Title: Evaluating the use of levothyroxine treatment to reduce miscarriage in women with mild thyroid dysfunction: an individual participant data meta-analysis.
Funder: Department of Health and Social Care

Abstract: Background: Normal functioning of the thyroid gland is essential for successful conception and pregnancy. Subclinical hypothyroidism (SCH) has been linked to adverse outcomes such as subfertility, miscarriage, pre-term birth, pre-eclampsia, gestational hypertension, and perinatal mortality. Internationally, there is variation in the diagnosis and management of SCH. There is also disagreement in the definition of SCH. Some international societies recommend lowering the preconception limit of TSH to 2.5mIU/L, particularly in women who are considered &ldquo;high risk&rdquo; such as those with history of subfertility or miscarriage. This management strategy is controversial, since data showing evidence of benefit are conflicting and often do not consider thyroid antibody status. Furthermore, there is insufficient evidence suggesting reduced fertility outcomes or higher miscarriage rates exist in women with mild thyroid dysfunction (TSH 2.5-5.0mIU/L). It is now known that up to 20% of women with history of subfertility or miscarriage will have TSH levels >2.5mIU/L. There is no clinical trial specifically exploring pregnancy outcomes in women with mild thyroid dysfunction, with or without thyroid antibodies, treated with levothyroxine. Given that this subgroup of women constitutes up to 20% of the population it is important to have clear evidence of whether levothyroxine treatment can improve pregnancy outcomes for these populations. Aims: The aim of this research is to investigate whether levothyroxine therapy, initiated preconception or in first trimester, in women with mild thyroid dysfunction, can reduce the risk of miscarriage and improve pregnancy outcomes. Objectives Primary. To assess the: miscarriage rates in women treated with levothyroxine who have mild thyroid dysfunction, compared with those who are untreated or on placebo. live birth rates in women treated with levothyroxine who have mild thyroid dysfunction, compared with those who are untreated or on placebo. Methods: This evidence synthesis study will begin with a systematic search to identify all relevant studies for inclusion in data analysis. The following databases will be searched: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL). Essential criteria for data inclusion (study must meet all inclusion criteria): Randomised study LT4 treatment commenced pre-conception or first trimester Participants with TSH concentrations up to 5.0mIU/L Data available for miscarriage (defined as a pregnancy loss We intend to conduct an individual participant data (IPD) meta-analysis to isolate the sub-population of specific interest to our research questions. Timeline This project will be completed over a 24month period. Impact We aim to publish our work in a high-impact scientific journal and present the findings at international conferences in order to disseminate findings to healthcare professionals. Within our research team we have experts who belong to national and international committees (NICE and American Thyroid Association) who will help to implement the findings of our work into national and international guidelines to directly impact on clinical practice. Finally, we have strong support from representatives of patient groups; Miscarriage Association UK, Tommy s Charity, Fertility Network UK and Thyroid UK. Through these links we will disseminate the findings widely to all relevant patient groups.

Lay abstract: Normal functioning of the thyroid gland is essential for successful conception and pregnancy. Thyroid problems are one of the most common conditions to affect women of reproductive age. Subclinical hypothyroidism (SCH) is a form of mild thyroid dysfunction and is a diagnosis given to those who have normal levels of thyroid hormone (thyroxine) and higher than normal levels of another hormone (thyroid stimulating hormone). SCH has been shown to be a risk factor for adverse pregnancy outcomes such as miscarriage and pre-term birth. It is unknown whether there is benefit in treating women who have mild thyroid dysfunction with a drug called levothyroxine, either prior to getting pregnant or in early pregnancy. This is an important subgroup of women as it is highly prevalent; data from a recently published large study, called TABLET trial, have shown that up to 20% of women in the UK are classified as having mild thyroid dysfunction. Despite the lack of evidence, international guidelines recommend that women who are undergoing infertility treatment or have a history of miscarriage should aim for tighter control of thyroid function before and during pregnancy, resulting in large numbers of women receiving a treatment of unknown value. The need for credible evidence is further amplified as there is research showing levothyroxine could in fact be harmful in pregnancy. Women who are on levothyroxine treatment require regular monitoring of their thyroid both during and after pregnancy. This results in costs to maternity services and repeated hospital visits for the women themselves. To date there is no clinical trial which has specifically explored levothyroxine treatment in pregnant women with mild thyroid dysfunction. However, there are several trials which have included this population of women as a subgroup. The numbers of women within the individual studies are too small to draw any firm conclusions. Consequently, there is inconsistent practice in the UK on the management of these women. We have been advised by the Miscarriage Association that many women who fall into this category of mild thyroid dysfunction are unclear on how they should be looked after both before and during pregnancy. The aim of this study is to investigate whether levothyroxine treatment in women with mild thyroid dysfunction, can reduce miscarriage rates and improve pregnancy outcomes. We wish to combine the data from all the existing clinical trials which have included this subgroup to create a larger dataset and allow us to draw clearer conclusions to help guide clinical practice. The findings of this study will help to improve care in the UK and will be incorporated into national and international guidelines.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE