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DRUGS IN PREGNANCY| Volume 34, ISSUE 11, P1077-1086, November 2012

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Motherisk Rounds

The Safety of Methimazole and Propylthiouracil in Pregnancy: A Systematic Review
  • Rinat Hackmon
    Affiliations
    Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto ON

    Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto ON
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  • Monica Blichowski
    Affiliations
    Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto ON

    Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto ON
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  • Gideon Koren
    Affiliations
    Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto ON

    Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto ON
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DOI:https://doi.org/10.1016/S1701-2163(16)35438-X
Motherisk Rounds
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      Abstract

      Background

      Hyperthyroidism is one of the most common endocrine disorders in pregnant women, and it can severely complicate the course and outcome of pregnancy. Methimazole (MMI) and propylthiouracil (PTU) are the standard anti-thyroid drugs used in the treatment of hyperthyroidism in pregnancy. Traditionally, MMI has been considered to have clearer evidence of teratogenicity than PTU. Recent studies suggest that PTU can be hepatotoxic, leading to a United States Food and Drug Administration “black box alert.” We wished to systematically review the effects of PTU and MMI during pregnancy, and to compare maternal and fetal safety.

      Methods

      We conducted a systematic search of PubMed, EMBASE,TOXNET, TOXLINK, DART, Medscape, EBSCO, and Google.Both English and non-English publications were included. Weexcluded studies using anti-thyroid therapies other than PTU andMMI, studies not allowing interpretation of results, and abstracts ofmeetings.

      Results

      Overall, insufficient statistical power precluded determination of accurate rates of either MMI teratogenicity or PTU hepatotoxicity in cohort studies. However, a case–control study helped identify the relative risk of MMI-induced choanal atresia. A second case–control study failed to show that aplasia cutis congenita is associated with MMI. PTU has been associated with a rare but serious form of hepatic failure.

      Conclusion

      MMI causes a specific pattern of rare teratogenic effects after first trimester exposure, while PTU therapy may be followed by rare but severe hepatotoxic sequelae. It is therefore appropriate to use PTU to treat maternal hyperthyroidism during the first trimester of pregnancy, and to switch to MMI for the remainder of the pregnancy.

      Résumé

      Contexte

      L’hyperthyroïdie est l’un des troubles endocriniens les plus courants chez les femmes enceintes et peut gravement compliquer l’évolution et l’issue de la grossesse. Le méthimazole (MMI) et le propylthiouracile (PTU) sont les antithyroïdiens standard qui sont utilisés dans la prise en charge de l’hyperthyroïdie pendant la grossesse. Traditionnellement, le MMI a été considéré comme présentant des signes de tératogénicité plus manifestes que le PTU. Des études récentes laissent entendre que le PTU peut être hépatotoxique, ce qui a mené à la publication d’un encadré (« black box alert ») à ce sujet par la Food and Drug Administration américaine. Nous souhaitions procéder à l’analyse systématique des effets du PTU et du MMI pendant la grossesse, ainsi qu’à la comparaison de leur innocuité chez la mère et le foetus.

      Méthodes

      Nous avons mené des recherches systématiques dans PubMed, EMBASE, TOXNET, TOXLINK, DART, Medscape, EBSCO et Google. Les documents publiés tant en anglais que dans d’autres langues ont été inclus. Nous avons exclu les études faisant appel à d’autres antithyroïdiens que le PTU et le MMI, les études ne permettant pas l’interprétation des résultats et les résumés de réunions.

      Résultats

      De façon globale, l’insuffisance de la puissance statistique a empêché la détermination de taux précis pour ce qui est de la tératogénicité du MMI ou de l’hépatotoxicité du PTU dans les études de cohorte. Toutefois, une étude cas-témoins a contribué à identifier le risque relatif d’atrésie choanale attribuable au MMI. Une deuxième étude cas-témoins n’est pas parvenue à démontrer que l’aplasie ectodermique congénitale était associée au MMI. Le PTU a été associé à une forme rare mais grave d’insuffisance hépatique.

      Conclusions

      Le MMI cause un ensemble particulier d’effets tératogènes rares à la suite d’une exposition au cours du premier trimestre, tandis que le traitement au PTU peut donner lieu à des séquelles hépatotoxiques rares mais graves. Il s’avère donc approprié d’utiliser le PTU pour la prise en charge de l’hyperthyroïdie maternelle au cours du premier trimestre de la grossesse, pour ensuite passer au MMI pour le reste de la grossesse.

      Key Words

      REFERENCES

        • Earl R.
        • Crowther C.A.
        • Middleton P.
        Interventions for preventing and treating hyperthyroidism in pregnancy.
        Cochrane Database Syst Rev. 2010; 9 (CD008633)
        • Rivkees S.A.
        63 years and 715 days to the “boxed warning”: unmasking of the propylthiouracil problem.
        Int J Pediatr Endocrinol 2010. 2010; (pii: 658267. Epub 2010 Jul 12)
        • Rashid M.
        • Rashid M.H.
        Obstetric management of thyroid disease.
        Obstet Gynecol Surv. 2007; : 680-688
        • Mestman J.H.
        • Goodwin T.M.
        • Montoro M.M.
        Thyroid disorders of pregnancy.
        Endocrinol Metab Clin North Am. 1995; 24: 41-71
        • Rosenfeld H.
        • Ornoy A.
        • Shechtman S.
        • Diav-Citrin O.
        Pregnancy outcome, thyroid dysfunction and fetal goiter after in utero exposure to propylthiouracil: a controlled cohort study.
        Br J Clin Pharmacol. 2009; 68: 609-617
        • Barbero P.
        • Ricagni C.
        • Mercado G.
        • Bronberg R.
        • Torrado M.
        Choanal atresia associated with prenatal methimazole exposure: three new patients.
        Am J Med Genet A. 2004; 129: 83-86
        • Barbero P.
        • Valdez R.
        • Rodriguez H.
        • Tiscornia C.
        • Mansilla E.
        • Allons A.
        • et al.
        Choanal atresia associated with maternal hyperthyroidism treated with methimazole: a case-controlled study.
        Am J Med Genet. 2008; 146: 2390-2395
        • Valdez R.M.
        • Barbero P.M.
        • Liascovich R.C.
        • De Rosa L.F.
        • Aguirre M.A.
        • Alba L.G.
        Methimazole embryopathy: a contribution to defining the phenotype.
        Reprod Toxicol. 2007; 23: 253-255
        • Okosieme O.E.
        • Marx H.
        • Lazarus JH.
        Medical management of thyroid dysfunction in pregnancy and the postpartum.
        Expert Opin Pharmacother. 2008; 13: 2281-2293
        • Chattaway J.M.
        • Klesper T.B.
        Propylthiouracil versus methimazole in treatment of Graves’ disease during pregnancy.
        Ann Pharmacother. 2007; 41: 1018-1022
        • Lazarus J.
        Thyroid function in pregnancy.
        Br Med Bull. 2011; 97: 137-148
      12. American College of Obstetricians and Gynecologists. Clinical management guidelines for obstetrician-gynecologists. ACOG practice bulletin. Clinical management guidelines for obstetrician-gynecologists.Number 37, August 2002. (Replaces practice bulletin no. 32, November2001).
        Thyroid disease in pregnancy. Obstet Gynecol. 2002; 100: 387-396
        • Mortimer R.H.
        • Cannell G.R.
        • Addison R.S.
        • Johnson L.P.
        • Roberts M.S.
        • Bernus I.
        Methimazole and propylthioracil equally cross the perfused human term placental lobule.
        J Clin Endocrinol Metab. 1997; 82: 3099-3102
        • Mandel S.J.
        • Cooper D.S.
        The use of antithyroid drugs m pregnancy and lactation.
        J Clin Endocrinol Metab. 2001; 86: 2354-2359
        • Rivkees S.
        Pediatric Graves’ disease: controversies in management.
        Horm Res Paediatr. 2010; 74: 305-311
        • Harris J.
        • Robert E.
        • Kallen B.
        Epidemiology of choanal atresia with special reference to the CHARGE association.
        Pediatrics. 1997; 99: 363-367
        • Clementi M.
        • Di Gianantonio E.
        • Pelo E.
        • Mammi I.
        • Basile R.T.
        • Tenconi R.
        Methimazole embryopathy: delineation of the phenotype.
        Am J Med Genet. 1999; 83: 43-46
        • Chan G.W.
        • Mandel SJ.
        Therapy insight: management of Graves’ disease during pregnancy.
        Nat Clin Pract Endocrinol Metab. 2007; 3: 470-477
        • Momotani N.
        • Ito K.
        • Hamada N.
        • Ban Y.
        • Nishikawa Y.
        • Mimura T.
        Maternal hyperthyroidism and congenital malformation in the offspring.
        Clin Endocrinol(Oxf). 1984; : 695-700
        • Wing D.A.
        • Millar L.K.
        • Koonings P.P.
        • Montoro M.N.
        • Mestman J.H.
        A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy.
        Am J Obstet Gynecol. 1993; 170: 90-95
        • Kim H.J.
        • Kim B.H.
        • Han Y.S.
        • Yang I.
        • Kim K.J.
        • Dong S.H.
        • et al.
        The incidence and clinical characteristics of symptomatic propylthiouracil- induced hepatic injury in patients with hyperthyroidism: a single-center retrospective study.
        Am J Gastroenterol. 2001; 96: 165-169
        • Gianantonio E.
        • Schaefer C.
        • Di Mastroiacovo P.P.
        • Cournot M.P.
        • Benedicenti F.
        • Reuvers M.
        • et al.
        Adverse effects of prenatal methimazole exposure.
        Teratology. 2001; 64: 262-266
        • Mujtaba Q.
        • Burrow G.N.
        Treatment of hyperthyroidism in pregnancy with propylthiouracil and methimazole.
        Obstet Gynecol. 1975; 46: 282-286
        • Eisenstein Z.
        • Weiss M.
        • Katz Y.
        • Bank H.
        Intellectual capacity of subjects exposed to methimazole or propylthiouracil in utero.
        Eur J Pediatr. 1992; 151: 558-559
        • Van Dijke C.P.
        • Heydendael R.J.
        • De Kleine M.J.
        Methimazole, carbimazole and congenital skin defects.
        Ann Intern Med. 1987; 106: 60-61
        • Ferraris S.
        • Valenzise M.
        • Lerone M.
        • Divizia M.T.
        • Rosaia L.
        • Blaid D.
        • et al.
        Malformations following methimazole exposure in utero: an open issue.
        Birth Defects Res A Clin Mol Teratol. 2003; 67: 989-992
        • Johnsson E.
        • Larsson G.
        • Ljunggren M.
        Severe malformations in infant born to hyperthyroid woman on Methimazole.
        Lancet. 1997; 350: 1520
        • Gripp K.W.
        • Kuryan R.
        • Schnur R.E.
        • Kothawala M.
        • Davey L.R.
        • Antunes M.J.
        • et al.
        Grade 1 microtia, wide anterior fontanel and novel type tracheo¬esophageal fistula in methimazole embryopathy.
        Am J Med Genet A. 2011; 155: 526-533
        • Greenberg F.
        Coanal atresia and athelia: methimazole teratogenicity or a new syndrome.
        Am J Med Genet. 1987; 28: 931-934
        • del Cacho M.J.
        • Frias M.L.
        Choanal atresia following methimazole exposure postconceptional.
        J Perinat Med. 2001; 29 (Suppl): 323
        • Milham S.
        • Ellege W.
        Maternal methimazole and congenital defects in children.
        Teratology. 1995; 5: 125
        • Iwayama H.
        • Hosono H.
        • Yamamoto H.
        • Oshiro M.
        • Ueda N.
        Aplasia cutis congenita with skull defect in a monozygotic twin after exposure to methimazole in utero.
        Birth Defects Res A Clin Mol Teratol. 2007; 79: 680-684
        • Osorio M.
        • Wohllk N.
        • Pineda G.
        Treatment of hyperthyroidism during pregnancy: experience with 19 cases [article in Spanish].
        Rev Med Chil. 1993; 21: 660-665
        • Morris C.V.
        • Goldstein R.M.
        • Cofer J.B.
        • Solomon H.
        • Klintmalm GB.
        An unusual presentation of fulminant hepatic failure secondary to propylthiouracil therapy.
        Clin Transpl. 1989; : 311
        • Bahn R.S.
        • Burch H.S.
        • Cooper D.S.
        • Garber J.R.
        • Greenlee C.M.
        • Klein I.L.
        • et al.
        The role of propylthiouracil in the management of Graves’ disease in adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration.
        Thyroid. 2009; 19: 673-674
        • Morris C.V.
        • Goldstein R.M.
        • Cofer J.B.
        • Solomon H.
        • Klintmalm G.B.
        An unusual presentation of fulminant hepatic failure secondary to propylthiouracil therapy.
        Clin Transpl. 1989; : 311
        • Parker W.
        Propylthiouracil-induced hepatotoxicity.
        Clin Pharm. 1982; 1: 474-478
        • Hayashida C.Y.
        • Duatre A.J.
        • Sato A.E.
        • Yamashiro-Kanashiro E.H.
        Neonatal hepatitis and lymphocyte sensitization by placental transfer of propylthiouracil.
        J Endocrinol Invest. 1990; 13: 937-941
        • Hare J.W.
        • Kitzmiller J.L.
        Diabetes and Graves disease complicating pregnancy.
        Obstet Gynecol. 1978; 51: 655-658
        • Devi L.
        • Tandon R.
        • Kumari I.
        • Huria A.
        • Goel P.
        Thyrotoxicosis in pregnancy complicated by propylthiouracil-induced hepatitis.
        Thyroid Science. 2010; 5: 1-3
        • Diav-Citrin O.
        • Omoy A.
        Teratogen update: antithyroid drugs— methimazole, carbimazole and propylthiouracil.
        Teratology. 2002; 65: 38-44
        • M. Rosove
        Agranulocytosis and antithyroid drugs.
        West J Med. 1977; 126: 339-343
        • Tajiri J.
        • Noguchi S.
        Antithyroid drug-induced agranulocytosis: how has granulocyte colony-stimulating factor changed therapy?.
        Thyroid. 2005; 15: 292-297
        • Azizi F.
        • Amouzegar A.
        Management of hyperthyroidism during pregnancy and lactation.
        Eur J Endocrinol. 2011; 164: 871-876
        • Momotani N.
        • Noh J.Y.
        • Ishikawa N.
        • Ito K.
        Effects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves’ hyperthyroidism.
        J Clin Endocrinol Metab. 1997; 82: 3633-3636
        • Karg E.
        • Bereg E.
        • Gaspar L.
        • Katona M.
        • Turi S.
        Aplasia cutis congenita after methimazole exposure in utero.
        Pediatr Dermatol. 2004; 21: 491-494
        • Nakamura S.
        • Nishikawa T.
        • Isaji M.
        • Ishimori M.
        • Shimizu N.
        • Iwamura M.
        • et al.
        Aplasia cutis congenita and skull defects after exposure to methimazole in utero.
        Intern Med. 2005; 44: 1202-1203
        • Valdez R.M.
        • Barbero P.M.
        • Liascovich R.C.
        • De Rosa L.F.
        • Aguirre M.A.
        • Alba LG.
        Methimazole embryopathy: a contribution to defining the phenotype.
        Reprod Toxicol. 2007; 23: 253-255
        • Ozgen H.M.
        • Reuvers-Lodewijks W.E.
        • Hennekam RC.
        Possible teratogenic effects of thiamazole [article in Dutch].
        Ned Tijdschr Geneeskd. 2006; 150: 101-104
        • B. Hall
        Methimazole as a teratogenic etiology of choanal atresia/multiple congenital anomaly syndrome.
        Am J Hum Genet. 1997; 61: 100
        • Vogt T.
        • Stolz W.
        • Landthaler M.
        Aplasia cutis congenita after exposure to methimazole: a causal relationship?.
        Br J Dermatol. 1995; 133: 994-996
        • Farine D.
        • Maidman J.
        • Rubin S.
        • Chao S.
        Elevated alpha-fetoprotein in pregnancy complicated by aplasia cutis after exposure to methimazole.
        Obstet Gynecol. 1988; : 996-997
        • Ono K.
        • Kikuchi A.
        • Takikawa K.M.
        • Hiroma T.
        • Yoshizawa K.
        • Sunagawa S.
        • et al.
        Hernia of the umbilical cord and associated ileal prolapse through a patent omphalomesenteric duct: prenatal ultrasound and MRI findings.
        Fetal Diagn Ther. 2009; 25: 72-75
        • Lollgen R.M.
        • Calza A.M.
        • Schwitzgebel V.M.
        • Pfister RE.
        Aplasia cutis congenita in surviving co-twin after propylthiouracil exposure in utero.
        J Pediatr Endocrinol Metab. 2011; 24: 215-218

      Article info

      Footnotes

      Competing Interests: None declared.

      Identification

      DOI: https://doi.org/10.1016/S1701-2163(16)35438-X

      Copyright

      © 2012 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.

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