Fetal and placental growth depends on maternal thyroid hormones (TH) early in pregnancy. As a result, pathological processes that alter maternal TH status can result in adverse outcomes for both mother and baby. Given the complicated nature of thyroid function testing in pregnancy, laboratories should implement reflex testing algorithms that incorporate appropriate tests, methods, and reference intervals to guide screening of high-risk patients. Implementing guideline-driven algorithms for thyroid function testing in pregnancy is critical to improve quality of care for these women.

Understanding Thyroid Dysfunction

Thyroid dysfunction is classified as either hypo or hyperthyroidism and further categorized as overt or subclinical disease. The general characteristics of these disease states are summarized in Table 1. It is important to note that clinical definitions of these states vary, leading to complications in interpreting thyroid function results and in defining cutoffs necessary to initiate appropriate treatment regimens. The relationship between thyroid stimulating hormone (TSH) and free thyroxine (fT4) is defined as inverse log/linear, where small perturbations in fT4 are associated with large changes in TSH. Thus, TSH quantitation is preferred as the primary screening strategy to assess thyroid function.

Overt thyroid disease in pregnancy is associated with several negative outcomes. Untreated overt hypothyroidism can result in preterm birth, low birth weight, miscarriage, stillbirth, placental abruption, preeclampsia, heart failure, and impaired neurocognitive development (3). Overt hypothyroidism also has both pre-pregnancy and postpartum consequences for affected mothers, including infertility and depression.

Overt hyperthyroidism in pregnancy causes some of the same problems, including preterm birth, miscarriage, intrauterine growth restriction, low birth weight, preeclampsia, thyroid storm, and heart failure. In fact, high concentrations of fT4 may be as detrimental to neurocognitive development as low fT4 (3). Autoimmune disease, called Graves’ disease, is the most common cause of overt hyperthyroidism in pregnancy. Transient hyperthyroidism secondary to significantly elevated human chorionic gonadotropin (hCG) occurs with hyperemesis gravidarum or molar pregnancies. Beyond untreated thyroid disease, over-treatment also raises concerns as anti-thyroid drugs cross the placenta and act on the fetal thyroid, complicating clinical management. The consequences of subclinical thyroid disease are highly debated and will be discussed in the following section.

Who Should Undergo Thyroid Function Testing in Pregnancy?

Experts continue to debate whether universal screening for thyroid function in pregnancy is necessary. Several randomized cohort studies have attempted to produce compelling evidence to settle this debate. Unfortunately, none of the recent large randomized controlled trials has produced sufficient data to support a clinical need for universal screening nor have they detected significant neurocognitive defects in children whose mothers had subclinical hypothyroidism in pregnancy.

Both the American College of Obstetricians and Gynecologists (ACOG) (2015) and the American Thyroid Association (ATA) (2017) clinical practice guidelines support screening of women at high risk for thyroid dysfunction before they become pregnant, or early in pregnancy (1,2). The recent European Thyroid Association guidelines concur with the ATA and ACOG regarding universal screening; however, these guidelines note that while not formally recommended, most of the authors support universal screening given that a substantial number of women with thyroid dysfunction may be missed with targeted screening strategies (4).

In the era of targeted screening approaches, identifying women considered high risk for thyroid dysfunction during pregnancy is essential. In addition to women with pre-existing thyroid disease (e.g. Graves’ or Hashimoto’s diseases) or family history of thyroid disease, women with clinical signs and/or symptoms of thyroid disease should also be screened.

Approximately 18% of all women are categorized in the highest-risk group for overt hypothyroidism in pregnancy. This group consists of women who are thyroid peroxidase antibody (TPOAb) or thyroglobulin antibody (TgAb) positive (1). In addition to the risk to the developing fetus, TPOAb positive mothers are also at a higher risk of developing postpartum thyroid dysfunction.

Other risk factors associated with higher prevalence of thyroid disease include: women older than age 30, those with type 1 diabetes or other autoimmune disorders, a history of infertility, previous therapeutic head or neck irradiation, a history of miscarriage or preterm birth, high body mass index, and those living in an area with iodine insufficiency. The Endocrine Society also indicates that thyroid status (TSH and TPOAb) should be evaluated in women with type 1 diabetes prior to conception when possible. (5)

Selecting the Best Assays

Changes in thyroid biochemistry during pregnancy lead to several challenges for both testing and interpreting the results of thyroid function tests. TSH and fT4 concentrations differ over the course of pregnancy, so results should be evaluated in the context of trimester-specific reference intervals (TSRI). Further, pregnancy-induced changes in binding protein concentrations and glycosylation status affect some testing methodologies for TSH and fT4. The gold standard assay for assessing fT4 during pregnancy is equilibrium dialysis liquid chromatography-tandem mass spectrometry (LC-MS/MS). This methodology is impractical in most hospital laboratories, so immunoassay methods (IA) are used instead.

Concerns over reliability of fT4 immunoassays during pregnancy are mostly related to discordance with TSH results, particularly in the third trimester and attributed to increased concentrations of thyroid binding globulins and free fatty acids (3). This perceived discrepancy has led to a debate among experts about the best assay to use to assess thyroid hormone concentrations in pregnancy.

Studies that directly compare fT4 measurements on IA platforms with gold standard methods such as LC-MS/MS found that the changes in fT4, i.e. decreases with gestational age, are consistent across methods. These findings suggest that fluctuating fT4 concentrations are physiological changes within the hypothalamic-pituitary-thyroidal axis and not assay related (7). Despite this, the ATA recommends that total T4 (TT4) or the fT4 index be utilized as secondary markers to TSH in evaluating thyroid disease, while ACOG recommends fT4. Unfortunately, both the TT4 and the fT4 index represent obsolete estimations of fT4 concentrations and have been replaced by more accurate IA and LC-MS/MS platforms (7).

A clear advantage of IA over equilibrium dialysis-tandem LC-MS/MS is its high-throughput, which is critical in high-volume medical centers. While IA and the gold standard methods for fT4 in pregnancy have an acceptable correlation, there is significant variability across assay platforms. Therefore, most guidelines recommend interpreting TSH and fT4 in the context of assay-specific and TSRI (1,2). This is daunting because statically defining the 2.5th and 97.5th percentile necessary for encompassing non-Gaussian, skewed distributions of TSH and fT4 in pregnancy requires hundreds of population-specific, healthy women with singleton pregnancies, per trimester, per assay (8). As an alternative, guidelines provide fixed reference ranges for TSH and fT4 values for each trimester. Using these values provides its own set of challenges, as several studies demonstrate that these ranges lead to over-diagnosis of thyroid disease.

Developing a Diagnostic Testing Algorithm

There are many recommendations for diagnosing and monitoring thyroid dysfunction, and they continually evolve. To ensure rapid and accurate diagnosis and monitoring of thyroid dysfunction, many clinical laboratories have adopted evidence-based reflex testing algorithms.

At the University of Kentucky, we created a diagnostic testing algorithm based on our review of recent clinical practice guidelines, laboratory medicine literature, and best practices (Figure 2). We reviewed recent clinical practice guidelines from ACOG, ATA, Society for Maternal-Fetal Medicine, and Endocrine Society (2,3,5,6). Most of their general recommendations agreed, especially related to screening, reference intervals, and treatment strategies. There were differences in which assays and/or algorithms to utilize as discussed previously, and in these cases we consulted laboratory medicine literature and in-house studies to make our recommendations.

To assess compliance with evidence-based practice and estimate the need for diagnostic testing algorithms for thyroid dysfunction in pregnancy, we conducted a comprehensive review of ordering practices of thyroid function testing in normal pregnancies at one large academic medical center. We reviewed laboratory information system (LIS) records for all pregnant patients presenting to obstetric or midwifery practices during a 6-month period (12/1/2014–5/30/2015) to assess thyroid function test ordering patterns and compliance with evidence based-practice guidelines. Patients were excluded from the study if they were younger than age 18, pregnant with multiples, and/or had a history of thyroid disease. We also reviewed electronic medical records from the 1,672 included patients to determine follow-up to thyroid function testing results and pregnancy outcomes. We defined guideline compliance as screening with TSH and then reflexing to fT4 testing in patients with abnormal TSH considered in the context of TSRI.

We found that adherence to practice guidelines for thyroid function testing in pregnancy was inconsistent. Of particular concern were the TSH values that were abnormally high using TSRIs but normal in non-pregnant terms, as these values could indicate hypothyroidism. In this population, 94% did not have indicated fT4 testing or any other follow-up (Figure 3). Further, in those individuals with low TSH—considered abnormal in non-pregnant women but normal for a pregnant patient—inappropriate and/or unnecessary follow-up occurred 50% of the time.

A root cause analysis revealed that the lack of adherence was twofold: 1) TSH and fT4 were bundled in an electronic order set for first time prenatal labs, and 2) TSRIs were not considered. Screening for thyroid dysfunction in pregnancy was indiscriminate and differed by practice because it was order set driven.

Conclusion

In the absence of universal screening recommendations, laboratories should outline carefully defined screening parameters to guide clinicians in determining when it is appropriate to screen for thyroid dysfunction in pregnancy. After identifying high-risk patients, screening for thyroid dysfunction in pregnancy should begin with a TSH measurement, followed by assessment of fT4 if TSH is abnormal using TSRIs. If overt thyroid disease is identified, assessment of thyroid antibody status should also be evaluated as this knowledge helps direct care particularly in the postpartum period.

Given the dependence of the developing fetus on maternal thyroid function, particularly early in pregnancy, as well as the severity of outcomes in untreated thyroid disease, appropriate screening should take place as early as possible such that the proper treatment course can be administered. If a patient’s thyroid antibody status is known to be positive, or if a patient has an autoimmune disease, thyroid screening should take place before conception if possible and be monitored appropriately throughout pregnancy.

Methodology is also important. While there are advantages to equilibrium dialysis and LC-MS/MS analysis of thyroid function tests in pregnant women, these methods are generally impractical in high-volume clinical settings. IAs are a practical way to assess thyroid function as results are reported and interpreted in the context of assay-specific and TSRIs that are representative of the local patient population.

In all these areas, patients rely on the unique expertise of clinical laboratorians to guide testing and help ensure patients receive timely and effective treatment.

Alison Woodworth, PhD, DABCC, FAACC, is medical director of the core clinical laboratory and point-of-care testing and an associate professor of pathology and laboratory medicine at the University of Kentucky Medical Center in Lexington. Email: Alison.Woodworth@uky.edu

Erin E. Schuler, PhD, is a clinical chemistry fellow at the University of Kentucky Medical Center in Lexington.Email: Erin.E.Schuler@uky.edu

**Correction: Due to a copyediting error, Figure 2 "Diagnostic Algorithm for Assessing Thyroid Function in Pregnancy, " linked high TSH and low FT4 to overt hyperthyroidism. In fact, high TSH and low FT4 indicate overt hypothyroidism. The figure in this version of the article has been corrected. CLN regrets the error.

References

  1. Korevaar TIM, Medici M, Visser TJ, et al. Thyroid disease in pregnancy: New insights in diagnosis and clinical management. Nat Rev Endocrinol 2017;13:610-22.
  2. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 2017;27:315-89.
  3. The American College of Obstetricians and Gynecologists. Practice bulletin: Thyroid disease in pregnancy. Obstet Gynecol 2015;125:996-1005.
  4. Lazarus J, Brown RS, Daumerie C, et al. 2014 European Thyroid Association guidelines for the management of subclinical hypothyroidism in pregnancy and in children. Eur Thyroid J 2014;3:76-94.
  5. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism 2012; 97 (8): 2543–2565.
  6. The Society for Maternal Fetal Medicine. Screening for thyroid disease during pregnancy. Contemporary OB/GYN 2012; 45-47.
  7. Gronowski AM. Evaluation of thyroid function during pregnancy: Have we taken a wrong turn? Clin Chem 2018;64:439-41.
  8. Medici M, Korevaar TIM, Visser WE, et al. Thyroid function in pregnancy: What is normal? Clin Chem 2015;61:704-13.
  9. Colby J, Lee L, Adams B, and Woodworth A. Screening for thyroid dysfunction in pregnancy - Review and update to laboratory utilization practices at one major academic medical center [Abstract]. Thyroid 2015;25:A-220.