Interventions for hyperthyroidism pre-pregnancy and during pregnancy

  • Review
  • Intervention

Authors

  • Rachel Earl,

    Corresponding author
    1. The University of Adelaide, Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, Adelaide, Australia
    • Rachel Earl, Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, The University of Adelaide, Medical School North Building, Frome Road, Adelaide, 5005, Australia. rachel.earl@adelaide.edu.au.

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  • Caroline A Crowther,

    1. The University of Auckland, Liggins Institute, Auckland, New Zealand
    2. The University of Adelaide, ARCH: Australian Research Centre for Health of Women and Babies, The Robinson Institute, Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia
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  • Philippa Middleton

    1. The University of Adelaide, ARCH: Australian Research Centre for Health of Women and Babies, The Robinson Institute, Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia
    Search for more papers by this author

Abstract

Background

Women with hyperthyroidism in pregnancy have increased risks of miscarriage, stillbirth, preterm birth, and intrauterine growth restriction; and they can develop severe pre-eclampsia or placental abruption.

Objectives

To identify interventions used in the management of hyperthyroidism pre-pregnancy or during pregnancy and to ascertain the impact of these interventions on important maternal, fetal, neonatal and childhood outcomes.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 September 2013).

Selection criteria

We planned to include randomised controlled trials, quasi-randomised controlled trials, and cluster-randomised trials comparing antithyroid interventions for hyperthyroidism pre-pregnancy or during pregnancy with another intervention or no intervention (placebo or no treatment).

Data collection and analysis

Two review authors assessed trial eligibility and planned to assess trial quality and extract the data independently.

Main results

No trials were included in the review.

Authors' conclusions

As we did not identify any eligible trials, we are unable to comment on implications for practice, although early identification of hyperthyroidism before pregnancy may allow a woman to choose radioactive iodine therapy or surgery before planning to have a child. Designing and conducting a trial of antithyroid interventions for pregnant women with hyperthyroidism presents formidable challenges. Not only is hyperthyroidism a relatively rare condition, both of the two main drugs used have potential for harm, one for the mother and the other for the child. More observational research is required about the potential harms of methimazole in early pregnancy and about the potential liver damage from propylthiouracil.

Résumé scientifique

Interventions pour traiter l'hyperthyroïdie avant et pendant la grossesse

Contexte

Les femmes atteintes d'hyperthyroïdie pendant la grossesse ont un risque accru de fausse couche, de mortinatalité, d'accouchement prématuré et de retard de croissance intra-utérine, elles peuvent également développer une pré-éclampsie grave ou un décollement placentaire.

Objectifs

Identifier les interventions utilisées pour traiter l'hyperthyroïdie avant et pendant la grossesse et déterminer l'impact de ces interventions sur les critères de jugement maternels, fœtale, néonatale et de la petite enfance.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre d'essais cliniques du groupe Cochrane sur la grossesse et la naissance (30 septembre 2013).

Critères de sélection

Nous avions prévu d'inclure des essais contrôlés randomisés, des essais contrôlés quasi-randomisés et des essais randomisés en cluster comparant des interventions antithyroïdien pour traiter l'hyperthyroïdie avant ou pendant la grossesse à une autre intervention ou à l'absence d'intervention (placebo ou à l'absence de traitement).

Recueil et analyse des données

Deux auteurs de la revue ont évalué l'éligibilité des essais et prévoyaient d'évaluer la qualité des essais et d’extraire les données de manière indépendante.

Résultats principaux

Aucun essai n'a été inclus dans la revue.

Conclusions des auteurs

Comme nous n'avons identifié aucun essai éligible, nous ne sommes pas en mesure de commenter les répercussions sur la pratique, bien qu'une détection précoce de l'hyperthyroïdie avant la grossesse puisse permettre à une femme de choisir le traitement à l'iode radioactif ou une intervention chirurgicale avant d'envisager de concevoir. L’élaboration et la réalisation d'un essai portant sur le traitement antithyroïdien chez les femmes enceintes atteintes d'hyperthyroïdie représente de nombreux problèmes. Non seulement l'hyperthyroïdie est une maladie relativement rare, mais les deux principaux médicaments utilisés sont potentiellement néfastes, l’un pour la mère et l'autre pour l'enfant. Des recherches observationnelles supplémentaires sont nécessaires pour déterminer les potentiels préjudices du méthimazole en début de grossesse et les potentielles lésions hépatiques du propylthiouracile.

Plain language summary

No evidence found from randomised trials for drugs to treat pregnant women with hyperthyroidism

Hyperthyroidism in pregnancy is a rare, serious condition which can increase the risks of miscarriage, stillbirth, preterm birth, and intrauterine growth restriction. Pregnant women who are hyperthyroid may also develop severe pre-eclampsia or placental abruption. Most of these women have Graves' disease, an autoimmune disease most common in women aged 20 to 40 years. Most pregnant women with hyperthyroidism are diagnosed with thyroid disease prior to conception and will have previously received treatment for the condition. Generally only drug therapy is considered for treating pregnant women with hyperthyroidism. Radioiodine treatment is not used in pregnancy because it destroys the fetal thyroid gland, resulting in permanent hypothyroidism in the newborn.

The main antithyroid drugs used are the thionamides, propylthiouracil (PTU), methimazole and carbimazole. PTU is currently the favoured drug for use in pregnancy, as it is associated with fewer teratogenic effects (scalp lesions) than methimazole. However, since there have been reports of liver damage in people taking PTU, it may be reasonable for pregnant hyperthyroid women to be treated with PTU in the first trimester (to reduce any teratogenic effects of methimazole) and then to change to methimazole.

We did not identify any randomised trials to help inform women and their doctors about which antithyroid drugs are most effective, with the lowest potential for harm.

Résumé simplifié

Aucune preuve issue d'essais randomisés n'a été trouvée sur les médicaments traitant les femmes enceintes atteintes d'hyperthyroïdie

L'hyperthyroïdie durant la grossesse est une affection grave et rare qui peut augmenter les risques de fausse couche, de mortinatalité, d'accouchement prématuré et une restriction de croissance fœtale intra-utérine. Les femmes enceintes souffrant d’hyperthyroïdie peuvent également développer une pré-éclampsie grave ou le décollement placentaire. La plupart de ces femmes souffrent de la maladie de Basedow, une maladie auto-immune plus fréquente chez les femmes de 20 à 40 ans. La plupart des femmes enceintes atteintes d'hyperthyroïdie ont été diagnostiquées avec des troubles thyroïdiens avant la conception et ont déjà reçu un traitement contre la maladie. Seul le traitement médicamenteux est généralement pris en compte pour traiter les femmes enceintes atteintes d'hyperthyroïdie. Le traitement par l’iode radioactif n'est pas utilisé pendant la grossesse, car il détruit la glande thyroïde du fœtus, entrainant une hypothyroïdie permanente chez le nouveau-né.

Les principaux antithyroïdiens utilisés sont les thionamide, propylthiouracile (PROP), méthimazole et carbimazole. PROP est actuellement le médicament privilégié pour être utilisé pendant la grossesse, car il est associé à moins d'effets tératogènes (lésions du cuir chevelu) que le méthimazole. Cependant, étant donné que des lésions hépatiques chez les patients prenant PROP ont été rapportées, le traitement PROP peut être justifié chez les femmes enceintes atteintes d’hyperthyroïdie au cours du premier trimestre (pour réduire tout effet tératogène de méthimazole), puis remplacer par le traitement méthimazole.

Nous n'avons pas identifié d'essais randomisés pour aider à guider les femmes et leurs médecins à savoir quels sont les antithyroïdiens les plus efficaces et avec le plus faible risque de préjudice.

Notes de traduction

Traduit par: French Cochrane Centre 14th January, 2014
Traduction financée par: Minist�re Fran�ais des Affaires sociales et de la Sant�, Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Laički sažetak

Liječenje pojačanog rada štitnjače (hipertireoze) prije i za vrijeme trudnoće

Hipertireoza (pojačani rad štitnjače) u trudnoći se rijetko dogodi, ali je to onda ozbiljno stanje koje povećava rizik pobačaja, mrvorođenja, preranog poroda ili intrauterinog (unutarmaterničnog) zastoja rasta. Trudnice s hipertireozom mogu razviti pre-eklampsiju (hipertenzija uzrokovana trudnoćom s proteinima u mokraći – proteinurijom; eklampsiju karakteriziraju konvulzivni napadi) ili prerano odljuštenje posteljice. Većina tih žena ima Gravesovu bolest, a što je autoimuna bolest s pojačanim radom štitnjače, učestala u žena u dobi od 20 do 40 godina. U većine trudnica je bolest štitnjače bila dijagnosticirana prije začeća i liječenje je bilo već započeto. U trudnica s hipertireozom u pravilu dolazi u obzir samo liječenje lijekovima. Liječenje radioaktivnim jodom se ne primjenjuje u trudnica budući da bi uništilo štitnjaču ploda s posljedičnom trajnom hipertireozom u djeteta.

Glavni lijekovi koji smanjuju rad štitnjače su tionamidi, propiltiouracil (PTU), metimazol i karbimazol. PTU je lijek koji se trenutačno najviše koristi za ova stanja u trudnoći, budući da je povezan s manje teratogenih (uzrokuje malformacije ploda) učinaka (promjene mekog oglavka) nego metimazol. Međutim budući da postoje dokazi o oštećenju jetre u osoba liječenih PTU, razumno je da trudnice s hipertireozom budu liječenje s PTU u prvom trimestru trudnoće (radi smanjenja eventualnih teratogenih učinaka metiomazola), a potom nastaviti liječenje metiomazolom.

Cochrane sustavnim pregledom nije nađena niti jedna randomizirana studija koja bi pružila dokaze ženama i njihovim doktorima o najučinkovitijim lijekovima protiv pojačanog rada štitnjače, a koji ujedno ima najmanji rizik štetnosti.

Bilješke prijevoda

Hrvatski Cochrane ogranak.
Prevela: Vesna Kušec

Background

Description of the condition

Maternal hyperthyroidism

Hyperthyroidism is caused by an over-active thyroid gland, resulting in excessive release of thyroid hormones such as thyroxine (T4) or triiodothyronine (T3) (Abraham 2010; Mestman 2004; Polak 2004).

The prevalence of hyperthyroidism in pregnancy ranges from 0.1% to 0.4%, with Graves' disease accounting for 85% of these cases (Abalovich 2007; Mestman 2004). Graves' disease is an autoimmune disease defined as hyperthyroidism that is specifically caused by stimulation of the thyroid by thyrotrophin receptor stimulating antibodies (TRAb) (Marx 2008). Symptoms of Graves' disease include palpitations, heat intolerance, increased sweating, increased appetite, weight loss, insomnia, irritability, mood swings, frequent bowel movements, diarrhoea, pruritus, nervousness, hand tremor, decreased tolerance to exercise, shortness of breath and eye symptoms (frequent lacrimation, double vision, retro-orbital pain).

Graves' disease is more common in women than in men, and is most common in women aged between 20 and 40 years (Abraham 2010), which corresponds with women's peak reproductive years.

About half the women who experience hyperemesis gravidarum (severe nausea and vomiting) have elevated T4 concentrations, but there does not appear to be a direct link between hyperemesis gravidarum and thyroid function (LeBeau 2006).

Other, less common causes of hyperthyroidism in pregnancy include single toxic adenoma, toxic multinodular goitre (less than 5%) (Mestman 2004), subacute thyroiditis (thyroid inflammation), trophoblastic tumour or hydatidiform molar disease (a mass forming in the uterus) (Abalovich 2007; Palmieri 2005), iodine induced hyperthyroidism, struma ovarii (an ovarian tumour composed partly or entirely of thyroid tissue (Papanikolaou 2007), or thyrotropin receptor activation (Marx 2008).

Transient gestational thyrotoxicosis (symptomatic or asymptomatic) can occur especially in the first trimester of pregnancy (Marx 2008), but usually resolves when human chorionic gonadotropin (HCG) concentrations decline; treatment with antithyroid drugs is usually not necessary (LeBeau 2006) or effective in cases of HCG-induced hyperthyroidism (Girling 2006).

The majority of women in remission from Graves' disease who become pregnant will relapse postpartum or will develop postpartum thyroiditis (abnormal thyroid concentrations) (Cooper 2005).

Diagnosis of maternal hyperthyroidism

Most pregnant women with hyperthyroidism are diagnosed with thyroid disease prior to conception (Marx 2008; Mestman 2004) and will have previously received treatment for the condition. Women with stable Graves' disease may experience an exacerbation during early pregnancy, or women in remission may experience a relapse of Graves' disease (LeBeau 2006). New diagnoses of hyperthyroidism in pregnancy are uncommon, perhaps because untreated hyperthyroidism can be associated with infertility (Girling 2006).

Since radioactive iodine diagnostic tests are contraindicated during pregnancy (Marx 2008); other laboratory tests, coupled with careful history and physical examination, are used to diagnose hyperthyroidism (American Thyroid Association 2005). Diagnosing Graves' disease in pregnancy may be difficult as symptoms such as heat intolerance may part be of normal pregnancy. Women with Graves' disease may have a goitre (enlargement of the thyroid gland), but elevated T4 and presence of TRAb usually confirm the diagnosis (LeBeau 2006).

Women who have pre-pregnancy ablation treatment for Graves' disease may need increased doses of thyroid replacement therapy soon after conception, or women with currently normal thyroid readings may have high concentrations of thyroid stimulating immunoglobulins, putting their fetuses at risk of developing hyperthyroidism (Mestman 2004).

Adverse maternal and pregnancy outcomes

Women with hyperthyroidism in pregnancy can develop severe pre-eclampsia or placental abruption. They have increased risks of miscarriage, stillbirth, preterm birth, and intrauterine growth restriction (Abalovich 2007; Casey 2007; LeBeau 2006; Marx 2008; Mestman 2004). Women with the poorest control of their hyperthyroidism have the highest risk of complications (LeBeau 2006).

Congestive heart failure can occur in 10% of untreated women, especially when cardiac demand is increased (for example, through exercise) (Mestman 2004; Sheffield 2004). Thyroid storm (thyrotoxic crisis or accelerated hyperthyroidism) is a rare but serious complication of hyperthyroidism. In a thyroid storm, women present severe symptoms of thyrotoxicosis such as hyperpyrexia (more than 39.4 ºC), neuropsychiatric symptoms, tachycardia (pulse rate exceeding 140 beats/minute), nausea, vomiting, liver dysfunction, congestive heart failure (Mestman 2004), diarrhoea, dehydration, coma and delirium (Casey 2007). In pregnancy, thyroid storm can be precipitated by pre-eclampsia, induction of labour and placenta praevia (Mestman 2004).

In order to prevent fetal death or lifelong impairment, it is important to establish fetal thyroid status early in the pregnancy of a woman with Graves' disease (Polak 2004).

In women with Graves' disease, maternal antibodies (TRAb) can cross the placenta and stimulate the fetal thyroid (Mestman 2004), which may result in fetal tachycardia, intrauterine growth retardation, cardiac failure and fetal goitre (Marx 2008). This fetal stimulation may rarely result in neonatal hyperthyroidism, with 2% to 5% of infants born to women with Graves’ disease being affected (American Thyroid Association 2005). 

Neonatal hyperthyroidism can occur even if a women has already been treated for Graves' disease in the past and is receiving thyroxine therapy (Mestman 2004).

Description of the intervention

Interventions for hyperthyroidism

Of the three recognised treatment options for hyperthyroidism (radioiodine therapy, antithyroid drug therapy and surgery), generally only drug therapy is considered for treating pregnant women. Radioiodine treatment is contraindicated in pregnancy (Marx 2008) because it destroys the fetal thyroid gland, resulting in permanent hypothyroidism in the newborn (American Thyroid Association 2005; Casey 2007). Subtotal thyroidectomy is a treatment option in cases where serious adverse responses to antithyroid drug therapy are observed, where consistently high doses of antithyroid drugs are needed to control the hyperthyroidism or if the woman has not been able to adhere to antithyroid drug therapy (Abalovich 2007; Casey 2007).

Pregnant women with Graves' disease usually show remission in the third trimester, allowing them to stop taking antithyroid drugs, but if remission does not occur, then neonatal hyperthyroidism/thyrotoxicosis is more likely (Horsley 2007).

The main antithyroid drugs used in pregnancy are the thionamides, propylthiouracil (PTU), methimazole and carbimazole. PTU is currently the favoured drug for use in pregnancy, as it is associated with fewer teratogenic effects (see below) (Marx 2008). However, since there have been reports of liver damage in people taking PTU, it may be reasonable for pregnant hyperthyroid women to be treated with PTU pre-pregnancy and in the first trimester (to reduce any teratogenic effects of methimazole) and then to change to methimazole (Cooper 2009).

Iodide drugs have rarely been used for hyperthyroidism during pregnancy due to reports of neonatal hypothyroidism (LeBeau 2006).

The beta-blocker, propranolol, may be used to relieve a woman's hyperthyroid symptoms (Abalovich 2007; Mestman 2004).

Maternal antithyroid drug treatment and teratogenicity

Congenital anomalies such as aplasia cutis (scalp lesions) and, very rarely, choanal atresia (blocked nasal passage) or oesophageal atresia have been reported with methimazole (Abalovich 2007; Cooper 2005).

Effects of maternal antithyroid drug treatment on the fetal thyroid; on the neonate; and long-term effects

The US Food and Drug Administration has classed both PTU and methimazole as being of risk to the fetus because of the potential for fetal hypothyroidism (Cooper 2005). For this reason, doses of antithyroid drug should be kept as low as possible and, once normal thyroid function has been achieved and symptoms stabilised, doses should be tapered down (Casey 2007; Cooper 2005; Marx 2008). The risk of fetal hypothyroidism is, however, negligible if maternal thyroxine is maintained at or slightly above the upper limit of normal (Cooper 2005). Avoiding maternal over-treatment is important since fetal thyrotropin stimulation, goitre formation and possibly respiratory compromise after birth from tracheal compression may result (LeBeau 2006).

Neonatal hyperthyroidism may develop several days after birth in babies whose mothers were treated with antithyroid drugs, since the neonates no longer have the benefit of the in utero exposure to the medication (Mestman 2004).

Long-term effects of exposure to antithyroid drug in utero (especially on measures of IQ and psychomotor development) are potentially possible (LeBeau 2006) but have not been shown (Azizi 2002; Eisenstein 1992; Marx 2008).

Maternal adverse effects of antithyroid drug treatment

Up to 15% of women prescribed antithyroid drug therapy experience adverse effects such as itching, rash, hives, joint pain and swelling, fever, altered taste sensation, nausea and vomiting (Abraham 2010). Serious adverse effects such as agranulocytosis (a fall in white cell blood count), sepsis, abnormal liver function and vasculitis (inflammation of blood vessels) are rare (Abraham 2010; Casey 2007; Cooper 2005). Fever and sore throat are the most common presenting symptoms of agranulocytosis and women with these symptoms should cease their drug therapy and seek medical advice (Cooper 2005).

Maternal antithyroid drug treatment and lactation

Antithyroid drugs such as PTU and methimazole are secreted in breast milk and hence concerns have been raised about the safety of breastfeeding while undergoing antithyroid drug therapy (Marx 2008). Mestman 2004 suggests that breastfeeding by mothers with Graves’ disease should be allowed when maternal daily doses of PTU are less than 150 to 200 mg/day or 10 mg/day of methimazole. The American Academy of Pediatricians has approved both PTU and methimazole for nursing mothers (American Academy of Pediatricians 2001).

Subclinical hyperthyroidism

Treatment of maternal subclinical hyperthyroidism has not been shown to improve pregnancy outcomes and may risk unnecessary exposure of the fetus to antithyroid drugs (Abalovich 2007; Casey 2007).

How the intervention might work

Thionamide drugs work by blocking the synthesis of thyroid production in the thyroid gland and may also help to control Graves' disease by indirectly influencing the immune system (Abraham 2010).

Why it is important to do this review

Rationale for review

A systematic review of trials evaluating interventions for managing hyperthyroidism in pregnant women (and in women pre-conception) will present the current evidence for averting maternal, fetal and neonatal adverse outcomes. This will allow women to make informed choices about managing their hyperthyroid condition pre-pregnancy and during pregnancy.

Objectives

The objective of this review update is to identify interventions used in the management of women with hyperthyroidism pre-pregnancy or during pregnancy and to ascertain the impact of these interventions on important maternal, fetal, neonatal, childhood and later outcomes.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials or quasi-randomised trials. We planned to include cluster-randomised trials, and studies published as abstracts only. We planned to exclude cross-over trials.

Types of participants

Women pre-pregnancy or during pregnancy with hyperthyroidism, including:

  • women diagnosed with hyperthyroidism for the first time during pregnancy;

  • women on antithyroid therapy at the time of conception;

  • women on remission from antithyroid therapy;

  • previous history of ablation therapy for hyperthyroidism, either by surgery or by iodine 131.

Types of interventions

Any form of antithyroid therapy compared with no therapy or compared with a different form of antithyroid therapy. 

Types of outcome measures

Primary outcomes
Maternal
  1. Overall clinical improvement in symptoms of hyperthyroidism (such as anxiety, tachycardia, heat intolerance, diarrhoea, palpitations, increased sweating, increased appetite, insomnia, irritability, mood swings, frequent bowel movements, pruritus, nervousness, hand tremor, decreased tolerance to exercise, shortness of breath, cardiac dysfunction, congestive heart failure, cardiac abnormality; ophthalmopathy (e.g. double vision, retro-orbital pain)).

  2. Pre-eclampsia/pregnancy-induced hypertension.

Infant
  1. Preterm birth.

Childhood
  1. Neurodevelopmental disabilities.

Secondary outcomes
Maternal
  1. Mode of birth.

  2. Induction of labour.

  3. Adverse effects (such as agranulocytosis, drug rash, abnormal liver function, vasculitis).

  4. Weight change.

  5. Postpartum thyroid dysfunction.

  6. Thyroid antibody status (free T4 concentrations, free thyroxine index (FT4I)).

  7. Health-related quality of life.

  8. Mortality.

  9. Miscarriage.

  10. Placental abruption.

Fetal, neonatal, infant
  1. Fetal, neonatal and postneonatal mortality.

  2. Fetal thyroid function.

  3. Congenital malformations.

  4. Admission to intensive care nursery.

  5. Neonatal hyperthyroidism.

Childhood
  1. Attention deficit hyperactivity disorder.

  2. Behavioural problems.

Search methods for identification of studies

Electronic searches

We contacted the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 September 2013). 

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. weekly searches of Embase;

  4. handsearches of 30 journals and the proceedings of major conferences;

  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords.

We did not apply any language restrictions.

Data collection and analysis

 See Appendix 1 'Methods of data collection and analysis to be used in future updates of this review'.

Results

Description of studies

We have excluded one randomised trial (Negro 2010), as this trial compares universal screening with case-finding for the detection (and subsequent management) of thyroid hormonal dysfunction during pregnancy (both hypothyroidism and hyperthyroidism), which will be covered in a forthcoming Cochrane review 'Screening and subsequent management for thyroid dysfunction in pregnancy for improving maternal and infant health'. See Characteristics of excluded studies for further details.

Risk of bias in included studies

No randomised trials were found for inclusion in the review.

Effects of interventions

No randomised trials were found for inclusion in the review.

Discussion

Pregnant women with hyperthyroidism are faced with the dilemma of "choosing between a drug associated with small risk of fetal birth defects and another drug associated with a similarly small but finite risk of serious liver injury in the mother" (Cooper 2009). As there is no evidence from trials to guide a choice between propylthiouracil (PTU) and then switching to methimazole, or staying with PTU, Cooper 2009 has emphasised the need to offer hyperthyroid women radioactive iodine therapy or surgery before they plan to become pregnant.

In any woman of reproductive age with hyperthyroidism, pre-pregnancy counselling and management to control the disease may decrease the risk of perinatal complications (Mestman 2004).

Authors' conclusions

Implications for practice

As we did not identify any eligible trials, we are unable to comment on implications for practice, although early identification of hyperthyroidism before pregnancy may allow a woman to choose radioactive iodine therapy or surgery before planning to have a child.

Implications for research

Designing and conducting a trial of antithyroid drugs for pregnant women with hyperthyroidism presents formidable challenges. Not only is hyperthyroidism a relatively rare condition, both of the two main drugs used have potential for harm, one for the mother and the other for the child.

More observational research is required about the potential harms of methimazole in early pregnancy and about the potential liver damage from propylthiouracil.

Acknowledgements

Thanks to Emily Bain, ARCH: Australian Research Centre for Health of Women and Babies, The University of Adelaide, who assisted with the update of this review.

As part of the pre-publication editorial process, this review has been commented on by four peers (an editor and three referees who are external to the editorial team) and the Group's Statistical Adviser.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pregnancy and Childbirth Group. The views and opinions expressed there in are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. Methods of data collection and analysis to be used in future updates of this review

Selection of studies

Two review authors will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult the third author.

Data extraction and management

We will design a form to extract data. For eligible studies, two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult the third author. We will enter data into Review Manager software (RevMan 2012) and check the data for accuracy. When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving a third assessor.

(1) Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number); or

  • unclear risk of bias.

(2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth); or

  • unclear risk of bias.

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

  • low, high or unclear risk of bias for participants; and

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertake.

We will assess methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation); or

  • unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

  • low risk of bias (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); or

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We will describe for each included study any important concerns we have about other possible sources of bias.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis.

Measures of treatment effect

Dichotomous data

For dichotomous data, we will present results as summary risk ratios (RRs) with 95% confidence intervals (CIs).

Continuous data

For continuous data, we will use the mean difference (MD) if outcomes are measured in the same way between trials. We will use the standardised mean difference (SMD) to combine trials that measure the same outcome, but use different methods.

Unit of analysis issues

Cluster-randomised trials

We will include cluster-randomised trials in the analyses along with individually-randomised trials. We will adjust their sample sizes or standard errors using the methods described in the Cochrane Handbook using an estimate of the intracluster correlation coefficient (ICC) derived from the trial (if possible), or from another source (Higgins 2011). If ICCs from other sources are used, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely. We will also acknowledge heterogeneity in the randomisation unit and perform a separate meta-analysis.

Cross-over trials

We will exclude cross-over trials from this review.

Multi-armed trials

Where a multi-armed trial is included, we will record and include all outcome data in the review as two-arm comparisons. We will include the data for the different arms in independent two-arm comparisons in separate meta-analyses. In instances where we cannot include the data in separate comparisons, we will combine it to create a single pair-wise comparison (Higgins 2011). If the control group is shared by two or more study arms, we will divide the control group between relevant subgroup categories to avoid double-counting the participants (for dichotomous data we will divide the events and the total population, while for continuous data we will assume the same mean and standard deviation (SD) but will divide the total population). We will describe the details in the 'Characteristics of included studies' tables.

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis. We will carry out all outcomes' analyses, as far as possible, on an intention-to-treat basis i.e. we will attempt to include all participants randomised to each group in the analyses. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta-analysis using the Tau², I² and Chi² statistics. We will regard heterogeneity as substantial if the I² is greater than 50% and either Tau² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity. If we identify substantial heterogeneity (above 50%), we will explore it by prespecified subgroup analysis.

Assessment of reporting biases

If there are 10 or more studies in the meta-analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2012). We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect, i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average of the range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials. If we use random-effects analyses, we will present the results as the average treatment effect with 95% CIs, and the estimates of Tau² and I².

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random-effects analysis to produce it.

We plan to carry out subgroup analyses,if sufficient data are available, based on:

  • reason for hyperthyroidism (Graves' disease versus other causes);

  • treatment regimen (drug A versus drug B: high versus lower dose; and shorter versus longer duration of treatment);

  • timing of the randomisation and when the intervention commenced (pre-conception versus first trimester versus second trimester versus third trimester).

We will restrict subgroup analyses to the review's primary outcomes.

We will assess differences between subgroups by interaction tests available within RevMan (RevMan 2012). We will report the results of subgroup analyses quoting the Chi2 statistic and P value, and the interaction test I² value.

Sensitivity analysis

We plan to carry out sensitivity analysis on primary outcomes to explore the effect of trial quality and design where there is an overall high risk of bias associated with included trials or where quasi-randomised or cluster-randomised trials are included in the review. We will carry out sensitivity analysis to explore the effects of trial quality assessed by allocation concealment and sequence generation, by omitting studies rated as 'high risk of bias' or 'unclear risk of bias' for these components, and to assess the effects of design by omitting quasi-randomised and cluster-randomised trials. We will restrict this to the primary outcomes.

What's new

Last assessed as up-to-date: 8 October 2013.

DateEventDescription
8 October 2013New search has been performedReview updated.
8 October 2013New citation required but conclusions have not changedSearch updated; no new studies found for inclusion (one study excluded (Negro 2010)). Methods updated.

Contributions of authors

Rachel Earl and Philippa Middleton drafted the protocol and review, with input from Caroline Crowther.

For this update, Philippa Middleton and Caroline Crowther assessed the eligibility of the trial identified; Philippa Middleton drafted the update, and all authors contributed to the final version.

Declarations of interest

None known.

Sources of support

Internal sources

  • ARCH, Robinson Institute, The University of Adelaide, Australia.

External sources

  • Australian Department of Health and Ageing, Australia.

  • National Health and Medical Research Council, Australia.

Differences between protocol and review

The methods have been updated for this update, and have been moved to Appendix 1.

We have removed the word 'prevention' from this update, as this review will focus only on interventions for the management of hyperthyroidism pre-pregnancy and during pregnancy.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Negro 2010This randomised trial, compared universal screening with case-finding for the detection and treatment of thyroid hormonal dysfunction during pregnancy (hypothyroidism and hyperthyroidism). The study therefore did not randomise women to interventions for hyperthyroidism pre-pregnancy or in pregnancy, as per the inclusion criteria of the review.

Ancillary