Do Preconception Subclinical Hypothyroidism and Thyroid Autoimmunity Predict Pregnancy in Infertile Women?

By Julie Tantibhedhyangkul, MD

Subclinical hypothyroidism, defined as a thyroid stimulation hormone (TSH) level greater than the upper limit of normal (4.5 -5.0 mIU/L) with a normal free thyroxine (FT4) level, is associated with miscarriage and adverse pregnancy outcomes1.

As the TSH reference range is lowered during pregnancy, some have suggested an upper limit TSH of 2.5 mIU/L for infertility patients. This suggestion is despite unclear evidence that TSH levels of 2.5-4 mIU/L increase the risk of miscarriage or poor obstetrical outcomes in this population.

A secondary analysis of two multicenter trials

A recent presentation at the 71st annual meeting of the American Society for Reproductive Medicine further explored this question. This study, supported by the NICHD Reproductive Medicine Network (RMN), examined the association between thyroid measures and pregnancy outcomes in infertile women2. The findings are derived from a secondary analysis of previous RMN studies.

• PPCOS II (Pregnancy in Polycystic Ovary Syndrome II): a multicenter, randomized, controlled trial comparing clomiphene citrate to letrozole treatments in PCOS patients
• AMIGOS (Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation): A multicenter, randomized, controlled trial comparing gonadotropins, clomiphene citrate and letrozole treatments in combination with intrauterine insemination in women with unexplained infertility

In the current study, baseline TSH and thyroid peroxidase antibodies (anti-TPO) levels were measured from 1,459 blood samples provided by participants in both trials prior to initiating treatments. Women taking thyroid supplements were excluded from the analysis.

Looking at conception, miscarriage and live births

Outcomes measures for this study included conception rate, miscarriage rate, and live birth rate. Investigators found no difference in the conception rate, miscarriage rate or live birth rate between women with TSH levels < 2.5 mIU/L and those with TSH levels ≥ 2.5 mIU/L.

Although conception rates were no different in women with positive and negative anti-TPO antibodies, women with positive anti-TPO showed a higher rate of miscarriage and a lower live birth rate when compared to women with negative anti-TPO.

The investigators concluded that preconception subclinical hypothyroidism is not associated with adverse reproductive outcomes, but that positive anti-TPO antibodies are associated with an increased miscarriage rate and decreased live birth rates in infertile women.

Levothyroxine treatment questioned

Current ASRM recommendations for women with preconception TSH of 2.5 – 4 mIU/L include either immediate treatment with levothyroxine to maintain TSH level < 2.5 mIU/L, or monitoring levels and initiating treatment when the TSH level is > 4 mIU/L. This study suggests that routine levothyroxine treatment may not be beneficial, especially in women with negative anti-TPO.

Current evidence (including results from this study) shows an association between thyroid autoimmunity and miscarriage. Levothyroxine treatment might improve pregnancy outcomes, especially in women with TSH >2.5 mIU/L. However, routine anti-TPO testing is not currently recommended unless TSH level is > 2.5 mIU/L or other risk factors for thyroid disease are present.

More studies are needed to determine the benefit of levothyroxine treatment in euthyroid women with thyroid autoimmunity.

References

1. Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril. 2015 Sep;104(3):545-53.
2. Seungdamrong AM, Steiner A, Gracia C, et al. Antithyroid antibodies but not thyroid stimulating hormone, are associated with decreased pregnancy rates in infertile women. In: the American Society for Reproductive Medicine Meeting: 2015 Oct 20: Baltimore, MA. O-92.

Dr. Tantibhedhyangkul is a member of the Section of Reproductive Endocrinology and Infertility in Cleveland Clinic’s Department of Obstetrics and Gynecology. She can be reached at tantibj@ccf.org or 216.839.3150.