By Robert W. Rebar, MD

Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo

Dr. Rebar reports no financial relationships relevant to this field of study.

SYNOPSIS: The current diagnosis and treatment of subclinical hypothyroidism in women of reproductive age is controversial and may well change as new studies become available.

Overt primary hypothyroidism is common in women. The diagnosis is simple to make, and the replacement therapy is simple to institute. What is not simple is what to do with individuals with so-called subclinical hypothyroidism (SCH). Even the definition of SCH is subject to question, and whether and when to institute treatment are controversial. Yet, this disorder has potential implications for infertility and for pregnancy.

Inconsistent Definitions

Generally speaking, SCH is defined as a normal serum free thyroxine (fT4) level in the presence of an elevated thyroid-stimulating hormone (TSH) level.1 The difficulty lies in determining just what is the upper limit of normal for TSH. According to the National Academy of Clinical Biochemistry, 95% of normal individuals without evidence of thyroid disease have a TSH concentration of < 2.5 mIU/L, with the normal range skewed to the right.2 Endocrine Society guidelines3 suggest that the reference range of a given laboratory should determine the upper limit of normal for a third-generation TSH assay. The normal TSH reference range changes with age. If there is no age-based reference range for a given assay in an iodine sufficient area, then the upper limit of normal should be considered to be 4.12 mIU/L in a nonpregnant individual. Despite this recommendation, most commercial laboratories regard 4.5 or even 5.0 mIU/L as the upper limit of the normal range. Because human chorionic gonadotropin (hCG) can bind to the TSH receptor and affect TSH levels, the Endocrine Society recommended further that the upper limit of TSH in pregnancy should change with the trimester, being 2.5 mIU/L in the first trimester, 3.0 mIU/L in the second trimester, and 3.5 mIU/L in third trimester. In 2017, the American Thyroid Association (with input from several societies, including the Endocrine Society and the American Congress of Obstetricians and Gynecologists) changed its recommendations from those similar to the Endocrine Society to suggest that 4.0 mIU/L be considered the upper limit of normal during pregnancy.4 Thus, there are disagreements regarding what should be considered the normal range.

What is more problematic is determining what should be the upper limit of normal in women attempting pregnancy. Some experts advocate using the earlier lower pregnancy thresholds for women who are attempting pregnancy (2.5 mIU/L) to minimize any potential risks associated with SCH.5 Unfortunately, the risks of SCH in pregnancy are debated and unclear. This is the case because of variability in the cutoffs for TSH used in the various studies reporting on SCH in pregnancy. These issues are particularly relevant for clinicians caring for infertile couples. Fortunately, the American Society for Reproductive Medicine (ASRM) provides some guidance here.

Who Should Be Screened?

After reviewing the literature, which is rife with large but poor studies with varying cutoff values for TSH, the ASRM concluded that, overall, there is good evidence against recommending universal screening of thyroid function before or during pregnancy.6 The Endocrine Society concurred with the recommendation against universal screening before pregnancy but was unable to reach consensus about screening during pregnancy.3 In an older document, the American College of Obstetricians and Gynecologists did not recommend routine screening for hypothyroidism in pregnancy.7 In all cases, screening women at high risk, including those with a family or personal history of thyroid disease, symptoms or physical findings suggestive of hypothyroidism or goiter, type 1 diabetes mellitus, infertility, history of miscarriage or preterm delivery, or history of autoimmune disorders generally is warranted.

The comment about individuals with a history of autoimmune disorders being at high risk warrants further discussion. Although measurement of anti-thyroid antibodies is not needed for the diagnosis of SCH, thyroid antibodies often are measured because their presence has been associated with an increased risk of later overt hypothyroidism.8 Although both antithyroglobulin and anti-thyroid peroxidase antibodies (anti-TPO-Abs) were present in 10-12% of the population, only anti-TPO-Abs were associated with thyroid dysfunction and thought to be of clinical importance.

What are the Implications of Not Treating SCH?

Although the data are controversial, there are no consistent data documenting that failure to treat women with TSH levels between 2.5 and 4.0 mIU/L leads to any increase in adverse obstetric outcomes. In a recent large, retrospective, observational study using a U.S. administrative claims database, a cohort of 5,405 pregnant women were identified as having SCH on the basis of a TSH test result between 2.5 and 10 mIU/L (in the presence of normal fT4) within four weeks before and three months after a first pregnancy visit claim. Only 16% of these women (n = 843) with a mean baseline TSH concentration of 4.8 mIU/L were treated with thyroid hormone, while the remainder (n = 4,562) were not.9 Treated women had 38% lower odds of pregnancy loss than did the untreated women. However, the treated women also had higher adjusted odds of preterm delivery (odds ratio [OR], 1.60), gestational diabetes (OR, 1.37), and preeclampsia (OR, 1.61). Notably, the odds of pregnancy loss were only significantly lower among those treated women with pre-treatment TSH levels between 4.1 to 10.0 mIU/L (OR, 0.45), but not among those treated women with pre-treatment TSH levels between 2.5 and 4.0 mIU/L. These findings suggest the need for counseling individuals with SCH about both the benefits and risks of replacement thyroid hormone treatment. Despite these findings, an accompanying editorial by two eminent thyroidologists noted that the early initiation of low-dose therapy with levothyroxine for SCH during pregnancy, as recommended by the American Thyroid Association, “may be of benefit, is inexpensive, and is unlikely to be harmful.”1

One of the most important reasons cited for treating individuals with SCH during pregnancy is to prevent abnormalities in the resulting offspring. In 1999, a widely publicized study noted that 62 children of women whose serum TSH levels during pregnancy were greater than the 98th percentile had lower full-scale IQs (by 7 points) than 124 children of matched controls with normal TSH levels.10 Subsequent studies have not all been confirmatory. In one of the largest studies to date, investigators at 15 sites in the NIH’s Maternal–Fetal Medicine Network screened more than 97,000 women with a singleton pregnancy before 20 weeks’ gestation to identify those with SCH, defined as a thyrotropin level of 4.00 mU/L and a normal fT4 level, and for hypothyroxemia, defined as a normal thyrotropin level (0.08 to 3.99 mU/L) and a low fT4 (< 0.86 ng/dL).11

In two separate trials, 677 women with SCH and 526 with hypothyroxemia randomly received either levothyroxine or placebo beginning at a mean of 16.7 and 17.8 weeks’ gestation, respectively. The median IQ score of the children at 5 years of age with the use of the Wechsler Preschool and Primary Scale of Intelligence III (WPPSI-III) did not differ in either trial between the treated and untreated groups. In addition, there were no significant differences between groups in either trial for neurodevelopmental and behavioral outcomes in the children, and the incidence of adverse events during pregnancy did not differ and was low in all groups.

These latest results should not be viewed as surprising because the fetal thyroid axis becomes functional in utero between 12 and 16 weeks’ gestation. In addition, basing SCH solely on the results of imprecise and controversial clinical testing is problematic. Still, these latest large studies do not provide us with clear evidence about any benefit of treatment of SCH during pregnancy.

Final Thoughts

Putting these thoughts together is not easy. It would seem reasonable to test women presenting for preconceptual counseling or because of infertility. It also would make sense to test women with previous miscarriages and pregnancy losses, as well as those at high risk of thyroid disease, as noted previously. Because there is fair evidence that thyroid autoimmunity is also associated with infertility and miscarriage, the ASRM further recommends levothyroxine for women with anti-TPO-Abs, especially those with TSH levels > 2.5 mIU/L.6 Thus, it makes sense to obtain anti-TPO-Abs in any woman with TSH > 4.0 mIU/L and in infertile women with TSH levels > 2.5 mIU/L. The data also support levothyroxine therapy for women with TSH levels > 4.0 mIU/L just because the risks are low. Finally, it is clear that this is an evolving field and that future data may well lead to modifications in these recommendations — as well as in my own thoughts about SCH.

REFERENCES

  1. Cooper DS, Pearce EN. Subclinical hypothyroidism and hypothyroxemia in pregnancy – still no answers. N Engl J Med 2017;376:876-877.
  2. Baloch Z, et al. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003;13:3-126.
  3. Garber JR, et al. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract 2012;18:988-1028.
  4. Alexander EK, et al. 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 2017;27:315-389.
  5. Haddow JE, et al. The reference range and within-person variability of thyroid stimulating hormone during the first and second trimesters of pregnancy. J Med Screen 2004;11:170-174.
  6. Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: A guideline. Fertil Steril 2015;104:545-553.
  7. Committee on Patient Safety and Quality Improvement; Committee on Professional Liability. ACOG Committee Opinion No. 381. Subclinical hypothyroidism in pregnancy. Obstet Gynecol 2007;110:959-960.
  8. Vanderpump MP, et al. The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995;43:55-68.
  9. Maraka S, et al. Thyroid hormone treatment among pregnant women with subclinical hypothyroidism: US national assessment. BMJ 2017;356:i6865. doi:10.1136/bmj.i6865.
  10. Haddow JE, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999:341:549-555.
  11. Casey BM, et al. Treatment of subclinical hypothyroidism or hypothyroxemia in pregnancy. N Engl J Med 2017;376:815-825.