Thiouracil, propylthiouracil, benzylthiouracil

Exposed non-exposed, cohort studies

Study Country
Study period
Study design		 Data source Exposure definition Non-exposure definition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Andersen 2017 (control exposed to MMI/CMZ)
2017 		Sweden
2006 - 2012
population based cohort retrospective 		Swedish nationwide register-based cohort study 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. 		early pregnancy 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.
Information on maternal use of ATDs was obtained from the Swedish Prescribed Drug Register (SPDR) which holds data on all prescriptions drugs in Swedish since 2005.
Andersen 2017 (control unexposed, disease free)
2017 		Sweden
2006 - 2012
population based cohort retrospective 		Swedish nationwide register-based cohort study 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. 		early pregnancy 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.
Information on maternal use of ATDs was obtained from the Swedish Prescribed Drug Register (SPDR) which holds data on all prescriptions drugs in Swedish since 2005.
Andersen 2017 (control unexposed, sick)
2017 		Sweden
2006 - 2012
population based cohort retrospective 		Swedish nationwide register-based cohort study 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. 		early 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.
Information on maternal use of ATDs was obtained from the Swedish Prescribed Drug Register (SPDR) which holds data on all prescriptions drugs in Swedish since 2005.
Andersen 2019 (control exposed to MMI/CMZ)
2019 		Denmark
1997 - 2016
population based cohort retrospective 		Danish nationwide register-based cohort study (NRBC) 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) 		early pregnancy 889 / 1574 Update of the previous study Andersen 2013 '(children born from 1996 to 2008) with this longer study (1997-2016).
The Danish National Prescription Register (DNPR) includes information on redeemed prescriptions of drugs coded according to the Anatomical Therapeutical Classification (ATC) system, and drugs used for the treatment of thyroid disease are included in the ATC group: H03.
Andersen 2019 (control unexposed, disease free)
2019 		Denmark
1997 - 2016
population based cohort retrospective 		Danish nationwide register-based cohort study (NRBC) 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 		early pregnancy 889 / 1159181 Update of the previous study Andersen 2013 '(children born from 1996 to 2008) with this longer study (1997-2016).
The Danish National Prescription Register (DNPR) includes information on redeemed prescriptions of drugs coded according to the Anatomical Therapeutical Classification (ATC) system, and drugs used for the treatment of thyroid disease are included in the ATC group: H03.
Chen (Control exposed to MMI)
2011 		Taiwan
Jan 2005 - Dec 2005
retrospective cohort (claims database) 		Two nationwide population-based data sets: Taiwan National Health Insurance Research Dataset (NHIRD) and the national birth certificate registry of Taiwan. 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. 		during pregnancy (anytime or not specified) 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.
Taiwan National Health Insurance Research Dataset (NHIRD) includes the cost of inpatient treatment and outpatient prescriptions.
Chen (control unexposed, disease free)
2011 		Taiwan
Jan 2005 - Dec 2005
retrospective cohort (claims database) 		Two nationwide population-based data sets: Taiwan National Health Insurance Research Dataset (NHIRD) and the national birth certificate registry of Taiwan. 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. 		during pregnancy (anytime or not specified) 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.
Taiwan National Health Insurance Research Dataset (NHIRD) includes the cost of inpatient treatment and outpatient prescriptions.
Chen (control unexposed, sick)
2011 		Taiwan
Jan 2005 - Dec 2005
population based cohort retrospective 		Two nationwide population-based data sets: Taiwan National Health Insurance Research Dataset (NHIRD) and the national birth certificate registry of Taiwan. 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. 		during pregnancy (anytime or not specified) 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.
Taiwan National Health Insurance Research Dataset (NHIRD) includes the cost of inpatient treatment and outpatient prescriptions.
Davis
1989 		USA
1974 - 1985
prospective cohort 		Files of the Parkland Memorial Hospital, USA Pregnant women (thyrotoxic and euthyroid) treated with propylthiouracil. unexposed, sick
Pregnant women with thyrotoxicosis who were never treated. 		during pregnancy (anytime or not specified) 52 / 8 Treated group: addition of « Treated, thyrotoxic » and « Treated, euthyroid ».
After treatment was begun, follow-up was scheduled at least twice monthly and medication was adjusted. All information was obtained by chart review. The management of women whose pregnancies were complicated by thyrotoxicosis was directed by one of the author.
Gianetti (control exposed to MMI)
2015 		Italy
1992 - 2005
retrospective cohort 		Clinical records of eight Italian Departments of Endocrinology retrospectively analyzed. 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). 		at least 1st trimester 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.
Records were reviewed retrospectively in order to collect data notably on specific antithyroid drug used and its dose.
Gianetti (control unexposed, sick)
2015 		Italy
1992 - 2005
retrospective cohort 		Clinical records of eight Italian Departments of Endocrinology retrospectively analyzed. 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. 		throughout 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.
Records were reviewed retrospectively in order to collect data notably on specific antithyroid drug used and its dose.
Hawken (control exposed to MMI)
2016 		France
2005 - 2012
retrospective cohort 		Hospitals and open-care endocrinologists working in the Poitou-Charentes region. Foetuses exposed to propylthiouracil (PTU) during pregnancy. exposed to other treatment, sick
Foetuses exposed to carbimazole (CMZ) during pregnancy. 		1st trimester, 2nd trimester, 3rd trimester 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
Review of the files obtained by hospitals in the region after having contacted hospitals and open-care endocrinologists working in the Poitou-Charentes region.
Korelitz (control exposed to MMI)
2013 		USA
2005 - 2009
retrospective cohort (claims database) 		The MarketScan Commercial Claims and Encounters database 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. 		3 months (or more) before pregnancy or during pregnancy 915 / 108
Prescription drug claims were used to determine ATD therapy.
Korelitz (control exposed to MMI)
2013 		USA
2005 - 2009
retrospective cohort (claims database) 		The MarketScan Commercial Claims and Encounters database 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. 		3 months (or more) before pregnancy or during pregnancy 915 / 108
Prescription drug claims were used to determine ATD therapy.
Korelitz (control unexposed, disease free)
2013 		USA
2005 - 2009
retrospective cohort (claims database) 		The MarketScan Commercial Claims and Encounters database 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 		3 months (or more) before pregnancy or during pregnancy, 3rd trimester 915 / 634858
Prescription drug claims were used to determine ATD therapy.
Korelitz (control unexposed, sick)
2013 		USA
2005 - 2009
retrospective cohort (claims database) 		The MarketScan Commercial Claims and Encounters database 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 		3 months (or more) before pregnancy or during pregnancy 915 / 3236
Prescription drug claims were used to determine ATD therapy.
Lo (control exposed to MMI)
2015 		USA
1996 - 2010
retrospective cohort (claims database) 		Kaiser Permanente Northern California (KPNC) 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. 		during pregnancy (anytime or not specified) 507 / 30
Kaiser Permanente Northern California (KPNC) is a large integrated health care delivery system. Pharmacologic exposures were obtained from health plan electronic databases.
Lo (control unexposed, sick)
2015 		USA
1996 - 2010
retrospective cohort (claims database) 		Kaiser Permanente Northern California (KPNC) 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. 		during pregnancy (anytime or not specified) 507 / 1171
Kaiser Permanente Northern California (KPNC) is a large integrated health care delivery system. Pharmacologic exposures were obtained from health plan electronic databases.
Momotani (control exposed to MMI)
1997 		Japan
Not specified
prospective cohort 		Ito Hospital, Tokyo, Japan 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. 		throughout pregnancy 34 / 43 34 were treated with PTU (group P), and 43 were treated with MMI (group M)
Administration of MMI or PTU by investigators.
Rosenfeld
2009 		Israel
1994 - 2004
prospective cohort 		Israeli Teratology Information Service (TIS) 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. 		1st trimester, during pregnancy (anytime or not specified) 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).
Details of exposure were collected during pregnancy using a structured questionnaire. Standardized data collection forms were used notably to record the following information by telephone: exposure details (dose, duration and timing of pregnancy), and concurrent exposures.
Seo (control exposed to MMI)
2018 		Korea
2008 - 2014
retrospective cohort (claims database) 		Korean National Health Insurance database 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. 		1st 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
National Health Insurance (NHI) database
Seo (control unexposed, NOS)
2018 		Korea
2008 - 2014
retrospective cohort (claims database) 		Korean National Health Insurance database 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. 		1st trimester 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
National Health Insurance (NHI) database
Wing (control exposed to MMI)
1994 		USA
1974 - 1990
cohort 		High-risk obstetrics clinic database, Los Angeles County/University of Southern California Medical Center, Women's Hospital, USA 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. 		1st trimester, during pregnancy (anytime or not specified) 99 / 36 A cohort was established to compare the outcome of patients treated with propylthiouracil and methimazole.
The patients were followed up prospectively during pregnancy with treatment administration.
Wing (control unexposed, sick)
1994 		USA
1974 - 1990
cohort 		Database of the High-risk obstetrics clinic, Los Angeles County / Southern California Medical Center, Women's Hospital 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. 		1st trimester, during pregnancy (anytime or not specified) 99 / 43 A cohort was established to compare the outcome of patients treated with propylthiouracil and methimazole.
The patients were followed up prospectively during pregnancy with treatment administration.
Yoshihara (control exposed to MMI)
2012 		Japan
1999 - 2010
retrospective cohort 		Database of Ito Hospital, Tokyo, Japan 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). 		1st trimester 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.
Review of the medical records.
Yoshihara (control unexposed, sick)
2012 		Japan
1999 - 2010
retrospective cohort 		Database of Ito Hospital, Tokyo, Japan 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). 		1st trimester 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.
Review of the medical records.
Yoshihara (Controls exposed to MMI)
2021 		Japan
2015 - 2019
retrospective cohort 		Database of Ito Hospital, Shibuya-ku, Tokyo, 150-8308, Japan 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). 		1st trimester 541 / 23
Not specified (Pregnant patients being treated at the institution were informed during their pregnancy that they would be asked about the outcome of their pregnancy after delivery).
Yoshihara (Controls unexposed, sick)
2021 		Japan
2015 - 2019
retrospective cohort 		Database of Ito Hospital, Shibuya-ku, Tokyo, 150-8308, Japan 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). 		1st trimester 541 / 475
Not specified (Pregnant patients being treated at the institution were informed during their pregnancy that they would be asked about the outcome of their pregnancy after delivery).
Zhang
2016 		China
2009 - 2014
retrospective cohort 		Database of the Sun Yat-Sen Memorial Hospital, China 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. 		during pregnancy (anytime or not specified) 43 / 18
Medical records

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Banhidy
2011 		Hungary
1980 – 1996
case control 		Hungarian Case–Control Surveillance of Congenital Abnormalities (HCCSCA) 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. Mothers were asked to send us the prenatal maternity logbook (obstetricians recorded maternal diseases, and related drug prescriptions in this logbook, in the first prenatal care visit was between the 6th and 12th gestational week) and other medical records particularly discharge summaries. throughout pregnancy 71 / 116 Of 71 case mothers, four (5.6%), while of 116 control mothers, eight (6.9%) were treated with antithyroid drugs.
Diagnosis of Congenital Anomalies was based on the compulsory notification of physicians to the HCAR. Pathologists sent a copy of the autopsy report to the HCAR if defects were identified in stillbirths and infant deaths.
Clementi
2010 		International (twelve surveillance programs)
Not specified
case control 		International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) 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. Not specified. The coverage, structure, methods, and sources of ascertainment, described elsewhere, varied from program to program (12 surveillance programs included). 1st trimester -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.
These data were reviewed for malformation classification by a clinician with expertise in genetics and dysmorphology to separate subjects of isolated major malformations from those of multiple congenital anomalies.
Howley
2017 		USA
1997 - 2011
case control 		The National Birth Defects Prevention Study (NBDPS) 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. Mothers reported medications taken during pregnancy, including timing, frequency, and duration of medication use. 1st trimester 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)
Case information, including medical record information, was obtained from birth defects surveillance programs in 10 states. Clinical geneticists reviewed each case to determine eligibility and to classify case infants.

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

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