Women's Health - Thyroid Function During Pregnancy

Laboratory Evaluation and Clinical Implications

Frank A. Quinn, Ph.D.

Proper maternal thyroid function during pregnancy is important for the health of both the mother and developing child (1). This is especially true during the first trimester, when the fetus is completely dependent on the mother for thyroid hormone. However, thyroid disorders are common in women of child-bearing age. Worldwide, maternal iodine deficiency is a common cause of thyroid dysfunction that can have serious consequences for the mother and child, and although progress has been made to ensure proper maternal iodine nutrition, there are many areas of the world (including developed countries) where pregnant women do not have an adequate intake of iodine (2). Overt hypo- and hyperthyroidism have long been known to have a significant impact on maternal/fetal health, and in recent years, there has been a growing awareness that even mild or “subclinical” forms of thyroid disease (e.g., elevated thyroid stimulating hormone (TSH) with normal free thyroxine) are associated with adverse outcomes for both the mother and child. Elevated serum TSH has been associated with increased risk of pre-term birth, placental abruption, fetal death, and impaired neuro-psychological development in the child (3, 4, 5). The presence of antibodies to thyroid peroxidase (TPO-Ab) has been associated with an increased risk of pre-term birth, miscarriage, and maternal post-partum thyroid disease (6, 7). These findings have been the cause of much discussion, because laboratory evidence of thyroid dysfunction is common in women of child-bearing age. For example, Canaris et al. (8) reported the prevalence of elevated TSH in women aged 18 - 45 years ranged from 4 to 9% and Hollowell et al. (9) reported the prevalence of TPO-Ab in women aged 20 – 49 years as 11.3 – 18%. Therefore, in order to ensure optimal maternal/fetal health, it is important to understand maternal thyroid status during pregnancy. However, pregnant women with thyroid disease do not always develop symptoms, and when they do, these symptoms are sometimes attributed to the pregnancy itself (10). In these situations, laboratory testing takes on an even greater significance in the assessment of maternal thyroid function.

Pregnancy produces a series of profound physiologic changes in the mother that have a significant effect on maternal thyroid function (see Table 1). These changes can, in turn, complicate the interpretation of maternal thyroid function tests (11). For these reasons, the National Academy of Clinical Biochemistry (NACB) in the United States recommend that “trimester specific reference values should be used when reporting thyroid test values for pregnant patients” (12). In order for these reference intervals to be relevant, they must be determined using well characterized specimens, and the NACB guidelines call particular attention to the fact that specimens used for such studies should not contain thyroid auto-antibodies (i.e., TPO-Ab, Tg-Ab). The question of what represents a “normal” TSH value during pregnancy has also been a topic of discussion in the recent literature. For healthy, non-pregnant populations, it has been suggested that the widely used upper reference limit for TSH of approximately 4.5 mIU/L is likely too high, and that a value of 2.5 may be more appropriate (12). This value has also been proposed as a conservative upper limit of normal during the first trimester of pregnancy (13). Additionally, subnormal TSH values can be seen in up to 20% of pregnancies during the first trimester (13). These changes in reference values are more than analytical curiosities, as illustrated in a recent report by Dashe et al. (14). In their study, they found that 28% of women with TSH values above the gestational week specific 97.5th percentile would not have been identified if a TSH upper reference limit of 4.0 mIU/ml had been used. Similarly, if a lower TSH reference limit of 0.4 mIU/ml had been used, 11% of euthyroid women would have been incorrectly identified as abnormal. Clearly, trimester specific reference intervals for thyroid hormones have the potential to improve interpretation of thyroid function test results in pregnant women.

Given the adverse outcomes associated with maternal thyroid dysfunction, considerable discussion has focused on the possibility that screening pregnant women for thyroid disease could improve outcomes for both the mother and child. Recently, a task force created by the American Association of Clinical Endocrinology (AACE), the American Thyroid Association (ATA), and The Endocrine Society (TES) issued the following consensus statement: “ … we favor routine screening for subclinical thyroid dysfunction in adults, including pregnant women, and those contemplating pregnancy. We also strongly agree with an aggressive approach to case-finding in patients presenting with symptoms and/or signs that suggest the possibility of thyroid dysfunction” (15). Similarly, the NACB recommends that “pre-pregnancy or first trimester screening for thyroid dysfunction using serum TSH and TPO-Ab measurements is important for both detecting mild thyroid insufficiency and for assessing the risk of post-partum thyroiditis” (13). Although several professional societies recommend screening of pregnant women for thyroid disease, this approach remains controversial (15, 16). Opponents of screening point to the lack of controlled clinical trails demonstrating efficacy for screening and subsequent treatment (14). Although it is worth mentioning that conducting such trials on pregnant women poses significant logistic obstacles. Recently, Negro and colleagues reported on their prospective trial in which thyroxine therapy in pregnant women positive for TPOAb significantly reduced rates of both premature birth and miscarriage (17). These provocative data await confirmation by other investigators. Until further studies are conducted, even opponents of screening support “aggressive case-finding … in pregnant women … and others at high risk for thyroid dysfunction.”(16). However, this approach is not without difficulty, given the overlap between signs and symptoms of thyroid disease and those of impending motherhood. In addition, a recent study by Vaidya et al. reported that targeted thyroid function testing of only high risk pregnant women (i.e., case-finding) would miss about one-third or pregnant women with overt of subclinical hypothyroidism (18). This prompted an editorial accompanying their article to state, “When the potential adverse outcomes are so significant, and the tools to diagnose and intervene are easily accessible … leaving maternal thyroid disease undiagnosed, even in one-third of pregnant women, is no longer acceptable.” (19). Regardless of how this debate is resolved, several groups of women are at increased risk for thyroid disease during pregnancy and warrant particular vigilance – including those with a personal or family history of thyroid disease, type 1 diabetes, other auto-immune disorders, established hypothyroidism prior to pregnancy, and women of South Asian ancestry (18). For these women, it is recommended that they have “measurement of serum TSH preferably prior to pregnancy or early in gestation” (20). In particular, pregnant women with previously diagnosed hypothyroidism require careful monitoring, and many will likely need an increase in their levothyroxine dosage to address the increased demands that pregnancy places on the thyroid (10).

Much is known about the important relationship between maternal thyroid status and the health of the mother and developing child – however, much remains to be discovered. It is clear that there is room for improvement in the diagnosis, treatment, and management of thyroid dysfunction in women during and after pregnancy. This situation is perhaps best reflected in a recent public health statement from the American Thyroid Association, “A coordinated program of patient education, practice review, and research on the impact of maternal thyroid status on pregnancy and fetal and childhood development should be instituted …” (21). Whatever the future holds, it seems certain the clinical laboratory will continue to play a central, if not increasing, role in the assessment of maternal thyroid status during pregnancy.

This article is based on one which first appeared in APFCB News 2006, the newsletter of the Asian and Pacific Federation of Clinical Biochemistry.

Frank A. Quinn, Ph.D., is Director of Global Scientific Affairs for Abbott Diagnostics. In this role, he is responsible for coordinating research, publications, and medical education programs in the fields of endocrinology, autoimmunity, and maternal health. Dr. Quinn has more than 20 years experience in the development and evaluation of immunoassays for a variety of applications. He received his Ph.D. in Chemistry/Biochemistry from the University of Texas at Austin, and his B.S. in Chemistry from the University of Florida. He is a member of the American Association for Clinical Chemistry, the American Thyroid Association, and the Endocrine Society.

Table 1. Physiologic and thyroid function test changes associated with pregnancy

Physiologic Change	Thyroid function test change
↑ Estrogen production	↑ Total T4, Total T3 (reference range 1.5x non-pregnant values)
↑ Thyroxine binding globulin (peak at 20 weeks)	↑ TSH (nadir 10 – 12 weeks)
↑ hCG (peak at 10 – 20 weeks)	↑ Free T4 (modest) – 1st trimesterß ↓ Free T4, Free T3 – 2nd, 3rd trimesters(20 – 40% below normal mean)
↑ Iodine clearance, requirement
↑ T4 and T3 degradation

Adapted from: Brent GA, Clin Obstet Gynecol 1997;40:3-15 and Demers LM, Spencer CA. Thyroid 2003;13:10-11.

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