Effect of levothyroxine on live birth rate in euthyroid women with recurrent miscarriage and TPO antibodies (T4-LIFE study)

Vissenberg, Rosa; Dijk, Myrthe M. van; Fliers, Eric; Post, Joris A. M. van der; Wely, Madelon van; Bloemenkamp, Kitty W. M.; Hoek, Annemieke; Kuchenbecker, Walter K. H.; Verhoeve, Harold R.; Scheepers, Hubertina C.J.; Weerd, Sabina Rombout-de; Koks, Carolien A.M.; Zwart, Joost J.; Broekmans, Frank J.; Verpoest, Willem; Christiansen, Ole Bjarne; Post, Marinka S.; Papatsonis, Dimitri; Verberg, M.F.G.; Sikkema, J.; Mol, Ben Willem J.; Bisschop, Peter H.; Goddijn, Mariëtte

doi:10.1016/j.cct.2015.08.005

Cited by 31 publications

(18 citation statements)

References 26 publications

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“…neurocognitive deficits in offspring (42,43), serve as a reminder of the need for randomised controlled trials both with regard to screening strategies and treatment options (i.e. levothyroxine) (2,44). A recent prospective randomised controlled trial published by Negro et al (45) did not find a reduced miscarriage rate in TPOAb-positive women treated with levothyroxine.…”

Section: Discussionmentioning

confidence: 99%

Increase in thyroglobulin antibody and thyroid peroxidase antibody levels, but not preterm birth-rate, in pregnant Danish women upon iodine fortification

Bliddal¹,

Boas

Hilsted

et al. 2017

European Journal of Endocrinology

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Section: Discussionmentioning

confidence: 99%

Increase in thyroglobulin antibody and thyroid peroxidase antibody levels, but not preterm birth-rate, in pregnant Danish women upon iodine fortification

Bliddal¹,

Boas

Hilsted

et al. 2017

European Journal of Endocrinology

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“…64 There is an ongoing trial, the T4-LIFE study, that is, a multicenter, placebo controlled randomized trial looking at levothyroxine administration in euthyroid women with recurrent miscarriage and positive TPO-Abs to see if there is an effect on live birth rates. 65 In summary, studies to date do not support the treatment of euthyroid women with positive antibodies during pregnancy. In the ATA 2017 guidelines, they state that there is insufficient evidence to determine whether levothyroxine therapy decreases pregnancy loss risk in TPO Ab-positive women and treatment in those with a previous loss could be considered.…”

Section: Effects On Pregnancy Outcomesmentioning

confidence: 98%

Maternal thyroid disease and its effects on the fetus and perinatal outcomes

Huget-Penner

Feig

2020

Prenatal Diagnosis

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Thyroid disease is common in women of childbearing age and can have significant effects on the development of the fetus and perinatal outcomes. Maternal thyroid hormone is critical for proper fetal neurodevelopment, and the fetus relies on thyroid hormone from its mother for the first half of pregnancy. Both overt maternal hypothyroidism and overt maternal hyperthyroidism have been shown to be associated with adverse effects on central nervous system gray matter and neurocognitive development of offspring as well as increased obstetrical risks. Treatment of overt thyroid conditions improves outcomes. Subclinical maternal hypothyroidism may increase adverse neurocognitive and obstetrical outcomes although data are conflicting. To date, treatment of subclinical hypothyroidism has not shown benefit. Subclinical hyperthyroidism is well tolerated in pregnancy. Thyroid autoantibodies alone may also affect neurodevelopment and obstetrical outcomes; however, recent data have shown no improvement with levothyroxine treatment. Several rare maternal genetic thyroid conditions can affect the fetus including a thyroid‐stimulating hormone receptor mutation leading to hypersensitivity to human chorionic gonadotropin and thyroid hormone resistance. The thyroid plays a crucial role in fetal health and understanding it is important for optimal care.

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“…Unlike the T4-LIFE study, 10 we did not titrate the dose to the baseline TSH or women's weight. The BNF suggests that thyroxine doses for hypothyroidism may need to be increased in pregnancy, but does not suggest a dosing algorithm.…”

Section: Possibly Suboptimal Dosementioning

confidence: 99%

“…Since the initiation of the TABLET trial, a further two randomised trials 10,11 have evaluated levothyroxine treatment for thyroid antibodies. Vissenberg et al 10 have designed a double-blind, randomised controlled trial (T4-Life) evaluating the use of levothyroxine in TPOAb-positive euthyroid women who have had recurrent miscarriages (defined as two or more consecutive losses). This trial is still in the recruitment phase and so the results are not yet available.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Effect of levothyroxine on live birth rate in euthyroid women with recurrent miscarriage and TPO antibodies (T4-LIFE study)

Cited by 31 publications

References 26 publications

Increase in thyroglobulin antibody and thyroid peroxidase antibody levels, but not preterm birth-rate, in pregnant Danish women upon iodine fortification

Increase in thyroglobulin antibody and thyroid peroxidase antibody levels, but not preterm birth-rate, in pregnant Danish women upon iodine fortification

Maternal thyroid disease and its effects on the fetus and perinatal outcomes

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

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