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

doi:10.1016/j.cct.2015.08.005

Contemporary Clinical Trials

Volume 44, September 2015, Pages 134-138

https://doi.org/10.1016/j.cct.2015.08.005 Get rights and content

Abstract

Background

Thyroid peroxidase antibodies (TPO-Ab) in euthyroid women are associated with recurrent miscarriage (RM) and other pregnancy complications such as preterm birth. It is unclear if treatment with levothyroxine improves pregnancy outcome.

Aim

The aim of this study is to determine the effect of levothyroxine administration on live birth rate in euthyroid TPO-Ab positive women with recurrent miscarriage.

Methods/design

We will perform a multicenter, placebo controlled randomized trial in euthyroid women with recurrent miscarriage and TPO-Ab. Recurrent miscarriage is defined as two or more miscarriages before the 20th week of gestation. The primary outcome is live birth, defined as the birth of a living fetus beyond 24 weeks of gestation. Secondary outcomes are ongoing pregnancy at 12 weeks, miscarriage, preterm birth, (serious) adverse events, time to pregnancy and survival at 28 days of neonatal life. The analysis will be performed according to the intention to treat principle. We need to randomize 240 women (120 per group) to demonstrate an improvement in live birth rate from 55% in the placebo group to 75% in the levothyroxine treatment group. This trial is a registered trial (NTR 3364, March 2012).

Here we discuss the rationale and design of the T4-LIFE study, an international multicenter randomized, double blind placebo controlled, clinical trial aimed to assess the effectiveness of levothyroxine in women with recurrent miscarriage and TPO-Ab.

Introduction

Recurrent miscarriage represents a significant health problem. Approximately 5% of couples trying to conceive suffer recurrent miscarriage (RM) [1], [2]. Different definitions for RM have been described. In this article recurrent miscarriage has been defined as two or more – not necessarily consecutive – miscarriages [3], [4], [5], [6], [7], [8]. Known risk-factors for RM are parental chromosome abnormalities, uterine anomalies and antiphospholipid syndrome [1], [9]. Even after comprehensive investigations, no underlying risk factor for RM is identified in ≥ 50% of couples [1].

The presence of thyroid peroxidase antibodies (TPO-Ab) indicates a state of thyroid autoimmunity and is strongly associated with sporadic and recurrent miscarriages [10]. Thyroid autoimmunity is present in 8–14% among all women at reproductive age [11]. The presence of thyroid peroxidase antibodies is not only associated with miscarriage, but also with other adverse pregnancy outcomes such as unexplained subfertility, preterm birth and postpartum thyroiditis [10]. A higher prevalence of TPO-Ab is reported in women with recurrent miscarriage, varying from 19 to 36% [11], [12], [13], [14], [15], [16].

Given the high prevalence of TPO-Ab and its association with RM and other pregnancy complications, screening for thyroid dysfunction in the work-up for RM or during pregnancy is proposed, but not generally accepted. The current guidelines for RM of the European Society of Human Reproduction and Embryology (ESHRE 2006), the Royal College of Obstetricians and Gynecologists (RCOG 2011) and the ‘Nederlandse Vereniging voor Obstetrie en Gynaecologie’ (NVOG 2007), advise not to screen for thyroid antibodies because no evidence exists for an effective treatment intervention [4], [17], [18], [19]. The guidelines on thyroid disorders and pregnancy of the Endocrine Society Clinical Practice Guideline (ESCPG 2012) and the American Thyroid Association (ATA 2011) state that screening during pregnancy is not indicated because the treatment possibilities and effects for women with thyroid autoimmunity are thus far unclear [20], [21].

Two small, randomized studies, including a total of 160 women with thyroid antibodies evaluated the effect of levothyroxine (T4) treatment on pregnancy outcomes. One trial studied pregnant euthyroid women with thyroid antibodies. The other trial studied women with TPO-Ab undergoing assisted reproduction technologies [22], [23]. Both studies showed a reduction in miscarriage rates (36% and 75% relative reductions). One of the studies found a 69% relative risk reduction in preterm births. Both studies did not have an adequate sample size [22], [23]. Meta-analysis of these studies showed a non-significant reduction in miscarriage rate, but the studies were too small to draw robust conclusions [19].

Although current RM guidelines do not support the screening for thyroid disorders, since lack of evidence on effective treatment interventions, endocrinologists are eager to prescribe levothyroxine during pregnancy for euthyroid women with TPO-Ab [21], [24]. A recent European survey demonstrated that almost 80% of endocrinologists prescribe levothyroxine during pregnancy for women with TPO-Ab in combination with a normal Thyroid Stimulating Hormone (TSH) level [25]. This can result in unnecessary screening and treatment.

The aim of this study is to determine the effect of levothyroxine treatment on live birth rates and pregnancy complications in women with recurrent miscarriage and TPO-Ab. To achieve this, we designed an international randomized double blinded placebo controlled trial with inclusions in multiple centers.

Section snippets

Study sample

Women with unexplained recurrent miscarriage and thyroid autoimmunity are eligible for the study. Women aged 18 years until 42 years at randomization will be included. Recurrent miscarriage is defined as two or more, not necessarily consecutive, pregnancy losses before 20 weeks of gestational age [5], [6]. The definition of miscarriage included documentation of pregnancy by a positive pregnancy test and clinical manifestations of miscarriage (e.g., abdominal pain, cramps, and vaginal bleeding); it

Discussion

Thyroid autoimmunity is associated with miscarriage, recurrent miscarriage, preterm birth and postpartum thyroiditis. Miscarriage and preterm birth have a high prevalence. Miscarriage occurs in 10–15% of every pregnancy and preterm delivery occurs in 7% of all deliveries (12,000 cases in the Netherlands per year). Both conditions are associated with a high maternal and neonatal morbidity. Miscarriage has a high emotional impact and causes distress in the subsequent pregnancy [27]. If a

Conclusion

The T4-LIFE study is a double-blinded, placebo-controlled, randomized, multicenter, international trial that will generate novel data about the efficacy and safety of levothyroxine treatment in TPO-Ab positive women with recurrent miscarriage. If levothyroxine proves to be effective, it may justify screening for TPO-Ab in women with unexplained recurrent miscarriage followed by levothyroxine treatment to increase the live-birth rate. If levothyroxine is not effective, this could prevent

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

This work is supported by a Fonds Nutsohra grant (1104-002) and by ZonMw (Netherlands organization for health research and development, 836011012). Schildklier Organisaties Nederland (SON), the patient association of thyroid disorders and the Jan Dekkerstichting en dr. Ludgardine Bouwmanstichting have provided small grants.

References (29)

R. Rai et al.
Recurrent miscarriage
Lancet
(2006)
C.R. Jaslow et al.
Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses
Fertil. Steril.
(2010)
A.T. Iravani et al.
Thyroid autoimmunity and recurrent spontaneous abortion in Iran: a case–control study
Endocr. Pract.
(2008)
S.P. Kaandorp et al.
Aspirin plus heparin or aspirin alone in women with recurrent miscarriage
N. Engl. J. Med.
(2010)
Evaluation and treatment of recurrent pregnancy loss: a committee opinion
Fertil. Steril.
(2012)
M. Goddijn et al.
The guideline ‘recurrent miscarriage’ (first revision) of the Dutch Society for Obstetrics and Gynaecology
Ned. Tijdschr. Geneeskd.
(2008)
R.G. Farquharson et al.
Updated and revised nomenclature for description of early pregnancy events
Hum. Reprod.
(2005)
E. van den Boogaard et al.
Consecutive or non-consecutive recurrent miscarriage: is there any difference in carrier status?
Hum. Reprod.
(2010)
A.M. Kolte et al.
Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group
Hum. Reprod.
(2015)
T.C. Li et al.
Recurrent miscarriage: aetiology, management and prognosis
Hum. Reprod. Update
(2002)

E. van den Boogaard et al.

Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review

Hum. Reprod.

(2011)

G.E. Krassas et al.

Thyroid function and human reproductive health

Endocr. Rev.

(2010)

J. Roberts et al.

Recurrent miscarriage is associated with increased numbers of CD5/20 positive lymphocytes and an increased incidence of thyroid antibodies

Eur. J. Endocrinol.

(1996)

D. Glinoer et al.

Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders

J. Clin. Endocrinol. Metab.

(1994)

Cited by (27)

Levothyroxine in euthyroid thyroid peroxidase antibody positive women with recurrent pregnancy loss (T4LIFE trial): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
2022, The Lancet Diabetes and Endocrinology
Citation Excerpt :
A centralised and independent Data and Safety Monitoring Board provided trial oversight and monitoring. The study protocol has been published previously.16 Women were randomly assigned (1:1) to receive levothyroxine (levothyroxine group) or placebo (placebo group).
Women positive for thyroid peroxidase antibodies (TPO-Ab) have a higher risk of recurrent pregnancy loss. Evidence on whether levothyroxine treatment improves pregnancy outcomes in women who are TPO-Ab positive women with recurrent pregnancy loss is scarce. The aim of this study was to determine if levothyroxine increases live birth rates in women who were TPO-Ab positive with recurrent pregnancy loss and normal thyroid function.
The T4LIFE trial was an international, double-blind, placebo-controlled, phase 3 study done in 13 secondary and tertiary hospitals in the Netherlands, one tertiary hospital in Belgium, and one tertiary hospital in Denmark. Women (18–42 years) who were TPO-Ab positive, had two or more pregnancy losses, and had a thyroid stimulating hormone (TSH) concentration within the institutional reference range were eligible for inclusion. Women were excluded if they had antiphospholipid syndrome (lupus anticoagulant, anticardiolipin IgG or IgM antibodies, or β2-glycoprotein-I IgG or IgM antibodies), other autoimmune diseases, thyroid disease, previous enrolment in this trial, or contraindications for levothyroxine use. Before conception, women were randomly assigned (1:1) to receive either levothyroxine or placebo orally once daily. The daily dose of levothyroxine was based on preconception TSH concentration and ranged from 0·5–1·0 μg/kg bodyweight. Levothyroxine or placebo was continued until the end of pregnancy. The primary outcome was live birth, defined as the birth of a living child beyond 24 weeks of gestation measured in the intention-to-treat population. The trial was registered within the Netherlands Trial Register, NTR3364 and with EudraCT, 2011-001820-39.
Between Jan 1, 2013, and Sept 19, 2019, 187 women were included in the study: 94 (50%) were assigned to the levothyroxine group and 93 (50%) were assigned to the placebo group. The trial was prematurely stopped when 187 (78%) of the 240 predefined patients had been included because of slow recruitment. 47 (50%) women in the levothyroxine group and 45 (48%) women in the placebo group had live births (risk ratio 1·03 [95% CI 0·77 to 1·38]; absolute risk difference 1·6% [95% CI –12·7 to 15·9]). Seven (7%) women in the levothyroxine group and seven (8%) in the placebo group reported adverse events, none of them were directly related to the study procedure.
Compared with placebo, levothyroxine treatment did not result in higher live birth rates in euthyroid women with recurrent pregnancy loss who were positive for TPO-Ab. On the basis of our findings, we do not advise routine use of levothyroxine in women who are TPO-Ab positive with recurrent pregnancy loss and normal thyroid function.
Dutch Organization for Health Research and Development, Fonds NutsOhra, Dutch Patient Organization of Thyroid Disorders, the Jan Dekkerstichting and Dr Ludgardine Bouwmanstichting, and a personal donation through the Dutch Patient Organization of Thyroid Disorders.
Early and recurrent pregnancy loss: Etiology, Diagnosis, Treatment
2021, Comprehensive Gynecology
TPO antibody positivity and adverse pregnancy outcomes
2020, Best Practice and Research: Clinical Endocrinology and Metabolism
Citation Excerpt :
When adding the results of the TABLET trial and the trial by Wang et al. [61] to those of the Negro et al. trials [22,60], a meta-analysis of all the existing studies which have looked at levothyroxine to reduce miscarriage in women with thyroid antibodies shows no significant reduction compared with control (Fig. 2). There is currently an ongoing trial lead by Vissenberg et al. [63] in the Netherlands (T4LIFE). They have designed a double blind RCT looking at the use of Levothyroxine in TPOAb positive euthyroid women who have had recurrent miscarriage (defined as 2 or more consecutive losses).
Thyroid autoimmunity (TAI) is prevalent amongst women of reproductive age. TAI describes the presence of circulating anti-thyroid autoantibodies that are targeted against the thyroid, with or without thyroid dysfunction. Thyroid peroxidase antibodies (TPOAb) are the most common anti-thyroid autoantibodies. Around 10% of biochemically euthyroid individuals also have an elevated TPOAb titre. Many studies have linked the presence of TPOAb to adverse maternal and fetal outcomes in pregnancy, in particular miscarriage and pre-term birth, even in the absence of thyroid dysfunction. The causal pathway is poorly understood and few trials have looked to find treatments to reduce adverse outcomes. This review discusses in detail the associated adverse outcomes of TPOAb in pregnancy and the results of trials exploring methods to reduce such outcomes. Recommendations for counselling and monitoring of women with TPOAb and suggested areas for future work are also outlined.
Universal screening for thyroid disease SHOULD NOT be recommended before and during pregnancy
2020, Best Practice and Research: Clinical Endocrinology and Metabolism
Citation Excerpt :
Subgroup analyses were performed looking at the individual populations; no difference was seen for those with history of miscarriage or those with subfertility [24]. The T4-Life trial in the Netherlands is a randomized double blind placebo controlled trial on the effects of levothyroxine treatment in euthyroid TPO + women with recurrent miscarriage [25]. This trial is studying live birth rates as a primary endpoint and secondary outcome measures are miscarriage rate, preterm birth, survival at 28 days and effects of levothyroxine and results are awaited.
Thyroid dysfunction in pregnancy is strongly associated with adverse maternal and foetal outcomes. The effects of treatment are less clear. There is ongoing discussion on whom to treat, when to treat and whether treatment is beneficial. Although universal screening for thyroid disease during pregnancy increases diagnosis and treatment of thyroid dysfunction, there is currently insufficient evidence demonstrating a positive effect of screening on maternal and foetal outcomes. We therefore, at present, recommend against universal screening for thyroid disease before and during pregnancy.
Universal screening for thyroid disease during pregnancy should be performed
2020, Best Practice and Research: Clinical Endocrinology and Metabolism
Citation Excerpt :
No benefit of treatment was reported; however, these results may not be generalizable to fertile women. One additional multi-center, double-blinded, placebo-controlled, randomized controlled trials is currently underway, namely the T4-Life trial in the Netherlands [122]. This study will examine the effect of levothyroxine treatment for TPOAb positive, euthyroid women with a history of recurrent miscarriage on live birth rates, will provide additional evidence for or against treating TPOAb positivity in pregnancy.
Thyroid disease can significantly impact the pregnant woman and her child. Human and animal studies have firmly linked overt hypothyroidism and overt hyperthyroidism to miscarriage, preterm delivery and other adverse pregnancy outcomes. Overt hypothyroidism and overt hyperthyroidism affect 1% of all pregnancies. Treatment is widely available, and if detected early, results in decreased rates of adverse outcomes. Universal screening for thyroid disease in pregnancy can identify patients with thyroid disease requiring treatment, and ultimately decrease rates of complications. Universal screening is cost-effective compared to the currently accepted practice of targeted screening and may even be cost-saving in some healthcare systems. Targeted screening, which is recommended by most professional associations, fails to detect a large proportion of pregnant women with thyroid disease. In fact, an increasing number of providers are performing universal screening for thyroid disease in pregnancy, contrary to society guidelines. Limited evidence concerning the impact of untreated and treated subclinical disease and thyroid autoimmunity has distracted from the core rationale for universal screening – the beneficial impact of detecting and treating overt thyroid disease. Evidence supporting universal screening for overt disease stands independently from that of subclinical and autoimmune disease. The time to initiate universal screening is now.
Subclinical hypothyroidism and thyroid autoimmunity in recurrent pregnancy loss: a systematic review and meta-analysis
2020, Fertility and Sterility
Citation Excerpt :
They are registered either in the United States Clinical Trials Registry or the European Union Clinical Trials Registry. The T4-Life Study is a multicenter, randomized, double-blind, placebo-controlled trial investigating whether levothyroxine treatment of euthyroid, Dutch women with RPL, defined as two or more pregnancy losses before 20 weeks’ gestational age, who have tested positive for thyroid antibodies, will impact live-birth rates (66). The secondary outcomes will include ongoing pregnancy at 12 weeks, miscarriage, preterm delivery, adverse events, time to conception, and infant survival at 28 days.
To determine whether overt/subclinical hypothyroidism and/or thyroid autoimmunity is associated with recurrent pregnancy loss (RPL) and whether treatment improves outcomes.
Systematic review and meta-analysis.
University obstetrics and gynecology departments.
Women with RPL and overt/subclinical hypothyroidism, and/or thyroid autoimmunity.
None.
Associations between RPL and overt/subclinical hypothyroidism and/or thyroid autoimmunity and any effects of treatment.
After our review of articles from PubMed, EMBASE, Web of Science, and CENTRAL, we found two interventional studies in which levothyroxine did not improve the subsequent live-birth rate in women with subclinical hypothyroidism with or without thyroid antibodies. A meta-analysis of five studies revealed the prevalence of subclinical hypothyroidism in RPL to be 12.9% (95% confidence interval [CI], 0%–35.2%). A meta-analysis of 17 studies revealed a statistically significant association between RPL and thyroid autoimmunity (odds ratio 1.94; 95% CI, 1.43–2.64). However, a randomized study suggested that levothyroxine does not benefit euthyroid women with thyroid autoimmunity.
Based on the limited observational studies available, no association exists between RPL and subclinical hypothyroidism, nor does levothyroxine improve subsequent pregnancy outcomes. An association exists between RPL and thyroid autoimmunity, but levothyroxine does not improve subsequent pregnancy outcomes. Women with RPL should be screened/treated for overt thyroid disease but not thyroid autoimmunity. Thyroid antibody screening is not supported by the published studies, and further randomized studies are needed. No recommendation regarding the treatment of subclinical hypothyroidism can be made at this time; prospective and randomized studies are urgently needed.
Hipotiroidismo subclínico y autoinmunidad tiroidea en pérdida gestacional recurrente: una revisión sistemática y meta-análisis
Determinar si el hipotiroidismo clínico/subclínico y/o la autoinmunidad tiroidea están asociados con pérdida gestacional recurrente (RPL) y si su tratamiento mejora los resultados.
Revisión sistemática y meta-análisis.
departamentos universitarios de Obstetricia y Ginecología.
Mujeres con RPL e hipotiroidismo clínico o subclínico y/o autoinmunidad tiroidea.
ninguna.
Asociaciones entre RPL e hipotiroidismo clínico o subclínico y/o autoinmunidad tiroidea y algún efecto de su tratamiento.
después de revisar artículos de PubMed, EMBASE, Web of Science y CENTRAL, encontramos dos estudios de intervención en los cuales la levotiroxina no mejoró la tasa de recién nacido vivo en mujeres con hipotiroidismo subclínico con o sin anticuerpos tiroideos. Un meta-análisis de 5 estudios reveló que la prevalencia de hipotiroidismo subclínico en RPL era del 12,9% (95% intervalo de confianza (CI), 0%-35.2%). Un meta-análisis de 17 estudios reveló una asociación estadísticamente significativa entre RPL y autoinmunidad tiroidea (odds ratio 1.94; 95% CI, 1.43-2.64). Sin embargo, un estudio aleatorizado sugirió que la levotiroxina no beneficia a mujeres eutiroideas con autoinmunidad tiroidea.
basado en los estudios observacionales disponibles, no existe asociación entre RPL e hipotiroidismo subclínico, ni la levotiroxina mejora los resultados de la gestación subsecuente. Existe una asociación entre RPL y autoinmunidad tiroidea, pero la levotiroxina no mejora los resultados de la gestación subsecuente. Las mujeres con RPL deben ser valoradas y tratadas por enfermedad tiroidea clínica pero no por autoinmunidad tiroidea. El screening de anticuerpos anti tiroideos no se justifica en los estudios publicados y se necesitan más estudios aleatorizados. No pueden hacerse recomendaciones respecto al tratamiento de hipotiroidismo subclínico en este momento; se necesitan de forma urgente, estudios prospectivos aleatorizados.

View all citing articles on Scopus

View full text

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

Abstract

Background

Aim

Methods/design

Introduction

Section snippets

Study sample

Discussion

Conclusion

Competing interests

Acknowledgments

Lancet

Fertil. Steril.

Endocr. Pract.

Aspirin plus heparin or aspirin alone in women with recurrent miscarriage

N. Engl. J. Med.

Evaluation and treatment of recurrent pregnancy loss: a committee opinion

Fertil. Steril.

The guideline ‘recurrent miscarriage’ (first revision) of the Dutch Society for Obstetrics and Gynaecology

Ned. Tijdschr. Geneeskd.

Updated and revised nomenclature for description of early pregnancy events

Hum. Reprod.

Consecutive or non-consecutive recurrent miscarriage: is there any difference in carrier status?

Hum. Reprod.

Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group

Hum. Reprod.

Recurrent miscarriage: aetiology, management and prognosis

Hum. Reprod. Update

Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review

Hum. Reprod.

Thyroid function and human reproductive health

Endocr. Rev.

Recurrent miscarriage is associated with increased numbers of CD5/20 positive lymphocytes and an increased incidence of thyroid antibodies

Eur. J. Endocrinol.

Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders

J. Clin. Endocrinol. Metab.