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Levothyroxine to increase live births in euthyroid women with thyroid antibodies trying to conceive: the TABLET RCT.

Source

Southampton (UK): NIHR Journals Library; 2019 Oct.
Efficacy and Mechanism Evaluation.

Author information

1
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
2
Tommy’s Centre for Miscarriage Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
3
Centre for Women’s and Newborn Health, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK
4
Birmingham Clinical Trials Unit, Institute of Applied Health Research, University of Birmingham, Birmingham, UK
5
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
6
The Miscarriage Association, Wakefield, UK
7
University Hospital Coventry, University Hospitals Coventry & Warwickshire NHS Trust, Coventry, UK
8
Burnley General Hospital, East Lancashire Hospitals NHS Trust, Burnley, UK
9
Saint Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, UK
10
Birmingham Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
11
University College Hospital, University College London Hospitals NHS Foundation Trust, London, UK
12
Assisted Conception Unit, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
13
Ayrshire Maternity Unit, University Hospital Crosshouse, NHS Ayrshire and Arran, Kilmarnock, UK
14
Royal Bolton Hospital, Bolton NHS Foundation Trust, Farnworth, UK
15
West Middlesex University Hospital, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
16
St Michael’s Hospital, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
17
St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK
18
Division of Child Health, Obstetrics and Gynaecology, Nottingham, UK
19
Nurture Fertility, The Fertility Partnership, Nottingham, UK
20
Early Pregnancy and Gynaecology Assessment Unit, King’s College Hospital NHS Foundation Trust, London, UK
21
The Princess Royal Hospital, The Shrewsbury and Telford Hospital NHS Trust, Telford, UK
22
Barts Research Centre for Women’s Health, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
23
Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, UK
24
Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Excerpt

BACKGROUND:

Thyroid autoantibodies, specifically thyroid peroxidase antibodies, have been associated with miscarriage and pre-term birth in women with a normal thyroid function. Small randomised controlled trials have found that treatment with levothyroxine may reduce such adverse outcomes in pregnancy.

OBJECTIVES:

The Thyroid AntiBodies and LEvoThyroxine (TABLET) trial was conducted to explore the effects of levothyroxine in euthyroid women with thyroid peroxidase antibodies. A concurrent mechanistic study was conducted to examine the effect of levothyroxine on immune responses.

DESIGN:

This was a randomised, double-blind, placebo-controlled, multicentre study.

SETTING:

The TABLET trial was conducted in 49 hospitals across the UK between 2011 and 2016.

PARTICIPANTS:

Euthyroid women who tested positive for thyroid peroxidase antibodies, were aged between 16 and 41 years and were trying to conceive either naturally or through assisted conception were eligible.

INTERVENTION:

Participants were randomised to levothyroxine at a dose of 50 µg daily or placebo. The intervention was commenced preconception and continued until the end of a pregnancy. Women were given a 12-month period to conceive from randomisation.

MAIN OUTCOME MEASURES:

The primary outcome was live birth at ≥ 34 completed weeks of gestation. The secondary outcomes included miscarriage at < 24 weeks; clinical pregnancy at 7 weeks; ongoing pregnancy at 12 weeks; gestation at delivery; birthweight; appearance, pulse, grimace, activity and respiration (Apgar) scores; congenital abnormalities; and neonatal survival at 28 days of life.

METHODS:

Participants were randomised in a 1 : 1 ratio. Minimisation was implemented for age (< 35 or ≥ 35 years), number of previous miscarriages (0, 1 or 2, ≥ 3), infertility treatment (yes/no) and baseline thyroid-stimulating hormone concentration (≤ 2.5 or > 2.5 mlU/l) to achieve balanced trial arms. Women were followed up every 3 months while trying to conceive to check thyroid function and general well-being, and, once pregnant, were seen each trimester: 6–8 weeks, 16–18 weeks and 28 weeks. Any abnormal thyroid results were managed in line with clinical guidance at the time.

RESULTS:

Of the 19,556 women screened, 1420 women were eligible and 952 were randomised to receive levothyroxine (n = 476) or placebo (n = 476). Six women from each arm either were lost to follow-up or withdrew from the trial. A total 540 women became pregnant: 266 in the levothyroxine arm and 274 in the placebo arm. The live birth rate was 37% (176/470) in the levothyroxine group and 38% (178/470) in the placebo group, translating to a relative risk of 0.97 (95% confidence interval 0.83 to 1.14; p = 0.74) and an absolute risk difference of –0.4% (95% confidence interval –6.6% to 5.8%). A subset of 49 trial participants (26 in the levothyroxine arm and 23 in the placebo arm) were recruited to assess changes in their serum chemocytokine concentrations. Treatment with levothyroxine resulted in some changes in chemocytokine concentrations in the non-pregnant state and in early pregnancy, but these had no association with clinical outcome.

CONCLUSIONS:

Levothyroxine therapy in a dose of 50 µg per day does not improve live birth rate in euthyroid women with thyroid peroxidase antibodies.

LIMITATIONS:

Titration of the levothyroxine dose based on thyroid-stimulating hormone/thyroid peroxidase concentrations was not explored.

FUTURE WORK:

Future research could explore the efficacy of levothyroxine administered for the treatment of subclinical hypothyroidism.

TRIAL REGISTRATION:

Current Controlled Trials ISRCTN15948785 and EudraCT 2011-000719-19.

FUNDING:

This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

Copyright © Queen’s Printer and Controller of HMSO 2019. This work was produced by Dhillon-Smith et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

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