Levothyroxine and treatment of other thyroid disorders
Thyroid disease is associated with ovulatory dysfunction, reduced rates of conception, miscarriage and adverse pregnancy and early neonatal outcomes (33). Hypothyroidism is a disease which prevalence increases, particularly in women, as they get older (34). As with the older average age of women undergoing ART, there are more patients likely to be on levothyroxine therefore it is important to establish the safety of this drug. One retrospective study analysed reproductive outcomes of euthyroid women compared to women with hypothyroidism on levothyroxine undergoing ART and found that despite the treated group having significantly lower implantation rates, both groups had similar pregnancy rates and miscarriage rates, irrespective of age (35).
Recently, guidelines have been updated as evidence suggests that even subclinical hypothyroidism, where patients are asymptomatic and bloods tests are borderline, should be treated in order to improve reproductive outcomes for patients undergoing ART (33, 36). Chung-Hoon K et al. performed a prospective randomised control trial involving 64 patients and found that levothyroxine treatment can improve embryo quality and pregnancy outcome in subclinical hypothyroid women undergoing ART compared to those who received placebo (37).
Pelliccione F et al. performed a retrospective study on the outcomes of levothyroxine-supplemented women with subclinical hypothyroidism. They analysed 6545 cycles from 4147 women and found that there was no discernible difference between implantation or pregnancy rates between the treated and untreated women. The study did note that the benefit of levothyroxine was that it mitigated the negative effects on the thyroid axis from controlled ovarian stimulation (38).
However, a double-blinded placebo controlled multicentre trial which randomised 19585 euthyroid women with positive thyroid peroxidase antibodies and history of previous miscarriage or infertility to 50 mcg thyroxine or placebo noted no significant difference in the live birth rate or other pregnancy and neonatal outcomes (39). Patients with clinical or subclinical hypothyroidism should have thyroid stimulating hormone levels maintained at less than 2.5mU/L pre-conception (which is lower than the normal range, 0.4 to 4 mU/L, for non-pregnant women) and throughout pregnancy to optimise reproductive outcomes (40).
Hyperthyroidism is thought to affect 2.3% of women presenting with subfertility compared to 1.5% of the general population (33). Most of these women present with oligomenorrhoea or polymenorrhoea and the impact of treatment of hyperthyroidism prior to and during ART is yet to be assessed. Commonly radioiodine treatment is used in these patients and no adverse effect on gonadal function or neonatal outcomes have been noted as long as radioiodine treatment has occurred at least 6 months prior to pregnancy. Thyroid dysfunction occurs less commonly in males compared to females however has been linked to male factor infertility. Further research is required on the treatment of thyroid disease in male partners and ART outcomes (41).