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

Research output: Contribution to journalArticle

Standard

Levothyroxine to increase live births in euthyroid women with thyroid antibodies trying to conceive : the TABLET RCT. / Dhillon-smith, Rima; Middleton, Lee; Sunner, Kirandeep; Cheed, Versha; Baker, Krys; Farrell-Carver, Samantha ; Bender Atik, Ruth; Agrawal, Rina ; Bhatia, Kalsang ; Edi-Osagie, Edmond ; Ghobara, Tarek ; Gupta, Pratima; Jurkovic, Davor ; Khalaf, Yacoub; MacLean, Marjory; McCabe, Chris; Mulbagal, Khashia ; Nunes, Natalie ; Overton, Caroline ; Quenby, Siobhan; Rai, Rajendra ; Raine-Fenning, Nick; Robinson, Lynne; Ross, Jackie; Sizer, Andrew ; Small, Rachel; Tan, Alex; Underwood, Martyn; Kilby, Mark; Boelaert, Kristien; Daniels, Jane; Thangaratinam, Shakila; Chan, Shiao-Yng; Coomarasamy, Arri.

In: Efficacy and Mechanism Evaluation, Vol. 6, No. 11, 31.10.2019, p. 1-102.

Research output: Contribution to journalArticle

Harvard

Dhillon-smith, R, Middleton, L, Sunner, K, Cheed, V, Baker, K, Farrell-Carver, S, Bender Atik, R, Agrawal, R, Bhatia, K, Edi-Osagie, E, Ghobara, T, Gupta, P, Jurkovic, D, Khalaf, Y, MacLean, M, McCabe, C, Mulbagal, K, Nunes, N, Overton, C, Quenby, S, Rai, R, Raine-Fenning, N, Robinson, L, Ross, J, Sizer, A, Small, R, Tan, A, Underwood, M, Kilby, M, Boelaert, K, Daniels, J, Thangaratinam, S, Chan, S-Y & Coomarasamy, A 2019, 'Levothyroxine to increase live births in euthyroid women with thyroid antibodies trying to conceive: the TABLET RCT', Efficacy and Mechanism Evaluation, vol. 6, no. 11, pp. 1-102. https://doi.org/10.3310/eme06110

APA

Dhillon-smith, R., Middleton, L., Sunner, K., Cheed, V., Baker, K., Farrell-Carver, S., Bender Atik, R., Agrawal, R., Bhatia, K., Edi-Osagie, E., Ghobara, T., Gupta, P., Jurkovic, D., Khalaf, Y., MacLean, M., McCabe, C., Mulbagal, K., Nunes, N., Overton, C., ... Coomarasamy, A. (2019). Levothyroxine to increase live births in euthyroid women with thyroid antibodies trying to conceive: the TABLET RCT. Efficacy and Mechanism Evaluation, 6(11), 1-102. https://doi.org/10.3310/eme06110

Vancouver

Author

Dhillon-smith, Rima ; Middleton, Lee ; Sunner, Kirandeep ; Cheed, Versha ; Baker, Krys ; Farrell-Carver, Samantha ; Bender Atik, Ruth ; Agrawal, Rina ; Bhatia, Kalsang ; Edi-Osagie, Edmond ; Ghobara, Tarek ; Gupta, Pratima ; Jurkovic, Davor ; Khalaf, Yacoub ; MacLean, Marjory ; McCabe, Chris ; Mulbagal, Khashia ; Nunes, Natalie ; Overton, Caroline ; Quenby, Siobhan ; Rai, Rajendra ; Raine-Fenning, Nick ; Robinson, Lynne ; Ross, Jackie ; Sizer, Andrew ; Small, Rachel ; Tan, Alex ; Underwood, Martyn ; Kilby, Mark ; Boelaert, Kristien ; Daniels, Jane ; Thangaratinam, Shakila ; Chan, Shiao-Yng ; Coomarasamy, Arri. / Levothyroxine to increase live births in euthyroid women with thyroid antibodies trying to conceive : the TABLET RCT. In: Efficacy and Mechanism Evaluation. 2019 ; Vol. 6, No. 11. pp. 1-102.

Bibtex

@article{64ff8b4b1f4549389635af7f471e66f6,
title = "Levothyroxine to increase live births in euthyroid women with thyroid antibodies trying to conceive: the TABLET RCT",
abstract = "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. ",
author = "Rima Dhillon-smith and Lee Middleton and Kirandeep Sunner and Versha Cheed and Krys Baker and Samantha Farrell-Carver and {Bender Atik}, Ruth and Rina Agrawal and Kalsang Bhatia and Edmond Edi-Osagie and Tarek Ghobara and Pratima Gupta and Davor Jurkovic and Yacoub Khalaf and Marjory MacLean and Chris McCabe and Khashia Mulbagal and Natalie Nunes and Caroline Overton and Siobhan Quenby and Rajendra Rai and Nick Raine-Fenning and Lynne Robinson and Jackie Ross and Andrew Sizer and Rachel Small and Alex Tan and Martyn Underwood and Mark Kilby and Kristien Boelaert and Jane Daniels and Shakila Thangaratinam and Shiao-Yng Chan and Arri Coomarasamy",
year = "2019",
month = oct,
day = "31",
doi = "10.3310/eme06110",
language = "English",
volume = "6",
pages = "1--102",
journal = "Efficacy and Mechanism Evaluation",
issn = "2050-4365",
publisher = "Prepress Projects Ltd",
number = "11",

}

RIS

TY - JOUR

T1 - Levothyroxine to increase live births in euthyroid women with thyroid antibodies trying to conceive

T2 - the TABLET RCT

AU - Dhillon-smith, Rima

AU - Middleton, Lee

AU - Sunner, Kirandeep

AU - Cheed, Versha

AU - Baker, Krys

AU - Farrell-Carver, Samantha

AU - Bender Atik, Ruth

AU - Agrawal, Rina

AU - Bhatia, Kalsang

AU - Edi-Osagie, Edmond

AU - Ghobara, Tarek

AU - Gupta, Pratima

AU - Jurkovic, Davor

AU - Khalaf, Yacoub

AU - MacLean, Marjory

AU - McCabe, Chris

AU - Mulbagal, Khashia

AU - Nunes, Natalie

AU - Overton, Caroline

AU - Quenby, Siobhan

AU - Rai, Rajendra

AU - Raine-Fenning, Nick

AU - Robinson, Lynne

AU - Ross, Jackie

AU - Sizer, Andrew

AU - Small, Rachel

AU - Tan, Alex

AU - Underwood, Martyn

AU - Kilby, Mark

AU - Boelaert, Kristien

AU - Daniels, Jane

AU - Thangaratinam, Shakila

AU - Chan, Shiao-Yng

AU - Coomarasamy, Arri

PY - 2019/10/31

Y1 - 2019/10/31

N2 - 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.

AB - 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.

U2 - 10.3310/eme06110

DO - 10.3310/eme06110

M3 - Article

VL - 6

SP - 1

EP - 102

JO - Efficacy and Mechanism Evaluation

JF - Efficacy and Mechanism Evaluation

SN - 2050-4365

IS - 11

ER -