Levothyroxine for euthyroid women with recurrent miscarriage and positive TPO antibodies: a randomized controlled trial

Recurrent miscarriage (RM) represents a significant health problem. When the
definition of RM includes two or more miscarriages, about 5% of couples trying
to conceive suffer from RM. A cause for RM is identified in less than 50% of
couples.
Unexplained recurrent miscarriage is a condition that affects at least 1300
couples in the Netherlands every year.
Thyroid autoimmunity is prevalent among women of reproductive age and is
associated with miscarriage, recurrent miscarriage, preterm birth and maternal
post partum thyroiditisTPO-Ab are present in 4-14 % of fertile women. In
clinical practice, thyroid antibodies can be found in women with RM. Different
prevalence*s have been described varying from 19 till 36 %. Given the high
prevalence of TPO-Ab and its association with adverse pregnancy outcomes, is
screening for thyroid dysfunction proposed, but not generally accepted. But the
treatment possibilities and effects for women with autoimmunity are thus far
unclear.
One trial studied levothyroxine therapy for pregnant euthyroid women with
TPO-Ab: a significantly decrease in preterm birth en miscarriage rate was
found. This trial didn*t study recurrent miscarriage.
Because no trial is available specific on the topic of recurrent miscarriage we
want to perform a RCT on levothyroxine supplementation for women with recurrent
miscarriage and thyroid autoimmunity.

First objective: To assess improvement in live birth rate after levothyroxine
supplementation.
Secondary objective: 1) to test the hypothesis that levothyroxine lowers the
risk for miscarriage and preterm birth 2) to test the hypothesis that
levothyroxine, compared to placebo, does not incur substantial adverse effects
to the mother or the neonate, time to pregnancy (defined as the interval
between thyroid function test and the month of conception of the next
pregnancy).

Randomised, double-blind, placebo controlled multicenter study

All women will be randomly allocated to receive either levothyroxie tabelts
once a day taken orally, or receive placebo tablets. Women will start with
medication from the beginning of the study till the end of their next
pregnancy.

Women with RM receive standard diagnostic care. The risks and burden of
participating in the trial are little. The women will use levothyroxine or
placebo after finishing the diagnostic work up for recurrent miscarriage and no
other cause has been found. The outcome of that particular 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 suscribe levothyroxine, no adverse
effects are known or described in the literature. Also in earlier studies women
with thyroid autoimmunity have been treated with levothyroxine, no adverse
effects have been described.

We will monitor the maternal thyroid function in the first and second
trimester to make sure it will stay between the reference intervals for a
normal thyroid function.