Abstract
Introduction
Hyperthyroidism is characterised by high levels of serum thyroxine and triiodothyronine, and low levels of thyroid-stimulating hormone. The main causes of hyperthyroidism in pregnancy are Graves' disease and chorionic gonadotrophin (hCG)-mediated hyperthyroidism.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of antithyroid drug treatments for hyperthyroidism in pregnancy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found no studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antithyroid drugs (carbimazole/thiamazole and propylthiouracil).
Key Points
Hyperthyroidism is characterised by high levels of serum thyroxine and triiodothyronine, and low levels of thyroid-stimulating hormone (TSH).
Thyrotoxicosis is the clinical effect of high levels of thyroid hormones, whether or not the thyroid gland is the primary source.
The main causes of hyperthyroidism in pregnancy are Graves' disease and chorionic gonadotrophin (hCG)-mediated hyperthyroidism.
Untreated severe hyperthyroidism in pregnancy is associated with obstetric and maternal complications.
We found no RCTs on the effects of antithyroid drugs (carbimazole/thiamazole and propylthiouracil) in hyperthyroidism in pregnancy. However, there is consensus that they are effective.
Observational studies have shown an increase risk of congenital malformation in children born to mothers taking antithyroid drugs.
There have been alerts on the risk of hepatotoxicity with propylthiouracil.
Clinical context
About this condition
Definition
Hyperthyroidism is characterised by high levels of serum thyroxine (T4), high levels of serum triiodothyronine (T3), or both, and low levels of thyroid-stimulating hormone (TSH, also known as thyrotrophin <0.05 mU/L). Subclinical hyperthyroidism is characterised by decreased levels of TSH (<0.1 mU/L) but with levels of T4 and T3 within the normal range. Healthy pregnancy can be characterised by a low or suppressed TSH (even <0.1 mU/l) in the first trimester. The terms hyperthyroidism and thyrotoxicosis are often used synonymously; however, they refer to slightly different conditions. Hyperthyroidism refers to overactivity of the thyroid gland leading to excessive production of thyroid hormones. Thyrotoxicosis refers to the clinical effects of unbound thyroid hormones, whether or not the thyroid gland is the primary source.Hyperthyroidism in pregnancy is most commonly caused by Graves' disease (diffusely enlarged thyroid gland on palpation, ophthalmopathy, and dermopathy), toxic multinodular goitre (thyrotoxicosis and increased radioiodine uptake with multinodular goitre on palpation), but can also be due to toxic adenoma (benign hyperfunctioning thyroid neoplasm presenting as a solitary thyroid nodule), or chorionic gonadotrophin (hCG)-mediated hyperthyroidism. Diagnosis Most pregnant women with hyperthyroidism are diagnosed prior to conception. The diagnosis of hyperthyroidism is established by a raised serum total or free T4 or T3 hormone levels, reduced TSH level, and high radioiodine uptake in the thyroid gland along with features of thyrotoxicosis. During pregnancy, radioactive iodine testing is contraindicated. Diagnosis is, therefore, usually by other laboratory tests (elevated T4 and the presence of thyrotrophin receptor stimulating antibodies). The usual symptoms are irritability, heat intolerance and excessive sweating, palpitations, weight loss with increased appetite, increased bowel frequency, and oligomenorrhoea. As many of these may be part of normal pregnancy, diagnosing new Graves' disease in pregnancy may be difficult.
Incidence/ Prevalence
In pregnancy, the most common causes of hyperthyroidism are Graves' disease and human chorionic gonadotrophin (hCG)-mediated hyperthyroidism. Graves' disease is seen in 0.1% to 1.0% (0.4% clinical and 0.6% subclinical) of pregnant women. HCG-mediated hyperthyroidism is transient and mild and usually does not require treatment; it is seen in 1% to 3% of pregnant women.
Aetiology/ Risk factors
Smoking is a risk factor, with an increased risk of both Graves' disease (OR 2.5, 95% CI 1.8 to 3.5) and toxic nodular goitre (OR 1.7, 95% CI 1.1 to 2.5). In areas with high iodine intake, Graves' disease is the major cause; whereas in areas of low iodine intake, the major cause is nodular goitre. A correlation between diabetes mellitus and thyroid dysfunction has been described. In a Scottish population with diabetes, the overall prevalence of thyroid disease was found to be 13%, highest in women with type 1 diabetes (31%). As a result of screening, new thyroid disease was diagnosed in 7% of people with diabetes (hyperthyroidism in 1%). Around 50% of women who experience hyperemesis gravidarum have elevated T4 levels.
Prognosis
Obstetric and medical complications are directly related to control of hyperthyroidism in pregnancy. Poor control is associated with miscarriages, prematurity, low birth weight, intrauterine growth restriction, stillbirth, thyroid storm, and maternal congestive heart failure. Pregnant women with Graves' disease usually show remission in the third trimester, allowing them to stop taking antithyroid drugs. In cases where remission does not occur, there is an increased risk of neonatal thyrotoxicosis.
Aims of intervention
To eliminate the symptoms of hyperthyroidism and hyperthyroidism-related complications in pregnancy, with minimum adverse effects of treatment.
Outcomes
Thyroid function (levels of T4, T3, TSH, change of state from hyperthyroid to euthyroid/hypothyroid); congenital abnormalities; and hepatotoxicity. Adverse effects.
Methods
Clinical Evidence search and appraisal June 2014. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2014, Embase 1980 to June 2014, and The Cochrane Database of Systematic Reviews 2014, issue 6 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in the English language, at least single-blinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs).
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
References
- 1.Earl R, Crowther CA, Middleton P. Interventions for hyperthyroidism pre-pregnancy and during pregnancy. In: The Cochrane Library, Issue 6, 2014. Chichester, UK: John Wiley & Sons, Ltd. Search date 2013. [DOI] [PubMed] [Google Scholar]
- 2.Patil-Sisioda K, Mestman JH. Graves hyperthyroidism and pregnancy: a clinical update. Endocr Pract 2010;16:118–129. [DOI] [PubMed] [Google Scholar]
- 3.Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev 2010;31:702–755. [DOI] [PubMed] [Google Scholar]
- 4.Goodwin TM, Montoro M, Mestman JH. Transient hyperthyroidism and hyperemesis gravidarum: clinical aspects. Am J Obstet Gynecol 1992;167:648–652. [DOI] [PubMed] [Google Scholar]
- 5.Tan JY, Loh KC, Yeo GS, et al. Transient hyperthyroidism of hyperemesis gravidarum. BJOG 2002;109:683–688. [DOI] [PubMed] [Google Scholar]
- 6.Vestergaard P, Rejnmark L, Weeke J, et al. Smoking as a risk factor for Graves' disease, toxic nodular goiter, and autoimmune hypothyroidism. Thyroid 2002;12:69–75. [DOI] [PubMed] [Google Scholar]
- 7.Laurberg P, Bulow Pedersen I, Pedersen KM, et al. Low incidence rate of overt hypothyroidism compared with hyperthyroidism in an area with moderately low iodine intake. Thyroid 1999;9:33–38. [DOI] [PubMed] [Google Scholar]
- 8.Perros P, McCrimmon RJ, Shaw G, et al. Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabet Med 1995;12:622–627. [DOI] [PubMed] [Google Scholar]
- 9.Stagnaro-Green A, Abalovich M, Alexander E, et al; American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081–1125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Andersen SL, Olsen J, Wu CS, et al. Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab 2013;98:4373–4381. [DOI] [PubMed] [Google Scholar]
- 11.Andersen SL, Laurberg P. Antithyroid drugs and congenital heart defects: ventricular septal defect is part of the methimazole/carbimazole embryopathy. Eur J Endocrinol 2014;171:C1–C3 . [DOI] [PubMed] [Google Scholar]
- 12.Yoshihara A, Noh J, Yamaguchi T, et al. Treatment of Graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation. J Clin Endocrinol Metab 2012;97:2396–2403. [DOI] [PubMed] [Google Scholar]
- 13.Andersen SL, Olsen J, Wu CS, et al. Severity of birth defects after propylthiouracil exposure in early pregnancy. Thyroid 2014;24:1533–1540. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Rivkees SA, Mattison DR. Propylthiouracil (PTU) hepatoxicity in children and recommendations for discontinuation of use. Int J Pediatr Endocrinol 2009;2009:132041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Russo MW, Galanko JA, Shrestha R, et al. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl 2004;10:1018–1023. [DOI] [PubMed] [Google Scholar]
- 16.US Food and Drug Administration. FDA Drug Safety Communication: new boxed warning on severe liver injury with propylthiouracil. 21 April 2010. Available at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm209023.htm (last accessed 15 December 2014). [Google Scholar]