Antithyroid drugs

Exposed non-exposed studies (cohort)

Study Country
Study period
Population source Exposure definition Non-exposure definition Sample size Rmk
Andersen, 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 Antihyroid drug (PTU or 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). Addition of data provided for PTU and MMI/CMZ. 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.
2718 / 1159181 Addition of data provided for PTU and MMI/CMZ. Update of the previous study Andersen 2013 '(children born from 1996 to 2008) with this longer study (1997-2016).
Andersen 2014 (MMI only), 2014 Denmark
1996 - 2008
All children live-born from 1996 to 2008. Live-born children exposed to MMI/CMZ in early pregnancy. unexposed, disease free
Children born to mothers with no prescriptions of ATD and/or thyroid hormones redeemed 1995 to 2008 and no diagnosis of hyperthyroidism in the DNHR from 1977 to 2008.
1097 / 811730 This study is a extension (focused on subtype of congenital heart defect) of the study previously published (Andersen et al. 2013), using methods previously described in detail. Therefore, methods are extracted from the article Andersen et al. 2013.
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 maternal ATD (MMI and/or 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.
446 / 682343 Addition of PTU only (n = 218), MMI only (n = 162) and both PTU and MMI (n= 66).
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 maternal ATD (MMI and/or 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.
446 / 1551 Addition of PTU only (n = 218), MMI only (n = 162) and both PTU and MMI (n= 66).
Azizi (MMI only), 2002 Iran
Not specified
Not clearly specified. Women with thyrotoxicosis who received methimazole (MMI) therapy during pregnancy, but not during lactation. unexposed (not otherwise specified)
Not exposed to methimazole (MMI) therapy during pregnancy (illness status not specified).
23 / 30
Besancon, 2014 France
1999 - 2002
Pregnant women with Graves' disease (GD) and their babies included prospectively and managed over a 3-year period at the Robert Debré Teaching Hospital (Paris, France). Pregnant women needed for ATD treatment in third trimester (TRAbpositive/ATDpositive group AND TRAbnegative/ATDpositive group) unexposed, disease free
Pregnant women negative TRAb assays and no ATD treatment (TRAbnegative/ATDnegative group)
41 / 27 Addition of (TRAbnegative or TRAbpositive) to constitute the exposed group.
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 or MMI 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.
703 / 14150 Analyze of live-born children exposed to MMI/CMZ or PTU (n= 703) during pregnancy. The study also analyzed separately live-born children exposed to PTU (n = 630) ; to MMI/CMZ (n= 73) 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 or MMI treatment during pregnancy for more than 30 days during pregnancy. unexposed, sick
Women with a diagnosis of hyperthyroidism not receiving antithyroid drug.
703 / 2127 Analyze of live-born children exposed to MMI/CMZ or PTU (n= 703) during pregnancy. The study also analyzed separately live-born children exposed to PTU (n = 630) ; to MMI/CMZ (n= 73) during pregnancy.
Davis (PTU only), 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 ».
Di Gianantonio (MMI only), 2001 France, Germany, Israel, Italy, The Netherlands
Not specified
Pregnant women who were referred to the TIS units for risk assessment Pregnant women exposed to MMI during the preconceptional period and/or the first trimester to treat hyperthyroidism, unexposed, disease free
Pregnant women exposed to nonteratogenic drugs during the preconceptional period and/or the first trimester
241 / 1089
Gianetti, 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 MMI or 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.
176 / 203 Addition of all exposed pregnancies: the 2 PTU groups (euthyroid and hyperthyroid at least twice during pregnancy) and the 2 MMI groups (euthyroid and hyperthyroid at least twice during pregnancy).
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 (MMI and/or PTU) 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.
1149 / 634858 Addition of MMI only, PTU only and both MMI and PTU.
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 (MMI and/or PTU) 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.
1149 / 3236 Addition of MMI only, PTU only and both MMI and PTU.
Lo (control unexposed, disease free), 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 Antithyroid drug (MMI and/or PTU) during pregnancy. unexposed, disease free
Pregnant women without a maternal diagnosis of thyrotoxicosis and with no ATD and no thyroid hormone during pregnancy.
586 / 451829
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 Antithyroid drug (MMI and/or PTU) during pregnancy. unexposed, sick
Pregnant women with a maternal diagnosis of thyrotoxicosis and with no ATD and no thyroid hormone during pregnancy.
586 / 1171
McCarroll (Buckinghamshire control group) (MMI only), 1976 Ireland
1960 - 1971
Not clearly defined. Children born to carbimazole-treated thyrotoxic women. unexposed, disease free
Original Buckinghamshire group.
25 / 6160
McCarroll (Northern Ireland control group) (MMI only), 1976 Ireland
1960 - 1971
Children born to carbimazole-treated thyrotoxic women. unexposed, disease free
Northern Ireland boys and girls obtained from medical inspections made in 1972.
25 / 20
Mitsuda, 1992 Japan
The last 14 years
Pregnancies in patients with Graves disease managed at the studied hospitals throughout all trimesters and the postpartum period. Graves disease women treated with antithyroid drugs during pregnancy. unexposed, sick
Graves disease women not treated with any drug during pregnancy (excepted thyroxine).
111 / 119 Sixty women received methimazole alone, 31 were treated with both methimazole and propylthiouracil, and 20 received propylthiouracil alone.
Momotani, 1997 Japan
Not specified
Pregnant women with Graves’ disease Pregnant women with Graves’ disease who continued propylthiouracil (PTU) or methimazole (MMI) until delivery. unexposed, disease free
Healthy women who had no history of thyroid disease and who were delivered at term.
77 / 32 34 were treated with PTU (group P), and 43 were treated with MMI (group M)
Momotani, 1977 Japan
Not specified
Pregnant women with thyroid dysfunction (thyrotoxic patients) managed in Itoh hospital. Patients who became pregnant during antithyroid drug therapy. unexposed, sick
Patients who became pregnant after completing antithyroid drug therapy.
170 / 125
Momotani (MMI only), 1984 Japan
1965 - 1980
Infants born alive between August 1965 and May 1980 to mothers who were seen at Ito Thyroid Clinic and Hospital and diagnosed as having Graves’ disease. Infants whose mothers were treated with MMI during 1st trimester and were hyperthyroid or euthyroid. unexposed, sick
Infants whose mothers were not treated with MMI during 1st trimester and were hyperthyroid or euthyroid.
243 / 400 Treated group: addition of « Treated, hyperthyroid » and « Treated, euthyroid ». Unexposed: addition of « Untreated, hyperthyroid » and « Untreated, euthyroid ».
Phoojaroenchanachai, 2001 Thailand
1982 - 1996
Pregnant women with present and past history of hyperthyroidism diagnosed and managed at Siriraj Hospital. Pregnant women who had hyperthyroidism during the first and second trimesters of pregnancy and who were treated with antithyroid drugs (that achieved euthyroidism thereafter (ET-2 group) or still hyperthyroid during the third trimester of pregnancy (HT group)). unexposed, sick
Pregnant women who had euthyroidism before and throughout pregnancy without antithyroid drug therapy during pregnancy (ET-1).
134 / 54 Treated group: addition of « Treated, hyperthyroid » and « Treated, euthyroid ». The hyperthyroid state in HT group: hyperthyroidism despite an appropriate regimen of antithyroid drug therapy. All mothers in ET-2 were treated with antithyroid drugs.
Rosenfeld (PTU only), 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 (not otherwise specified)
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).
Schurmann, 2016 Denmark
1995 - 2010
All pregnancies reaching a gestational age of at least 12 weeks, recorded as a live birth or stillbirth in the Danish Medical Birth Registry or as miscarriage or termination of pregnancy in the National Patient Register (DNPR). Redemption of at least one prescription of medication for treatment of hyperthyroidism (MMI, CMZ, PTU) in the time interval from 91 days before to 91 days after start of LMP. unexposed (not otherwise specified)
Pregnancies with no exposure of antithyroid drugs or levothyroxine.
1843 / 969303 1843 pregnancies exposed to ATD (0.19%). Among the pregnancies exposed to ATD 64.4% were exposed to MMI/CMZ and 46.0% were exposed to PTU.
Seo, 2018 Korea
2008 - 2014
About all live-born infants (90.0% of nationwide live births during the period). At least one maternal prescription of Antithyroid drugs (PTU and/or MMI) during the first trimester. Addition of the 3 groups of ATD exposure: PTU alone, MMI alone, and both PTU and MMI. unexposed (not otherwise specified)
Women who had no prescription claims for Antithyroid drugs (ATDs) from the beginning of pregnancy to the day before childbirth.
12891 / 2872109 Addition of the 3 types of ATD exposure: PTU alone (n = 9930), MMI alone (n = 1120), and both PTU and MMI (n = 1841). Dose-effect studied by authors.
Stice, 1984 USA
1960 - 1979
Pregnant women with Graves disease treated by the authors. Patients medically treated with antithyroid drugs. (This is a subgroup of exposure among the exposed group considered in the study). unexposed, sick
Patients surgically treated.
5 / 10 Of the 6 medically treated, only 5 was treated with antithyroid drugs. These ones are reported here.
Wing, 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 and/or methimazole during pregnancy. Addition of PTU only, MMI only and both PTU and MMI (co-exposure). unexposed, sick
Patients who were either euthyroid throughout pregnancy and required no medications or were hyperthyroid but were seen late in pregnancy.
142 / 43 Addition of PTU only, MMI only and both PTU and MMI (co-exposure). Extraction of data concerning 1st trimester exposure for congenital malformations.
Yoshihara, 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 or thiamazole (MMI) 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).
564 / 475 Addition of mothers exposed to MMI alone (23) and PTU alone (541).
Yoshihara, 2012 Japan
1999 - 2010
Women with Graves’ disease who became pregnant during the study period. Mothers who received MMI or 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).
3004 / 2065 Exposure: PTU or MMI (addition of the cases in PTU group and MMI group; analysis not performed by authors).
Zhang (PTU only), 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.
Barbero (MMI only), 2008 Argentina
1976 - 2006
Patients with unilateral or bilateral choanal atresia who received surgical treatment during the period 1976–2006. Children without choanal atresia but treated at the same centers because of other respiratory diseases 61 / 183 Non exposed women had mainly not reported hyperthyroidism (only in 2 (2/183) controls’ mothers).
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 Addition of PTU and MMI (analysis not performed by authors). “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 anti-thyroid 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 Brown 2009.
Khoury (MMI only), 1989 USA
1981 - 1983
Stillborn and liveborn babies with birth defects (cases were classified into 66 broad and specific birth defect groups). A random sample of babies without birth defects, frequency-matched to cases by race, hospital of birth, and period of birth. 4904 / 3027

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