T4Life trial.

Rationale:

The presence of thyroid antibodies in euthyroid women is strongly associated with recurrent miscarriage (RM) and pregnancy complications like preterm birth and postpartum thyroiditis. Until now no randomized controlled trial exists for endocrine treatment of women with recurrent miscarriage and thyroid autoimmunity. Thyroid peroxidase antibodies (TPO-Ab) are present in 4-14% of fertile women. In clinical practice, thyroid antibodies can be found in women with RM. High prevalences have been described varying from 20 till 36%. But although thyroid hormone supplementation is sometimes prescribed in this subgroup, it is still unclear whether treatment will actually improve pregnancy outcomes. Therefore, we have designed a randomized double blind placebo controlled clinical trial to assess the efficacy of thyroid hormone supplementation, as compared with placebo, on the live birth rate in women with at least 2 preceding miscarriages and the effect on adverse pregnancy complications.



Objective:

To assess improvement in live birth rate and pregnancy outcome after levothyroxine supplementation.



Study design:

Randomised double blind placebo controlled multi centre clinical trial.



Study population:

Women with recurrent miscarriage, i.e. at least 2 miscarriages, aged 18-42 years. Women will be recruited in the Netherlands (Coordinating Centre Academic Medical Centre, Amsterdam) and internationally.



Intervention:

The intervention group receives levothyroxine, and the control group receives placebo of identical appearance.



Main study parameters/endpoints:

Primary outcome measure: live birth rate.
Secondary outcome measures: miscarriage rate, preterm birth, any maternal or neonatal adverse pregnancy outcomes.



Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Women with RM receive standard diagnostic care. The risks and burden of participating in the trial are small. After a complete diagnostic work-up for recurrent miscarriage, the women will be randomized for preconceptual use of levothyroxine versus placebo. The outcome of that particular next pregnancy will be followed. The (minimal) risk of participation is the risk of thyroid hormone use. Substantial evidence exists that thyroid hormone supplementation is safe to the mother and foetus as a treatment for hypothyroidism. For the indication thyroid autoimmunity, clinicians sometimes already prescribe levothyroxine; no adverse effects are known or reported in the literature. And no adverse effects have been described in studies of women with thyroid autoimmunity being treated with levothyroxine.
Women are euthyroid and are given a small dose of levothyroxine; we expect the thyroid hormone levels to stay in the reference interval.

In euthyroid women with thyroid autoimmunity and recurrent miscarriage, levothyroxine started preconceptional, increases live births beyond 24 completed weeks by at least 20%, compared to placebo.

1. 12 weeks of pregnancy;

2. 24 weeks of pregnancy;

3. End of pregnancy.

Levothyroxine tablets started preconceptually after diagnostic work up for recurrent miscarriage till the end of the next pregnancy.