 1985	Women at Parkland Memorial Hospital whose pregnancies were complicated by thyrotoxicosis.	Pregnant women (thyrotoxic and euthyroid) treated with propylthiouracil.	unexposed, sick Pregnant women with thyrotoxicosis who were never treated.	52 / 8	Treated group: addition of « Treated, thyrotoxic » and « Treated, euthyroid ».
Gianetti (control exposed to MMI), 2015	Italy 1992 - 2005	Pregnant women affected by thyroid diseases and followed in eight Italian Departments of Endocrinology around Italy.	Pregnancies of women being treated with PTU for Graves’ disease (GD) or toxic nodular goiter (TNG).	exposed to other treatment, sick Pregnancies of women being treated with MMI for Graves’ disease (GD) or toxic nodular goiter (TNG).	52 / 124	Addition of the 2 groups of pregnancies exposed to PTU (euthyroid and hyperthyroid) and also for MMI. All patients included in the study received their diagnosis and started their therapies at least 3 months before pregnancy.
Gianetti (control unexposed, sick), 2015	Italy 1992 - 2005	Pregnant women affected by thyroid diseases and followed in eight Italian Departments of Endocrinology around Italy.	Pregnancies of women being treated with PTU for Graves’ disease (GD) or toxic nodular goiter (TNG).	unexposed, sick Pregnant women who were affected by thyroid diseases but were euthyroid (either on LT4 therapy for hypothyroidism or without treatment) and did not receive any ATD medication during pregnancy.	52 / 203	Addition of the 2 groups of pregnancies exposed to PTU (euthyroid and hyperthyroid at least twice during pregnancy). All patients included in the study received their diagnosis and started their therapies at least 3 months before pregnancy.
Hawken (control exposed to MMI), 2016	France 2005 - 2012	Pegnant women with Graves' disease (progressive or not), treated with Synthetic antithyroid drugs (SAT) and/or surgery and/or RAI therapy, discovered before or during pregnancy and followed by a hospital or open-care endocrinologist in the Poitou-Charentes region.	Foetuses exposed to propylthiouracil (PTU) during pregnancy.	exposed to other treatment, sick Foetuses exposed to carbimazole (CMZ) during pregnancy.	13 / 19	Treatment of Graves’ disease diagnosed during pregnancy (14 patients) : - 6 PTU en T1 => 0 malfo - 2 CMZ en T1 => 1 malfo Treatments in patients under SAT at the time of starting pregnancy (24 patients). - 7 PTU en T1 => 0 malfo - 17 CMZ en T1 => 3 malfo
Korelitz (control exposed to MMI), 2013	USA 2005 - 2009	Women aged 15–44 years who were enrolled for at least 24 months with prescription drug benefits and had at least two pregnancy-related medical service claims between 2005 and 2009	Antithyroid (PTU only) drug use within 6 months before the pregnancy start date or during pregnancy.	exposed to other treatment, sick Antithyroid (MMI only) drug use within 6 months before the pregnancy start date or during pregnancy.	915 / 108
Korelitz (control exposed to MMI), 2013	USA 2005 - 2009	Women aged 15–44 years who were enrolled for at least 24 months with prescription drug benefits and had at least two pregnancy-related medical service claims between 2005 and 2009	Antithyroid (PTU only) drug use within 6 months before the pregnancy start date or during pregnancy.	exposed to other treatment, sick Antithyroid (MMI only) drug use within 6 months before the pregnancy start date or during pregnancy.	915 / 108
Korelitz (control unexposed, disease free), 2013	USA 2005 - 2009	Women aged 15–44 years who were enrolled for at least 24 months with prescription drug benefits and had at least two pregnancy-related medical service claims between 2005 and 2009	Antithyroid (PTU only) drug use within 6 months before the pregnancy start date or during pregnancy	unexposed, disease free No Antithyroid (MMI or PTU) drug use in women without thyrotoxicosis	915 / 634858
Korelitz (control unexposed, sick), 2013	USA 2005 - 2009	Women aged 15–44 years who were enrolled for at least 24 months with prescription drug benefits and had at least two pregnancy-related medical service claims between 2005 and 2009	Antithyroid (PTU only) drug use within 6 months before the pregnancy start date or during pregnancy	unexposed, sick No Antithyroid (MMI or PTU) drug use in women with thyrotoxicosis before/during pregnancy	915 / 3236
Lo (control exposed to MMI), 2015	USA 1996 - 2010	All pregnancies resulting in a live birth during the study period among women age 15–49 years at the time of delivery	Pregnant women with a maternal diagnosis of thyrotoxicosis and treated with PTU only during pregnancy.	exposed to other treatment, sick Pregnant women with a maternal diagnosis of thyrotoxicosis and treated with MMI only during pregnancy.	507 / 30
Lo (control unexposed, sick), 2015	USA 1996 - 2010	All pregnancies resulting in a live birth during the study period among women age 15–49 years at the time of delivery	Pregnant women with a maternal diagnosis of thyrotoxicosis and treated with PTU only during pregnancy.	unexposed, sick Pregnant women with a maternal diagnosis of thyrotoxicosis and with no ATD and no thyroid hormone during pregnancy.	507 / 1171
Momotani (control exposed to MMI), 1997	Japan Not specified	Pregnant women with Graves’ disease	Pregnant women with Graves’ disease who continued propylthiouracil (PTU) until delivery.	exposed to other treatment, sick Pregnant women with Graves’ disease who continued methimazole (MMI) until delivery.	34 / 43	34 were treated with PTU (group P), and 43 were treated with MMI (group M)
Rosenfeld, 2009	Israel 1994 - 2004	All women who contacted (directly or through their healthcare providers) the service between for information about gestational exposure were prospectively enrolled in the study.	Pregnant women counseled for gestational exposure to Propylthiouracil (PTU).	unexposed (general population or NOS) Pregnant women consulted with the TIS regarding exposures not known to be teratogenic taken before pregnancy and no later than the first 4–5 weeks of gestation.	115 / 1141	For major anomalies: exposure to PTU between weeks 4 and 13. For fetal/neonatal thyroid status with or without goitre: data of control group not provided. Hyperthyroid: 9/87 (of whom 2 goiters). Hypothyroid: 7/74 (of whom 4 goiters).
Seo (control exposed to MMI), 2018	Korea 2008 - 2014	About all live-born infants (90.0% of nationwide live births during the period).	At least one maternal prescription of PTU alone during the first trimester.	exposed to other treatment, sick At least one maternal prescription of MMI alone during the first trimester.	9930 / 1120	3 types of ATD exposure: PTU alone (n = 9930), MMI alone (n = 1120), and both PTU and MMI (n = 1841). 210 cases of carbimazole use were included in the MMI groups
Seo (control unexposed, NOS), 2018	Korea 2008 - 2014	About all live-born infants (90.0% of nationwide live births during the period).	At least one maternal prescription of PTU during the first trimester.	unexposed (general population or NOS) Women who had no prescription claims for Antithyroid drugs (ATDs) from the beginning of pregnancy to the day before childbirth.	9930 / 2872109	3 types of ATD exposure: PTU alone (n = 9930), MMI alone (n = 1120), and both PTU and MMI (n = 1841). 210 cases of carbimazole use were included in the MMI groups
Wing (control exposed to MMI), 1994	USA 1974 - 1990	Patients with a history or diagnosis of hyperthyroidism evaluated in our high-risk obstetrics clinic between July 1974 and June 1990. The patients were followed up prospectively during pregnancy.	Pregnant women who were diagnosed with or had a history of hyperthyroidism treated with propylthiouracil only during pregnancy.	exposed to other treatment, sick Pregnant women who were diagnosed with or had a history of hyperthyroidism treated with methimazole only during pregnancy.	99 / 36	A cohort was established to compare the outcome of patients treated with propylthiouracil and methimazole.
Wing (control unexposed, sick), 1994	USA 1974 - 1990	Patients with a history or diagnosis of hyperthyroidism evaluated in our high-risk obstetrics clinic between July 1974 and June 1990. The patients were followed up prospectively during pregnancy.	Pregnant women who were diagnosed with or had a history of hyperthyroidism treated with propylthiouracil only during pregnancy.	unexposed, sick Patients who were either euthyroid throughout pregnancy and required no medications or were hyperthyroid but were seen late in pregnancy.	99 / 43	A cohort was established to compare the outcome of patients treated with propylthiouracil and methimazole.
Yoshihara (control exposed to MMI), 2012	Japan 1999 - 2010	Women with Graves’ disease who became pregnant during the study period.	Mothers who received PTU for the treatment of Graves’ disease in the first trimester of pregnancy (0 –12 wk gestation).	exposed to other treatment, sick Mothers who received MMI for the treatment of Graves’ disease in the first trimester of pregnancy (0 –12 wk gestation).	1578 / 1426	Compare the proportions of infants born with congenital malformations to mothers in the groups treated with each of the antithyroid drugs and to the mothers who were not treated with any antithyroid drugs during the first trimester of pregnancy.
Yoshihara (control unexposed, sick), 2012	Japan 1999 - 2010	Women with Graves’ disease who became pregnant during the study period.	Mothers who received PTU for the treatment of Graves’ disease in the first trimester of pregnancy (0 –12 wk gestation).	unexposed, sick Mothers who received no medication for the treatment of Graves’ disease during the first trimester of pregnancy (0 –12 wk gestation).	1578 / 2065	Compare the proportions of infants born with congenital malformations to mothers in the groups treated with each of the antithyroid drugs and to the mothers who were not treated with any antithyroid drugs during the first trimester of pregnancy.
Yoshihara (Controls exposed to MMI), 2021	Japan 2015 - 2019	Women with Graves disease (GD) who gave birth between January 1, 2015, and May 31, 2019.	Mothers with Graves disease (GD) treated with propylthiouracil (PTU) alone during the first trimester of pregnancy (0-12 weeks’ gestation).	exposed to other treatment, sick Mothers with Graves disease (GD) treated with thiamazole (MMI) alone during the first trimester of pregnancy (0-12 weeks’ gestation).	541 / 23
Yoshihara (Controls unexposed, sick), 2021	Japan 2015 - 2019	Women with Graves disease (GD) who gave birth between January 1, 2015, and May 31, 2019.	Mothers with Graves disease (GD) treated with propylthiouracil (PTU) alone during the first trimester of pregnancy (0-12 weeks’ gestation).	unexposed, sick Women with Graves disease (GD) that had not been treated with any medication for GD in the first trimester of pregnancy (427 were in remission after ATD therapy for GD before their pregnancy, and all the others had been treated for GD before their pregnancy).	541 / 475
Zhang, 2016	China 2009 - 2014	Pregnant women consulted at the Sun Yat-Sen Memorial Hospital (Department of Nuclear Medicine and Department of Obstetrics).	Female Graves’ disease patients who became pregnant at least six months after 131I therapy for hyperthyroidism and treated with PTU during pregnancy.	unexposed, sick Female Graves’ disease patients who became pregnant at least six months after 131I therapy for hyperthyroidism and not treated with medicine during pregnancy.	43 / 18

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Banhidy, 2011	Hungary 1980 – 1996	Fetus/infants affected with major Congenital anomaly, selected from the data set of the Hungarian Congenital Abnormality Registry (HCAR), born of mother with hyperthyroidism.	Newborn infants without any Congenital anomaly, selected from the National Birth Registry of the Central Statistical Office for the HCCSCA, born of mother with hyperthyroidism.	71 / 116	Of 71 case mothers, four (5.6%), while of 116 control mothers, eight (6.9%) were treated with antithyroid drugs.
Clementi, 2010	International (twelve surveillance programs) Not specified	Cases with the specific malformation being tested and reported first-trimester exposure to medication.	Cases with any other malformation and reported first-trimester exposure to medication.	-9 / -9	“exposed case-only” design: all infants had a major birth defect and were exposed to some medication. TOTAL: 18131 cases with malformations and reported first-trimester exposure to medication.
Howley, 2017	USA 1997 - 2011	Infants with one or more of 30 different categories of major structural birth defects.	Infants live births without major birth defects randomly selected from hospital records or birth certificates in the same time period and geographic area as the cases.	31409 / 11536	Of those reporting periconceptional ATD medication use, 30 mothers (25 case and 5 control) exclusively used PTU, 6 mothers (3 case and 3 control) used only MMI, and 8 mothers (6 case and 2 control) used both PTU and MMI. Update of Browne 2009 (excluded)

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