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Antithyroid Drug Side Effects in the Population and in Pregnancy
Abstract
OBJECTIVE: Methimazole (MMI) and propylthiouracil (PTU) are both associated with birth defects and may also rarely be associated with agranulocytosis and liver failure. The frequency of these side effects when antithyroid drugs (ATDs) are used in the population in general or in pregnancy remains to be elucidated. DESIGN: All individuals registered as the parent of a live-born child in Denmark, 1973–2008, were identified (n = 2 299 952) and studied from 1995 through 2010 for the use of ATDs. Outcomes were agranulocytosis, liver failure, and birth defects in their offspring. To evaluate the frequency of these side effects associated with the use of ATDs in pregnancy, all live-born pregnancies (n = 830 680), 1996–2008, were identified in a subanalysis. RESULTS: In the population studied, 28 998 individuals redeemed prescriptions of ATDs (exposure in 2115 pregnancies), which was associated with 45 cases of agranulocytosis (one in pregnancy) and 10 cases of liver failure (one in pregnancy). This corresponded to 41 and 11 cases of agranulocytosis and liver failure per 5 million inhabitants during a 10-year period (agranulocytosis: 0.16% of ATDs exposed [MMI: 0.11% vs PTU: 0.27%, P = .02]; liver failure: 0.03% of ATDs exposed [MMI: 0.03% vs PTU: 0.05%, P = .4]). The majority (83%) developed the side effect within 3 months of ATD treatment and 25% during hyperthyroidism relapse. The use of ATDs in pregnancy was associated with birth defects in 3.4% of exposed children (44 cases per 5 million inhabitants per 10 y), and the frequency of birth defects after ATD exposure was 75 times higher than both maternal agranulocytosis and liver failure in pregnancy. CONCLUSIONS: In the Danish population in general, ATDs associated birth defects and agranulocytosis had similar frequencies and were more common than liver failure, whereas for the use of ATDs in pregnancy, birth defects were dominant. The burden of side effects to the use of ATDs can be reduced by restricting the use of ATDs in early pregnancy.
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“In the third study from Denmark, the frequency of agranulocytosis was 0.27% with PTU and 0.11% with MMI (129).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [129]
In the citing paper
“Two studies were from Japan and one was from Denmark.In both countries the majority of patients are treated with MMI, so data are more limited for PTU-associated agranulocytosis.”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [129]
In the citing paper
“Three recent reports of large numbers of ATD-treated patients who developed hematologic complications provide information on risk factors, treatment, and outcomes (127-129).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [129]
In the citing paper
“In the study from Denmark (129), hepatotoxic reactions were not classified as cholestatic or hepatocellular, but the frequency of ''liver failure'' was similar for MMI (0.03%) and PTU (0.03%).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [129]
In the citing paper
“As in prior studies, the median duration of therapy prior to the development of agranulocytosis was 36 and 38 days for MMI and PTU, respectively.”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [129]
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Self-citation
Metadata
- Authors
- Andersen, S. L., Olsen, J., & Laurberg, P.
- Affiliations
- Aalborg University Hospital (DK)
- Corresponding author
- Andersen, Stine Linding
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2016-04
- Volume
- 101
- Issue
- 4
- Pages
- 1606-1614
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2268312181
- Cited by
- 107
- References
- 44
- Citations by year
- 2026: 4 · 2025: 6 · 2023: 10 · 2022: 15 · 2021: 13 · 2020: 14 · 2019: 7 · 2018: 13 · 2017: 14 · 2016: 11
- FWCI
- 15.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion)
- Funders
- Aalborg Universitet
- Aalborg Universitetshospital
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy and Medication Impact
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Keywords
- antithyroid drugs, methimazole, propylthiouracil, pregnancy, congenital malformations, agranulocytosis, liver failure, adverse drug reactions, hyperthyroidism, drug safety, prenatal drug exposure, hyperthyroidism relapse, pregnancy registry
- MeSH terms
- Abnormalities, Drug-Induced, Adult, Agranulocytosis, Female, Humans, Hyperthyroidism, Middle Aged, Pregnancy, Pregnancy Complications, Prenatal Exposure Delayed Effects, Antithyroid Agents, Liver Failure, Young Adult
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