Intervention Protocol

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Thyroxine replacement for subfertile women with euthyroid autoimmune thyroid disease or subclinical hypothyroidism

  1. Muhammad A Akhtar1,*,
  2. David J Owen2,
  3. Panagiotis Peitsidis3,
  4. Yasmin Sajjad4,
  5. Julie Brown5,
  6. Rina Agrawal6,7

Editorial Group: Cochrane Menstrual Disorders and Subfertility Group

Published Online: 5 MAR 2014

Assessed as up-to-date: 6 JAN 2014

DOI: 10.1002/14651858.CD011009


How to Cite

Akhtar MA, Owen DJ, Peitsidis P, Sajjad Y, Brown J, Agrawal R. Thyroxine replacement for subfertile women with euthyroid autoimmune thyroid disease or subclinical hypothyroidism (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD011009. DOI: 10.1002/14651858.CD011009.

Author Information

  1. 1

    St Mary's Hospital, Reproductive Medicine, Manchester, UK

  2. 2

    Liverpool Womens Hospital NHS Foundation Trust, Obstetrics and Gynaecology, Liverpool, UK

  3. 3

    Helena Venizelou Hospital, Obstetrics and Gynaecology, Athens, Greece

  4. 4

    St Marys Hospital, Central Manchester University Hospital NHS Trust, Gynaecology, Manchester, UK

  5. 5

    University of Auckland, The Liggins Institute and Department of Obstetrics and Gynaecology, Auckland, New Zealand

  6. 6

    University Hospitals Coventry and Warwickshire NHS Trust, Department of Obstetrics and Gynaecology, Coventry, UK

  7. 7

    University of Warwick, Coventry, UK

*Muhammad A Akhtar, Reproductive Medicine, St Mary's Hospital, Hathersage Road, Manchester, M13 0JH, UK. drmakh@hotmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 5 MAR 2014

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Description of the condition

Thyroid disease is the second most common endocrine disorder affecting women of reproductive age. Thyroid hormones maintain the basal metabolic rate and regulate body temperature. They affect carbohydrate, fat, protein and vitamin metabolism and energy production thereby enabling body organs to function effectively. Symptoms of hypothyroidism include fatigue, intolerance of cold, weight gain, constipation, dry skin and muscle cramps (Reid et al., 2010). Thyroid hormones are essential for normal development of the brain in the fetus (Porterfield et al.,1993).

 
Clinical hypothyroidism

This is defined as symptomatic thyroid hormone deficiency. It is diagnosed by an elevated thyroid stimulating hormone (TSH) concentration with a low concentration of free thyroxine hormone (FT4). If the TSH is elevated, a FT4 concentration is needed to confirm the presence of clinical hypothyroidism. Clinical hypothyroidism occurs in 2% to 3% of women of child-bearing age (Jameson et al., 2011).

 
Subclinical hypothyroidism

Subclinical hypothyroidism is defined as biochemical evidence of thyroid hormone deficiency in women with few or no apparent symptoms. It is diagnosed by an elevated thyroid stimulating hormone (TSH) concentration with a normal concentration of free thyroxine hormone (FT4). Subclinical hypothyroidism is observed in 6% to 8% of women of child-bearing age (and 10% in women over the age of 60 years). The annual risk of progressing from subclinical to clinical hypothyroidism is 4% when thyroid peroxidase (TPO) antibodies are also present (Jameson et al., 2011).

 
Euthyroid autoimmune thyroid disease (ATD)

Women with euthyroid autoimmune thyroid disease (ATD) have normal TSH and FT4 concentrations with the presence of thyroid autoantibodies. ATD is detected by measuring the concentrations of TPO antibody and thyroglobulin antibody (Tg). As antibodies to Tg alone are uncommon, it is reasonable to measure TPO antibodies. Almost all patients with ATD have high concentrations of TPO antibodies. Autoimmune thyroid disease may be associated with goitre (Hashimoto's thyroiditis) or, at the later stages of the disease, minimal residual thyroid tissue (atrophic thyroiditis) (Jameson et al., 2011).

The susceptibility to ATD is determined by a combination of genetic and environmental factors (Iddah et al.,2013). Transplacental passage of Tg or TPO antibodies has no effect on the fetal thyroid, which suggests that ATD is T cell–mediated autoimmunity (Kim et al., 2011).

ATD affects 5% to 20% of women of child-bearing age (Artini et al., 2013; Karassas et al., 2010). ATD is more prevalent in infertile women (Artini et al., 2013; Karassas et al., 2010; Kim et al., 2011; Poppe et al., 2008; Torkoudes et al., 2006; Van den Boogaard et al., 2011) and has been associated with an increased miscarriage rate both after spontaneous conception (Artini et al., 2013; Kim et al., 2011; Poppe et al., 2008; Torkoudes et al., 2006; Van den Boogaard et al., 2011) and in subfertile women achieving pregnancy by assisted reproduction (Toulis et al., 2010). The oocyte fertilisation and pregnancy rates were lower whilst the miscarriage rates were higher in women with ATD undergoing assisted reproduction treatment. There was a significant presence of thyroid autoantibodies (TPO, Tg) in the follicular fluid of all women with ATD and the concentrations of TPO and Tg positively correlated with serum concentrations (Monteleone et al., 2011). A higher prevalence of ATD is also reported in subfertile women with endometriosis (Artini et al., 2013; Poppe et al., 2008; Torkoudes et al., 2006) and polycystic ovarian syndrome (PCOS) (Janssen et al., 2004; Poppe et al., 2008). There is also significant positive correlation between the presence of ATD and premature ovarian failure (Abalovich et al., 2007). ATD is associated with impaired cellular and humoral immune responses including an increase in the natural killer (NK) cell concentrations in women with unexplained infertility, although there were no significant differences in NK cytotoxic activity (Kim et al., 2011). It is suggested that the presence of thyroid antibodies and an elevated TSH concentration increase interleukin 2 (IL-2) production causing IL-2 mediated NK cell activation, thus leading to reproductive failures and miscarriages (Konova et al., 2010).

 

Description of the intervention

There is no consensus regarding the dosage, timing and follow up of thyroxine treatment during assisted reproduction for subfertile women with subclinical hypothyroidism or euthyroid women with ATD. This area will be explored in the review.

Thyroid hormones have diverse effects on ovarian function. They may be important for ovarian follicle development and maturation of the cumulus–oocyte complex (COC). Several isoforms of thyroid hormone receptor mRNA are expressed in the human oocyte. Hence thyroid hormones may have direct and indirect effects on the oocyte, as well as on the granulosa and cumulus cells (Zhang et al.,1997). Hypothyroidism can thus disrupt normal ovarian function (Van Voorhis et al., 1994). 

Thyroid hormone receptors have been described in human oocytes, where they synergize with the luteinizing hormone and human chorionic gonadotrophin receptor, mediated by follicle-stimulating hormone, to exert direct stimulatory effects on granulosa cell function (that is progesterone production) and on trophoblastic differentiation (Poppe et al., 2008).

Thyroxine (T4) circulates in the blood bound to thyroxine-binding globulin (TBG) and only free, unbound T4 is available to tissues. TBG production by the liver, similar to other binding proteins, rises in states of high circulating estradiol concentrations such as the pregnant state (Glinoer and Gershengorn et al., 1977; Glinoer and McGuire et al., 1977).

Thyroid dysfunction is more frequent in women with positive TPO antibody titres and this may interfere with normal ovarian function (Poppe et al., 2008).

Controlled ovarian hyperstimulation (COH) during assisted reproduction treatment (ART) cycles involves down-regulation of the pituitary–gonadal axis by using gonadotrophin-releasing hormone (GnRH) analogues and then triggering final oocyte maturation with human chorionic gonadotrophins (hCG). COH induces an increase in estradiol (E2) concentrations resulting in excess TBG production by the liver, which leads to an increase in the circulating thyroxine-binding sites. This causes a reduction in FT4 concentrations thus resulting in a compensatory increase in TSH production from the pituitary gland (Mintziori et al., 2011).

Both TSH and hCG share structural homologies and receptors. This results in endogenous hCG having thyrotropic effects (Haddow et al., 2008). High hCG concentrations during COH may be associated with thyroid stimulation of function (lower serum TSH concentrations) and anatomically an increased thyroid volume (Mintziori et al., 2011).  A significant elevation in TSH concentrations has been reported in women who have COH during ART (Garcia et al., 2012). Therefore euthyroid women with ATD before pregnancy may develop overt hypothyroidism during ART cycles, with or without resulting pregnancy, as a result of these hormonal changes (Kim et al., 2011; Poppe et al., 2004).

COH leads to a significant increase in circulating estradiol concentration, which in turn may have an adverse effect on thyroid hormones and TSH. In the presence of ATD, the impact of COH on thyroid dysfunction may become more severe (Karassas et al., 2010; Muller et al., 2000).

 

How the intervention might work

The goal of thyroxine treatment is to normalise serum TSH concentrations (De Groot et al., 2012; Stagnaro-Green et al., 2011). Other thyroid preparations (such as T3) are not recommended (De Groot et al., 2012). Replacement with levothyroxine to normalise TSH concentrations is a well-known intervention for hypothyroidism in an iodine-sufficient population (Reid et al., 2010).

The menstrual pattern is influenced by thyroid hormones, directly through an effect on the ovaries and indirectly through an impact on sex hormone-binding globulin (SHBG), prolactin (PRL), GnRH secretion and coagulation factors. Treating thyroid dysfunction can reverse menstrual abnormalities and therefore improve fertility. In subfertile women, the prevalence of ATD is significantly higher than in parous age-matched women. This is especially the case in women with endometriosis and PCOS. It has also been demonstrated that COH in preparation for ART has a significant negative impact on thyroid function, particularly in women with ATD. It is therefore advisable to measure thyroid function and diagnose ATD in infertile women before ART and to follow up these parameters after COH and during pregnancy, particularly if ATD was initially present (Janssen et al., 2004; Poppe et al., 2007).

Serum TSH concentrations are a significant predictor of fertilisation failure in women undergoing IVF, supporting the importance of the role of thyroid hormones in oocyte physiology. Cramer and colleagues in their prospective study reported that TSH concentrations were significantly higher among women who produced oocytes that failed to fertilise (Cramer et al., 2003). Among women who had at least one oocyte inseminated, the likelihood that they would have fewer than 50% of their eggs fertilised was significantly related to higher TSH concentrations in a multivariate model. It was therefore concluded that TSH may predict poor fertilisation rates in IVF and this reflects the importance of thyroid hormones in oocyte physiology (Cramer et al., 2003).

Further, two meta-analyses (Prummel et al., 2004; Thangaratinam et al., 2011) reported that there was an association between the presence of thyroid antibodies and miscarriage in subfertile women in cohort and case control studies (Thangaratinam et al., 2011) and in longitudinal studies involving populations of unselected women (Prummel et al., 2004). It has also been reported that levothyroxine treatment is helpful in reducing miscarriage in populations of unselected women with normal thyroid function and thyroid autoantibodies (risk ratio 0.48, 95% confidence interval (CI) 0.25 to 0.92, P = 0.03) (Thangaratinam et al., 2011).

The presence of ATD is associated with a significantly higher risk of miscarriage in women who become pregnant following an ART procedure, but it has no effect on the pregnancy rate. Therefore, determining the presence of ATD before embryo transfer may be useful in identifying women at risk of miscarriage. Women with ATD treated with thyroid replacement therapy had a lower risk of miscarriage compared with a similar group treated with intravenous immunoglobulin (Torkoudes et al., 2006). Babies born in women undergoing assisted reproduction with a pre-conception TSH concentration of > 2.5 mIU/L had a lower gestational age at delivery and a lower birth weight (Baker et al., 2006). 

The US National Centre on Birth Defects and Developmental Disability of the Centres for Disease Control and Prevention (CDC) and the American Thyroid Association have recommended that euthyroid woman with known ATD prior to conception should have a serum TSH concentration assessed and levothyroxine therapy initiated if the serum TSH concentration is greater than 2.5 mIU/L prior to pregnancy, for all women not known to have overt clinical hypothyroidism (Mandel et al., 2005). The American Thyroid Association published guidelines in 2011 and have advised that there is insufficient evidence to recommend universal levothyroxine treatment in all pregnant women with subclinical hypothyroidism; however, if they have subclinical hypothyroidism with presence of thyroid antibodies then the women should be treated with levothyroxine treatment (Stagnaro-Green et al., 2011).

The Endocrine Society clinical practice guidelines (De Groot et al., 2012) recommend screening all women over the age of 30 years or all infertile women seeking pregnancy, or both, for targeted thyroid disease case finding. Women with the presence of thyroid antibodies in their circulation are at increased risk of miscarriage, preterm delivery, progression of hypothyroidism and postpartum thyroiditis. Therefore, if identified, such women should be screened for serum TSH abnormalities before pregnancy. If serum TSH is over 2.5 mIU/l at the time of testing, then levothyroxine therapy should be initiated. It also recommends levothyroxine replacement in women with subclinical hypothyroidism with or without the presence of thyroid antibodies and, if already treated, that a pre-pregnancy TSH concentration should not be in excess of 2.5 mIU/l (De Groot et al., 2012).

 

Why it is important to do this review

This review will provide fertility experts and consumers with evidence-based knowledge of the efficacy of thyroxine treatment in terms of improving clinical pregnancy and live birth rates in subfertile women with subclinical hypothyroidism or euthyroid autoimmune thyroid disease (ATD) during assisted reproduction. In this review we will not assess the efficacy of thyroxine on the outcome of pregnancy or in women with a history of recurrent miscarriage.

Thyroxine is offered sporadically to women with subclinical hypothyroidism or euthyroid women with ATD during assisted reproduction treatment in an attempt to improve implantation and pregnancy rates and to reduce the miscarriage rate.

A systematic review is required to determine the efficacy of levothyroxine treatment in these women with the aim of improving the live birth rate and clinical pregnancy rate and to reduce adverse perinatal outcomes.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

To evaluate the efficacy and safety of levothyroxine treatment in subfertile women with subclinical hypothyroidism or with euthyroid autoimmune thyroid disease (ATD) undergoing assisted reproduction.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

Only randomised controlled trials (RCTs) will be included in the review. Quasi-randomised trials will be excluded. Cross-over trials will be included in the review for completeness but data from the first phase only will be included in the meta-analysis as the cross-over trial is not a valid design in this context.

 

Types of participants

All women undergoing assisted reproduction treatment (ART), both in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI), with a history of subfertility. Women having stimulated and unstimulated intrauterine insemination (IUI) treatment will be excluded.

Women with subclinical hypothyroidism or with euthyroid ATD will be included.

Women with a previously known clinical hypothyroidism or 'taking thyroxine or tri-iodothyronine' will be excluded.

We will identify women randomised to the thyroxine or placebo group according to the diagnositic criteria by which they were recruited to the study, for example goitre and positive thyroid antibodies, past subclinical hypothyroidism, normal (that is no evidence of thyroid disease).

 

Types of interventions

Trials comparing thyroxine at any dosage with no treatment or placebo will be eligible for inclusion.

 

Types of outcome measures

 

Primary outcomes

1. Live birth rate per woman randomised (live birth is defined as delivery of one or more live infants)

 

Secondary outcomes

1. Clinical pregnancy rate per woman randomised (defined as a pregnancy diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy)

2. Multiple pregnancy rate per woman randomised and per total number of pregnancies (defined as ultrasonographic visualization of more than one gestational sac or definitive clinical signs of pregnancy)

3. Miscarriage rate per woman randomised and per pregnancy with per woman data prioritised

4. Maternal pregnancy complications e.g. preterm delivery, pre-eclampsia

5. Fetal complications during pregnancy e.g.intrauterine growth restriction

6. Adverse effects of thyroxine

 
Additional outcomes not appropriate for statistical pooling

Implantation rate, the number of fetal sacs divided by the number of embryos transferred.

 

Search methods for identification of studies

We will search for all published and unpublished RCTs comparing thyroxine with no treatment or placebo, without language restriction and in consultation with the Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co-ordinator.

 

Electronic searches

We will search the following electronic databases, trial registers and websites: the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL) (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), PsycINFO (Appendix 4) and CINAHL. The MEDLINE search will be combined with the Cochrane highly sensitive search strategy for identifying randomised trials which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.0.2; chapter 6, 6.4.11). The EMBASE, PsycINFO and CINAHL searches will be combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) at http://www.sign.ac.uk/methodology/filters.html#random.

Other electronic sources of trials will include:

  • trial registers for ongoing and registered trials
    • http://www.clinicaltrials.gov (a service of the US National Institutes of Health),
    • http://www.who.int/trialsearch/Default.aspx (The World Health Organization International Trials Registry Platform search portal);
  • DARE (Database of Abstracts of Reviews of Effects) in The Cochrane Library at http://onlinelibrary.wiley.com/o/cochrane/cochrane_cldare_articles_fs.html (for reference lists from relevant non-Cochrane reviews);
  • the Web of Knowledge at http://wokinfo.com/ (another source of trials and conference abstracts);
  • OpenGrey at http://www.opengrey.eu/ for unpublished literature from Europe;
  • LILACS database at http://regional.bvsalud.org/php/index.php?lang=en (for trials from the Portuguese and Spanish speaking world);
  • PubMed and Google (for recent trials not yet indexed in MEDLINE).

 

Searching other resources

We will handsearch reference lists of articles retrieved by the search and contact experts in the field to obtain additional data. We will also handsearch relevant journals and conference abstracts that are not covered in the MDSG register, in liaison with the Trials Search Co-ordinator.

 

Data collection and analysis

We will perform statistical analysis in accordance with the Cochrane Handbook for Systematic Reviews of Interventions Version 5.2.0 (Higgins et al., 2011). Review Manager 5.2 will be used for input of data.

 

Selection of studies

The selection process will be documented with a PRISMA flow chart.

The title, abstract and keywords of every record retrieved will be scrutinized independently by two review authors to determine which studies require further assessment. The full texts will be retrieved when the information given in the titles, abstracts and keywords suggest that the randomized controlled study intervention is thyroxine as an adjunct to ART.

If there are any doubts regarding these criteria from scanning the titles and abstracts, the full article will be retrieved for clarification. Disagreements will be resolved by discussion with a third review author (GP, RA) if necessary. The authors of trials will be contacted to provide missing data if required.

 

Data extraction and management

We will extract data from the included studies using a data extraction form designed and adapted by the authors. Where a trial has multiple publications the main trial report will be used as the primary source of evidence and additional material will be supplemented by the secondary publications. We will attempt to correspond with authors of original papers where there are any missing data or lack of clarity. Two of the review authors will independently extract the data and any disagreements will be resolved by a third author (RA).

 

Assessment of risk of bias in included studies

Assessment of risk of bias in the included studies will be independently performed by two review authors; disagreements will be noted and resolved by a third review author. The authors will specifically assess the quality of allocation (random sequence generation and allocation concealment), blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective reporting and other bias. Any disagreements will be resolved by a third review author. We will describe all judgments fully and they will be presented in the 'Risk of bias' tables using the criteria specified by the Cochrane Handbook for Systematic Reviews of Interventions.

 

Measures of treatment effect

For dichotomous outcomes (for example adverse events) we will record the number of participants experiencing the event in each group of the trial. We will look at the odds ratio in each study. We will present 95% confidence intervals for all outcomes. None of the outcomes proposed are continuous variables.

 

Unit of analysis issues

The primary analysis will be per woman randomised. Data reported that do not allow valid analysis (for example 'per cycle' rather than 'per woman' where women contribute more than one cycle) will be briefly summarised in an additional table and will not be used in the meta-analysis. Multiple live births (for example twins or triplets) will be counted as one live birth event. Only first-phase data from cross-over trials will be included.

 

Dealing with missing data

Analysis will be conducted using the intention-to-treat principle where possible. We will contact the authors of the RCTs to source any missing data or to resolve any queries that may arise.

Where included studies fail to report on the primary outcome of live birth but do report on interim measures such as clinical pregnancy rates we will undertake informal assessment as to whether these interim values are similar to those reported in the trials that did report on live birth.

 

Assessment of heterogeneity

The review authors will check to see if the participants, interventions and outcomes in the included studies are similar enough to consider pooling in a meta-analysis. If so, then the rest of the section will refer to statistical heterogeneity after pooling.

Tests for heterogeneity will be carried out using the Chi2 test, with significance set at P < 0.1. The I2 statistic will be used to estimate the total variation across studies that is due to heterogeneity, where < 25% is considered as low heterogeneity, 25% to 50% as moderate, and > 50% as high heterogeneity. If high levels of heterogeneity (I2 > 50%) are seen for the primary outcomes, we will explore possible sources of heterogeneity using the sensitivity and subgroup analyses described below. These will be performed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et al., 2011).

 

Assessment of reporting biases

We will be vigilant for duplication of publications. In order to assess for publication bias we will produce a funnel plot where there are 10 or more trials reporting on an outcome, or we will use other corrective analytical methods depending on the number of included studies (Egger et al., 1997).

 

Data synthesis

We will combine studies in a meta-analysis if sufficient studies are available for inclusion.

The data from primary studies will be combined using a fixed-effect model in the following comparison:

1. thyroxine versus no treatment or placebo.

An increase in the odds of a particular outcome, which may be beneficial (for example live birth) or detrimental (for example adverse effects), will be displayed graphically in the forest plot to the right of the centre-line and a decrease in the odds of an outcome to the left of the centre-line.

For reporting purposes the primary outcomes will be translated to absolute risks.

 

Subgroup analysis and investigation of heterogeneity

Where data are available, we will conduct subgroup analyses to determine the separate evidence within the following subgroups:                                                                

1. different ART methods; 

2. women with subclinical hypothyroidism undergoing ART; 

3. euthyroid women with ATD undergoing ART;

4. duration and dosage of thyroxine during ART.

Factors such as length of follow up and adjusted or unadjusted analysis will be considered in the interpretation of any heterogeneity.

 

Sensitivity analysis

We will perform sensitivity analyses for the primary outcomes to determine whether the conclusions are robust to arbitrary decisions made regarding the eligibility of studies and analysis. These sensitivity analyses will include consideration of whether the review conclusions would have differed if:

1. eligibility was restricted to studies without high risk of bias;

2. a random-effects model had been adopted;

3. alternative imputation strategies had been implemented;

4. the summary effect measure was relative risk rather than odds ratio.

 

Overall quality of the body of evidence: 'Summary of findings' table

We will present a 'Summary of findings' table using GRADEPRO or Guideline Development Tool software. This table will evaluate the overall quality of the body of evidence for the primary review outcome (live birth) using the GRADE criteria (study limitations (that is risk of bias), consistency of effect, imprecision, indirectness and publication bias). Judgments about evidence quality (high, moderate or low) will be justified, documented and incorporated into the reporting of results for each outcome.

 
Updating plan

Completion of the review is expected within one year of publication of the protocol in The Cochrane Library. It is also the intention of the review authors that a new search for RCTs will be performed every two years. If an important study is published that may alter the conclusions, we will update the review accordingly.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

We thank Dr Gordana Prelevic for her expert advice on autoimmune thyroid disease.

We thank Helen Nagels (Managing Editor), Marian Showell (Trials Search Co-ordinator), and the editorial board of the Cochrane MDSG for their invaluable assistance in developing this protocol.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. CENTRAL search strategy

Database: EBM Reviews - Cochrane Central Register of Controlled Trials <December 2012>
Search Strategy:

1 exp embryo transfer/ or exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/
2 embryo transfer$.tw.
3 vitro fertili?ation.tw.
4 ivf-et.tw.
5 ivf.tw.
6 icsi.tw.
7 intracytoplasmic sperm injection$.tw.
8 (blastocyst adj2 transfer$).tw.
9 exp reproductive techniques, assisted/ or exp insemination, artificial/ or exp ovulation induction/
10 assisted reproduct$.tw.
11 artificial insemination.tw.
12 iui.tw.
13 intrauterine insemination$.tw.
14 ovulation induc$.tw.
15 (ovari$ adj2 stimulat$).tw.
16 superovulat$.tw.
17 super-ovulat$.tw.
18 ovarian hyperstimulation.tw.
19 COH.tw.
20 infertil$.tw.
21 subfertil$.tw.
22 (ovari$ adj2 induction).tw.
23 (euthyroid adj5 women).tw.
24 (hypothyroid$ and women).tw.
25 or/1-24
26 exp Thyroxine/
27 Thyroxine.tw.
28 triiodothyronine.tw.
29 Levothyroxine.tw.
30 L-thyroxine.tw.
31 liotrix.tw.
32 liothyronine.tw.
33 Levothroid.tw.
34 (Levoxyl or Synthroid or Unithroid).tw.
35 Tetraiodothyronine.tw.
36 eltroxin.tw.
37 l-thyroxin.tw.
38 levothyroxin.tw.
39 thyroxin.tw.
40 eltroxine.tw.
41 or/26-40
42 25 and 41

 

Appendix 2. MEDLINE search strategy

Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present>
Search Strategy:

1 exp embryo transfer/ or exp fertilization in vitro/ or exp sperm injections, intracytoplasmic/
2 embryo transfer$.tw.
3 vitro fertili?ation.tw.
4 ivf-et.tw.
5 ivf.tw.
6 icsi.tw.
7 intracytoplasmic sperm injection$.tw.
8 (blastocyst adj2 transfer$).tw.
9 exp reproductive techniques, assisted/ or exp insemination, artificial/ or exp ovulation induction/
10 assisted reproduct$.tw.
11 artificial insemination.tw.
12 iui.tw.
13 intrauterine insemination$.tw.
14 ovulation induc$.tw.
15 (ovari$ adj2 stimulat$).tw.
16 superovulat$.tw.
17 super-ovulat$.tw.
18 ovarian hyperstimulation.tw.
19 COH.tw.
20 infertil$.tw.
21 subfertil$.tw.
22 (ovari$ adj2 induction).tw.
23 (euthyroid adj5 women).tw.
24 (hypothyroid$ and women).tw.
25 or/1-24
26 exp Thyroxine/
27 Thyroxine.tw.
28 triiodothyronine.tw.
29 Levothyroxine.tw.
30 L-thyroxine.tw.
31 liotrix.tw.
32 liothyronine.tw.
33 Levothroid.tw.
34 (Levoxyl or Synthroid or Unithroid).tw.
35 Tetraiodothyronine.tw.
36 eltroxin.tw.
37 l-thyroxin.tw.
38 levothyroxin.tw.
39 thyroxin.tw.
40 eltroxine.tw.
41 or/26-40
42 25 and 41
43 randomized controlled trial.pt.
44 controlled clinical trial.pt.
45 randomized.ab.
46 randomised.ab.
47 placebo.tw.
48 clinical trials as topic.sh.
49 randomly.ab.
50 trial.ti.
51 (crossover or cross-over or cross over).tw.
52 or/43-51
53 exp animals/ not humans.sh.
54 52 not 53
55 42 and 54

 

Appendix 3. EMBASE search strategy

Database: Embase <1980 to 2013 Week 02>
Search Strategy:

1 exp embryo transfer/ or exp fertilization in vitro/ or exp intracytoplasmic sperm injection/
2 embryo$ transfer$.tw.
3 in vitro fertili?ation.tw.
4 icsi.tw.
5 intracytoplasmic sperm injection$.tw.
6 (blastocyst adj2 transfer$).tw.
7 ivf.tw.
8 exp infertility therapy/ or exp artificial insemination/ or exp intrauterine insemination/ or exp ovulation induction/
9 assisted reproduct$.tw.
10 artificial insemination.tw.
11 iui.tw.
12 intrauterine insemination$.tw.
13 ovulation induc$.tw.
14 (ovari$ adj2 stimulat$).tw.
15 superovulat$.tw.
16 ovarian hyperstimulation.tw.
17 COH.tw.
18 infertil$.tw.
19 subfertil$.tw.
20 (ovari$ adj2 induction).tw.
21 (euthyroid adj3 women).tw.
22 (hypothyroid$ adj3 women).tw.
23 or/1-22
24 exp thyroxine/
25 Thyroxine.tw.
26 triiodothyronine.tw.
27 Levothyroxine.tw.
28 L-thyroxine.tw.
29 liotrix.tw.
30 liothyronine.tw.
31 Levothroid.tw.
32 (Levoxyl or Synthroid or Unithroid).tw.
33 Tetraiodothyronine.tw.
34 eltroxin.tw.
35 l-thyroxin.tw.
36 levothyroxin.tw.
37 thyroxin.tw.
38 eltroxine.tw.
39 or/24-38
40 23 and 39
41 Clinical Trial/
42 Randomized Controlled Trial/
43 exp randomization/
44 Single Blind Procedure/
45 Double Blind Procedure/
46 Crossover Procedure/
47 Placebo/
48 Randomi?ed controlled trial$.tw.
49 Rct.tw.
50 random allocation.tw.
51 randomly allocated.tw.
52 allocated randomly.tw.
53 (allocated adj2 random).tw.
54 Single blind$.tw.
55 Double blind$.tw.
56 ((treble or triple) adj blind$).tw.
57 placebo$.tw.
58 prospective study/
59 or/41-58
60 case study/
61 case report.tw.
62 abstract report/ or letter/
63 or/60-62
64 59 not 63
65 40 and 64

 

Appendix 4. PsycINFO search strategy

Database: PsycINFO <1806 to January Week 2 2013>
Search Strategy:

1 exp Infertility/ or exp Reproductive Technology/
2 embryo transfer$.tw.
3 vitro fertili?ation.tw.
4 ivf.tw.
5 icsi.tw.
6 intracytoplasmic sperm injection$.tw.
7 assisted reproduct$.tw.
8 artificial insemination.tw.
9 iui.tw.
10 intrauterine insemination$.tw.
11 ovulation induc$.tw.
12 (ovari$ adj2 stimulat$).tw.
13 superovulat$.tw.
14 ovarian hyperstimulation.tw.
15 COH.tw.
16 infertil$.tw.
17 subfertil$.tw.
18 (ovari$ adj2 induction).tw.
19 (euthyroid adj5 women).tw.
20 (hypothyroid$ and women).tw.
21 or/1-20
22 exp Thyroxine/
23 Thyroxine.tw.
24 triiodothyronine.tw.
25 Levothyroxine.tw.
26 L-thyroxine.tw.
27 eltroxin.tw.
28 l-thyroxin.tw.
29 thyroxin.tw.
30 or/22-29
31 21 and 30
32 random.tw.
33 control.tw.
34 double-blind.tw.
35 clinical trials/
36 placebo/
37 exp Treatment/
38 or/32-37
39 31 and 38

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Akhtar Muhammad A (Contact author):

All correspondence with drafting of the protocol and developing search strategies.

Owen David J:

Drafting of the protocol.

Panagiotis Peitsidis:

Drafting of the protocol.

Yasmin Sajjad:

Drafting of the protocol and development of search strategies.

Brown Julie:

Drafting of the protocol and development of search strategies.

Agrawal Rina:

Expert advice on drafting of the protocol.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

The authors have no commercial interests to disclose.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • Cochrane Menstrual Disorders and Subfertility Group, New Zealand.
  • Department of Obstetrics and Gynaecology, University of Auckland, New Zealand.
  • Centre of Reproductive Medicine, University Hospitals Coventry & Warwickshire NHS Trust, UK.
  • Department of Reproductive Endocrinology, Royal Free Hospital NHS Trust, London, UK.
  • Department of Reproductive Medicine, St Marys Hospital, Central Manchester University Hospitals NHS Trust, UK.

 

External sources

  • None, Not specified.

References

Additional references

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  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
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