Clinical Review

2017 Update on fertility

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Optimal management of subclinical hypothyroidism in women with infertility

Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril. 2015;104(3):545-553.

Thyroid disorders long have been associated with the potential for adverse reproductive outcomes. While overt hypothyroidism has been linked to infertility, increased miscarriage risk, and poor maternal and fetal outcomes, controversy has existed regarding the association between subclinical hypothyroidism (SCH) and reproductive problems. The ASRM recently published a guideline on the role of SCH in the infertile female population.

How is subclinical hypothyroidism defined?

SCH is classically defined as a thyrotropin (TSH) level above the upper limit of normal range (4.5−5.0 mIU/L) with normal free thyroxine (FT4) levels. The National Health and Nutrition Examination Survey (NHANES III) population has been used to establish normative data for TSH for a disease-free population. These include a median serum level for TSH of 1.5 mIU/L, with the corresponding 2.5 and 97.5 percentiles of 0.41 and 6.10, respectively.19 Data from the National Academy of Clinical Biochemistry, however, reveal that 95% of individuals without evidence of thyroid disease have a TSH level <2.5 mIU/L, and that the normal reference range is skewed to the right.20 Adjusting the upper limit of the normal range to 2.5 mIU/L would result in an additional 11.8% to 14.2% of the United States population (22 to 28 million individuals) being diagnosed with hypothyroidism.

This information raises several important questions.

1. Should nonpregnant women be treated for SCH?

No. There is no benefit from the standpoint of lipid profile or alteration of cardiovascular risk in the treatment of TSH levels between 5 and 10 mIU/L and, therefore, treatment of individuals with TSH <5 mIU/L is questionable. Furthermore, the risk of overtreatment resulting in bone loss is a concern. The Endocrine Society does not recommend changing the current normal TSH range for nonpregnant women.

2. What are normal TSH levels in pregnant women?

Because human chorionic gonadotropin (hCG) can bind to and affect the TSH receptor, thereby influencing TSH values, the normal range for TSH is modified in pregnancy. The Endocrine Society recommends the following pregnancy trimester guidelines for TSH levels: 2.5 mIU/L is the recommended upper limit of normal in the first trimester, 3.0 mIU/L in the second trimester, and 3.5 mIU/L in the third trimester.

3. Is untreated SCH associated with miscarriage?

There is fair evidence that SCH, defined as a TSH level >4 mIU/L during pregnancy, is associated with miscarriage, but there is insufficient evidence that TSH levels between 2.5 and 4 mIU/L are associated with miscarriage.

4. Is untreated SCH associated with infertility?

Limited data are available to assess the effect of SCH on infertility. While a few studies show an association between SCH on unexplained infertility and ovulatory disorders, SCH does not appear to be increased in other causes of infertility.

5. Is SCH associated with adverse obstetric outcomes?

Available data reveal that SCH with TSH levels outside the normal pregnancy range are associated with an increased risk of such obstetric complications as placental abruption, preterm birth, fetal death, and preterm premature rupture of membranes (PPROM). However, it is unclear if prepregnancy TSH levels between 2.5 and 4 mIU/L are associated with adverse obstetric outcomes.

6. Does untreated SCH affect developmental outcomes in children?

The fetus is solely dependent on maternal thyroid hormone in early pregnancy because the fetal thyroid does not produce thyroid hormone before 10 to 13 weeks of gestation. Significant evidence has associated untreated maternal hypothyroidism with delayed fetal neurologic development, impaired school performance, and lower intelligence quotient (IQ) among offspring.21 There is fair evidence that SCH diagnosed in pregnancy is associated with adverse neurologic development. There is no evidence that SCH prior to pregnancy is associated with adverse neurodevelopmental outcomes. It should be noted that only one study has examined whether treatment of SCH improves developmental outcomes (measured by IQ scored at age 3 years) and no significant differences were observed in women with SCH who were treated with levothyroxine versus those who were not.22

7. Does treatment of SCH improve miscarriage rates, live-birth rates, and/or clinical pregnancy rates?

Small randomized controlled studies of women undergoing infertility treatment and a few observational studies in the general population yield good evidence that levothyroxine treatment in women with SCH defined as TSH >4.0 mIU/L is associated with improvement in pregnancy, live birth, and miscarriage rates. There are no randomized trials assessing whether levothyroxine treatment in women with TSH levels between 2.5 and 4 mIU/L would yield similar benefits to those observed in women with TSH levels above 4 mIU/L.

8. Are thyroid antibodies associated with infertility or adverse reproductive outcomes?

There is good evidence that the thyroid autoimmunity, or the presence of TPO-Ab, is associated with miscarriage and fair evidence that it is associated with infertility. Treatment with levothyroxine may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L.

9. Should there be universal screening for hypothyroidism in the first trimester of pregnancy?

Current evidence does not reveal a benefit of universal screening at this time. The American College of Obstetricians and Gynecologists does not recommend routine screening for hypothyroidism in pregnancy unless women have risk factors for thyroid disease, including a personal or family history of thyroid disease, physical findings or symptoms of goiter or hypothyroidism, type 1 diabetes mellitus, infertility, history of miscarriage or preterm delivery, and/or personal or family history of autoimmune disease.

The bottom line

SCH, defined as a TSH level greater than the upper limit of normal range (4.5&#8722;5.0 mIU/L)with normal FT4 levels, is associated with adverse reproductive outcomes including miscarriage, pregnancy complications, and delayed fetal neurodevelopment. Thyroid supplementation is beneficial; however, treatment has not been shown to improve long-term neurologic developmental outcomes in offspring. Data are limited on whether TSH values between 2.5 mIU/L and the upper range of normal are associated with adverse pregnancy outcomes and therefore treatment in this group remains controversial. Although available evidence is weak, there may be a benefit in some subgroups, and because risk is minimal, it may be reasonable to treat or to monitor levels and treat above nonpregnant and pregnancy ranges. There is fair evidence that thyroid autoimmunity (positive thyroid antibody) is associated with miscarriage and infertility. Levothyroxine therapy may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L. While universal screening of thyroid function in pregnancy is not recommended, women at high risk for thyroid disease should be screened.23

WHAT THIS EVIDENCE MEANS FOR PRACTICEClinicians should be aware of the risks and benefits of treating subclinical hypothyroidism in female patients with a history of infertility and miscarriage.

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