The attraction of reproductive endocrinology and infertility (REI), personally, is the hormonal interplay of the hypothalamus and pituitary with the end organs that are intimately involved in female reproduction. While the sex hormone–producing organs, such as the ovaries and adrenal glands, are directly related to reproductive function, the thyroid gland is typically overlooked until dysfunction occurs, resulting in ovulation dysfunction and pregnancy complications, namely miscarriage and preterm labor. This month we address thyroid function, given its vital role for fertility and pregnancy health and the fetus’ reliance on maternal thyroid hormone during the first trimester to ensure normal neurologic development.
Dr. Mark P. Trolice
Thyroid disease is the second most common endocrine disorder affecting women of reproductive age; the first being polycystic ovary syndrome (PCOS). Thyroid dysfunction can impair ovulation and, consequently, fertility. Hyperthyroidism is found in approximately 2.3% of women presenting with fertility problems, compared with 1.5% of women in the general population. Hypothyroidism affects 0.5% of women of reproductive age and has been shown to result in impaired reproductive outcomes, including miscarriage, along with adverse obstetric and fetal outcomes. Subclinical hypothyroidism (SCH), defined as an elevated thyroid-stimulating hormone (TSH) level with a normal free T4, has an incidence of 4%-8% in the reproductive-age population. While there is fair evidence SCH increases miscarriage, treatment may result in improved outcomes.
The prevalence of thyroid autoimmunity (TAI) among women of reproductive age is 8%-14% worldwide and it is increased in the infertility population. TAI, defined as the presence of thyroid peroxidase and thyroglobulin antibodies, has been shown to be associated with a reduced live birth rate, increase in preterm birth, and a two- to threefold increase in miscarriage.
The endocrinologic “pendulum” of guidance regarding the effect on and management of thyroid function regarding fertility, pregnancy, and baby has conflicting results. Controlled ovarian hyperstimulation for in vitro fertilization appears to alter TSH levels and levothyroxine requirements increase in the first trimester by approximately 50%. The controversy lies in which population of women should be tested for TAI, which TSH level is acceptable, and how to manage, if at all, euthyroid women with TAI or women with SCH who are trying to conceive. Ultimately, which women would benefit from levothyroxine while trying to conceive and during pregnancy?
Summary of salient studies
- In a meta-analysis, untreated women with SCH had a higher prevalence of miscarriage, compared with euthyroid women (RR, 1.90). Miscarriage rates were even higher in SCH with TIA, compared with women with SCH. The authors recommend “early treatments to avoid adverse pregnancy outcomes and complications.”
- A randomized controlled trial from China studied women who were euthyroid with TAI undergoing IVF. The authors demonstrated levothyroxine did not reduce miscarriage rates or increase live birth rates. To dive further into their cohort, the authors addressed whether TSH above 2.5 mIU/L or above 4 mIU/L (per the American Society for Reproductive Medicine cutoff values) impaired reproductive outcome and found no benefit of levothyroxine in any subgroup. This is consistent with other studies that showed no detrimental effect on pregnancy outcome with TSH levels above 2.5 mIU/L in the normal range and no reduction in miscarriage with the addition of levothyroxine.
- An observational cohort study of IVF patients that underwent preimplantation genetic testing for aneuploidy did not demonstrate an association between chromosomally normal embryos that miscarried and maternal antithyroid antibodies in recurrent miscarriage patients.
- A double-blind, placebo-controlled trial on the use of levothyroxine in euthyroid women with TAI did not result in a higher rate of live births, lower rate of pregnancy loss, or preterm birth, compared with placebo.