COMMENTARY

Subclinical Hypothyroidism and Infertility: Who Should Be Treated?

Peter Kovacs, MD, PhD

Disclosures

October 29, 2015

Subclinical Hypothyroidism in the Infertile Female Population: A Guideline

Practice Committee of the American Society for Reproductive Medicine
Fertil Steril. 2015;104:545-553

Why a New Guideline?

In recent years, accumulating evidence has suggested that the normal range for thyroid-stimulating hormone (TSH) levels should be lowered during pregnancy and a new category of subclinical hypothyroidism be created.[1] Since then, several reviews have dealt with the problem of TSH levels between 2.5 mIU/L and 4 mIU/L (or the upper normal value for the lab) and fertility and pregnancy outcomes.[2,3] This publication summarizes the recommendations of the American Society for Reproductive Medicine on the management of subclinical hypothyroidism in the infertile female patient.

Guideline Summary

Thyroid dysfunction can be classified as hypo- or hyperthyroidism. Hypothyroidism can be further classified as overt hypothyroidism (elevated TSH and low thyroid hormone levels) and subclinical hypothyroidism (SCH) (elevated TSH and normal thyroid hormone levels).

Most laboratories use an upper normal value for TSH between 4 mIU/L and 4.5 mIU/L. Some evidence suggests that the upper normal TSH level in pregnancy should be lowered to 2.5 mIU/L in the first trimester, 3 mIU/L in the second trimester, and 3.5 mIU/L in the third trimester.

Overt hypothyroidism is associated with infertility, miscarriage, and adverse pregnancy outcomes, and may result in delayed neurodevelopment in the fetus. Therefore, this condition requires treatment. The associations between SCH and infertility or pregnancy outcome are less obvious, however.

SCH can be further divided into persons with TSH levels above the upper limit of normal and those with TSH levels between 2.5 mIU/L and 4 mIU/L. SCH seems to be more common in infertile women (especially those with unexplained infertility) compared with the general population. Miscarriage rates are higher among women with SCH and a TSH level > 4 mIU/L, but the association is less clear in women with TSH levels between 2.5 mIU/L and 4 mIU/L.

Likewise, placental abruption, preterm delivery, and premature rupture of membranes are more common among women with SCH and TSH levels > 4 mIU/L, but perinatal outcomes of women with TSH levels between 2.5 mIU/L and 4 mIU/L have not yet been studied adequately.

The evidence is at best fair for an association between SCH with TSH levels > 4 mIU/L and neurodevelopmental delay, and there is no evidence for adverse central nervous system effects of SCH with TSH levels between 2.5 mIU/L and 4 mIU/L.

Women with SCH and TSH levels > 4 mIU/L who receive levothyroxine treatment have improved pregnancy rates and perinatal outcomes. The evidence is insufficient, however, on the impact of levothyroxine treatment on pregnancy rates or perinatal outcomes with TSH levels between 2.5 mIU/L and 4 mIU/L.

The presence of thyroid antibodies (primarily anti-thyroid peroxidase [anti-TPO]) is a main cause of SCH and hypothyroidism. The presence of anti-TPO antibodies is associated with higher miscarriage rates, and levothyroxine treatment lowers miscarriage rates, especially in women with a TSH level > 2.5 mIU/L.

In summary, women with overt hypothyroidism should receive proper thyroid replacement. Those with SCH and a TSH level > 4 mIU/L will benefit from levothyroxine supplementation. The goal of supplementation is to maintain the TSH level below 2.5 mIU/L.

Women with TSH levels between 2.5 mIU/L and 4 mIU/L and positive anti-TPO antibodies seem to benefit from levothyroxine supplementation, but there is no evidence that fertility or pregnancy outcomes improve with levothyroxine treatment in the absence of anti-TPO antibodies.

Viewpoint

Hypothyroidism affects up to 5% of women, and the incidence increases with age. Subclinical hypothyroidism, using a TSH cut-off of 4.5-5.0 mIU/L, affects 4%-8.5% of the US population; this condition also increases with age.[4] A small proportion of SCH cases will progress to overt hypothyroidism each year.[1]

The management of SCH can be controversial even in the nonpregnant population, but the decisions that we need to make during pregnancy or as part of the evaluation of an infertile woman are based on little scientific evidence.[1] Thyroid dysfunction may be detected among infertile women, especially those with ovulatory dysfunction, unexplained infertility, recurrent miscarriage, or other adverse obstetric outcome.

Many centers routinely screen patients by measuring TSH levels to detect subtle or overt thyroid disease. The management of overt hypothyroidism is straightforward. Up until the end of the first trimester, the developing embryo depends on maternal thyroid hormones, because the fetal thyroid gland will only start its secretory activity around week 11-13 of gestation. Hypothyroidism increases the risk for infertility and miscarriage, and has an adverse effect on fetal neurodevelopment. Thyroid supplementation improves all of these parameters.[5]

SCH with TSH levels > 4 mIU/L is also associated with adverse pregnancy and perinatal outcomes, and therefore thyroid supplementation is recommended.[3] The normal TSH level in the first trimester is < 2.5 mIU/L. There is limited, high-level scientific evidence that could guide the care of women who plan a pregnancy or are in the first trimester of a pregnancy and have values between 2.5 mIU/L and 4 mIU/L. Testing these women for thyroid antibodies could help with these clinical decisions.

Women with TSH levels between 2.5 mIU/L and 4 mIU/L and positive anti-TPO antibodies would most likely benefit from levothyroxine supplementation. In these women, the TSH level should be maintained below 2.5 mIU/L. Even if the benefit is not robust, the supplementation is associated with no to minimal risk.

Women who are antibody-negative most likely will not benefit from levothyroxine supplementation and therefore should not be treated. In these women, TSH levels could be monitored every 4-6 weeks, and if the TSH starts to rise, supplementation could be initiated. Future studies with larger sample sizes will hopefully provide more guidance for this group of women.

Abstract

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