Antithyroid drugs

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 Overall risk of bias
Andersen
2019
Denmark
1997 - 2016
population based cohort retrospective
Danish nationwide register-based cohort study (NRBC) 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.
early pregnancy 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). NA
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 2014 (MMI only)
2014
Denmark
1996 - 2008
population based cohort retrospective
Danish nationwide register-based cohort study 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.
early pregnancy 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. NA
Danish National Prescription Register. Thyroid hormones (ATC H03A) and ATD (ATC H03B) are sold solely as prescription drugs in Denmark.
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 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.
early pregnancy 446 / 682343 Addition of PTU only (n = 218), MMI only (n = 162) and both PTU and MMI (n= 66). NA
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 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.
early pregnancy 446 / 1551 Addition of PTU only (n = 218), MMI only (n = 162) and both PTU and MMI (n= 66). NA
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.
Azizi (MMI only)
2002
Iran
Not specified
retrospective cohort
The Endocrine Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, I.R. Iran 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).
throughout pregnancy 23 / 30 NA
Women with thyrotoxicosis who had regular follow-up in the endocrine office were recalled.
Besancon
2014
France
1999 - 2002
prospective cohort
The cohort of pregnant women with GD and their babies from the Robert Debre 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)
3rd trimester 41 / 27 Addition of (TRAbnegative or TRAbpositive) to constitute the exposed group. NA
Pregnant women were included prospectively and managed (with administration of ATD if needed) by the investigator.
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 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.
during pregnancy (anytime or not specified) 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. NA
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
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 or MMI 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) 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. NA
Taiwan National Health Insurance Research Dataset (NHIRD) includes the cost of inpatient treatment and outpatient prescriptions.
Davis (PTU only)
1989
USA
1974 - 1985
prospective cohort
Files of the Parkland Memorial Hospital 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 ». NA
All information was obtained by chart review. The management of women whose pregnancies were complicated by thyrotoxicosis was directed by one of the author.
Di Gianantonio (MMI only)
2001
France, Germany, Israel, Italy, The Netherlands
Not specified
prospective cohort
10 Teratology Information Services (TIS) of the European Network of Teratology Information Services (ENTIS) 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
1st trimester 241 / 1089 NA
Prospective data were collected at the time of the inquiry and included questions on commercial preparation used, its dosage, indication for use, and the time during the pregnancy when it was taken.
Gianetti
2015
Italy
1992 - 2005
retrospective cohort
Clinical records of eight Italian Departments of Endocrinology retrospectively analyzed. 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.
at least 1st trimester 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). NA
Records were reviewed retrospectively in order to collect data notably on specific antithyroid drug used and its dose.
Korelitz (control unexposed, disease free)
2013
USA
2005 - 2009
retrospective cohort (claims database)
The MarketScan Commercial Claims and Encounters database 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.
3 months (or more) before pregnancy or during pregnancy 1149 / 634858 Addition of MMI only, PTU only and both MMI and PTU. NA
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 (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.
3 months (or more) before pregnancy or during pregnancy 1149 / 3236 Addition of MMI only, PTU only and both MMI and PTU. NA
Prescription drug claims were used to determine ATD therapy.
Lo (control unexposed, disease free)
2015
USA
1996 - 2010
retrospective cohort (claims database)
Kaiser Permanente Northern California (KPNC) 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.
during pregnancy (anytime or not specified) 586 / 451829 NA
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 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.
during pregnancy (anytime or not specified) 586 / 1171 NA
Kaiser Permanente Northern California (KPNC) is a large integrated health care delivery system. Pharmacologic exposures were obtained from health plan electronic databases.
McCarroll (Buckinghamshire control group) (MMI only)
1976
Ireland
1960 - 1971
retrospective cohort
Database of the Metabolic Unit, Royal Belfast Hospital for Sick Children, Belfast Children born to carbimazole-treated thyrotoxic women. unexposed, disease free
Original Buckinghamshire group.
throughout pregnancy 25 / 6160 NA
Carbimazole was administered in every case during the first two trimesters of pregnancy then reduced in the last trimester.
McCarroll (Northern Ireland control group) (MMI only)
1976
Ireland
1960 - 1971
retrospective cohort
Database of the Metabolic Unit, Royal Belfast Hospital for Sick Children, Belfast Children born to carbimazole-treated thyrotoxic women. unexposed, disease free
Northern Ireland boys and girls obtained from medical inspections made in 1972.
throughout pregnancy 25 / 20 NA
Carbimazole was administered in every case during the first two trimesters of pregnancy then reduced in the last trimester.
Mitsuda
1992
Japan
The last 14 years
retrospective cohort
The records of the hospital, Osaka University Medical School, Osaka, Japan. Graves disease women treated with antithyroid drugs during pregnancy. unexposed, sick
Graves disease women not treated with any drug during pregnancy (excepted thyroxine).
during pregnancy (anytime or not specified) 111 / 119 Sixty women received methimazole alone, 31 were treated with both methimazole and propylthiouracil, and 20 received propylthiouracil alone. NA
Review of records of patients treated in the hospital where antithyroid drugs were given during pregnancy to maintain the serum thyroid hormone level at the upper limit of normal.
Momotani
1997
Japan
Not specified
prospective cohort
Ito Hospital, Tokyo, Japan 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.
throughout pregnancy 77 / 32 34 were treated with PTU (group P), and 43 were treated with MMI (group M) NA
Administration of MMI or PTU by investigators.
Momotani
1977
Japan
Not specified
retrospective cohort
Records of the Itoh Hospital, Tokyo, Japan Patients who became pregnant during antithyroid drug therapy. unexposed, sick
Patients who became pregnant after completing antithyroid drug therapy.
1st trimester, during pregnancy (anytime or not specified) 170 / 125 NA
Retrospective study of hospital records.
Momotani (MMI only)
1984
Japan
1965 - 1980
retrospective cohort
Database of the Ito Thyroid Clinic and Hospital 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.
1st trimester 243 / 400 Treated group: addition of « Treated, hyperthyroid » and « Treated, euthyroid ». Unexposed: addition of « Untreated, hyperthyroid » and « Untreated, euthyroid ». NA
Treatment administered by physicians in the clinics.
Phoojaroenchanachai
2001
Thailand
1982 - 1996
retrospective cohort
Medical and obstetric records of 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).
1st and 2nd trimester 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. NA
Extraction and analyse of the medical and obstetric records of pregnant women with present and past history of hyperthyroidism diagnosed and managed at Siriraj Hospital.
Rosenfeld (PTU only)
2009
Israel
1994 - 2004
prospective cohort
Israeli Teratology Information Service (TIS) 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.
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). NA
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.
Schurmann
2016
Denmark
1995 - 2010
population based cohort retrospective
The Danish Medical Birth Registry and 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.
3 months or more before pregnancy or1st trimester 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. NA
The Danish National Patient Register (DNPR) contains data on all prescribed medication redeemed from Danish pharmacies.
Seo
2018
Korea
2008 - 2014
retrospective cohort (claims database)
Korean National Health Insurance database 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.
1st trimester 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. NA
National Health Insurance (NHI) database.
Stice
1984
USA
1960 - 1979
retrospective cohort
Records of the patients managed by the authors, the May Clinic and Mayo Foundation, Rochester, Minnesota 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.
during pregnancy (anytime or not specified) 5 / 10 Of the 6 medically treated, only 5 was treated with antithyroid drugs. These ones are reported here. NA
Records of patients treated by the authors.
Wing
1994
USA
1974 - 1990
retrospective 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 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.
1st trimester, during pregnancy (anytime or not specified) 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. NA
The patients were followed up prospectively during pregnancy with treatment administration.
Yoshihara
2012
Japan
1999 - 2010
retrospective cohort
Database of Ito Hospital, Tokyo, Japan 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).
1st trimester 3004 / 2065 Exposure: PTU or MMI (addition of the cases in PTU group and MMI group; analysis not performed by authors). NA
Review of the medical records.
Yoshihara
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 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).
1st trimester 564 / 475 Addition of mothers exposed to MMI alone (23) and PTU alone (541). NA
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 (PTU only)
2016
China
2009 - 2014
retrospective cohort
Database of the Sun Yat-Sen Memorial Hospital 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 NA
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 Overall 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. at least 1st trimester, during pregnancy (anytime or not specified) 71 / 116 Of 71 case mothers, four (5.6%), while of 116 control mothers, eight (6.9%) were treated with antithyroid drugs. NA
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.
Barbero (MMI only)
2008
Argentina
1976 - 2006
case control
Three hospitals in Buenos Aires city, Argentina 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 A structured questionnaire was applied to all the mothers of eligible patients containing exposure during pregnancy, notably to acute and chronic maternal diseases, and medicines (detailed on the period/dose of MMI intake was also obtained (MMI is the only antithyroid drug available in Argentina)). 1st trimester 61 / 183 Non exposed women had mainly not reported hyperthyroidism (only in 2 (2/183) controls’ mothers). NA
Cases of choanal atresia were selected among patients of 3 hospitals in Argentina.
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, de- scribed elsewhere, varied from program to program (12 surveillance programs included). 1st trimester -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. NA
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 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. NA
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.
Khoury (MMI only)
1989
USA
1981 - 1983
case control
Atlanta Birth Defects Case-Control Study (ABDCCS) including cases of the Metropolitan Atlanta Congenital Defects Programme 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. Mothers of cases and controls were interviewed using a computer-assisted telephone questionnaire, notably whether or not they took medications for their illness, the names of specific medications, duration of treatment and intake of such medications during the index pregnancy. during pregnancy (anytime or not specified) 4904 / 3027 NA
Cases came from the Metropolitan Atlanta Congenital Defects Programme (MACDP). Babies with malformations are ascertained via multiple methods by Centres for Disease Control trained staff, including review of hospital records, vital records, cytogenetic laboratories and specialised clinics.

See the method used to produce these results