Is there enough evidence of poor fetal growth to merit narrowing free T4 reference ranges during pregnancy

Thyroid function undergoes profound changes during pregnancy, with enlargement of the thyroid gland, up to 50% increase in thyroid hormone production and in iodine requirements, changes in thyroid hormone binding proteins, as well as decreases in TSH due to direct thyroidal stimulation by human chorionic gonadotropin (1). Maternal hypothyroidism and hyperthyroidism during pregnancy are associated with increases in maternal and fetal morbidity, and hypothyroidism and hypothyroxinemia are also associated with adverse cognitive development in offspring (1–3). The American Thyroid Association and The Endocrine Society both recommend measuring serum TSH concentration in women with high risk for or with symptoms of hypothyroidism or hyperthyroidism to diagnose thyroid diseases during pregnancy as well as when adjusting levothyroxine treatment in hypothyroid pregnant patients (1–3). Both guidelines note the importance of measuring free T4 concentrations in distinguishing between overt and subclinical thyroid disease as well as in adjusting antithyroid drug treatment in patients with Graves' disease, but they also note the potential for error when measuring free T4 concentrations by immunoassays in pregnant patients (1–3). The guidelines suggest that each laboratory should establish trimester-specific reference intervals of free T4, use calculations of free T4 index, measure total T4, or preferably use the “gold standard” method of measuring free T4 in the dialysate or ultrafiltrate of serum samples with liquid chromatography-tandem mass spectrometry (1–3). Most studies evaluating pregnant women with thyroid diseases have used laboratory-specific measures of free T4 rather than the gold standard and place a higher emphasis on serum TSH concentrations in the diagnoses of thyroid diseases. This approach clearly limits the quality of evidence regarding the possible adverse effects of changes in free T4 concentrations within the established reference intervals (1–3). In the current issue of the JCEM, Medici et al. (4) show that increases in early pregnancy free T4 concentrations in euthyroid women within assay- and pregnancy-specific reference intervals increased the odds of having infants that were small for gestational age and infants with low birth weight. More specifically, they found that high-normal early pregnancy free T4 concentrations (between 17.01 and 22.00 pmol/liter) were associated with reduced growth in the fetus, resulting in 116 g lower birth weight and 2.8-fold increased odds for infants weighing less than 2500 g compared with free T4 concentrations in the lowest quintile (between 10.38 and 12.80 pmol/liter). Similar results have been previously shown by Shields et al. with high-normal free T4 in late pregnancy associated with lower birth size (5). Both studies measured free T4 concentrations only once during pregnancy, an inherent limitation when trying to evaluate possible mechanisms underlying this association. In addition, although Medici et al. (4) employed appropriate statistical methods to estimate the relation between early pregnancy free T4 levels and longitudinally measured fetal growth, they might suffer from some selection bias because 15% of their original cohort had missing data on birth weight, and the comparability of free T4 levels among those with missing data was not reported. Do these studies suggest that we should redefine “normal” for free T4 concentrations in pregnancy or start measuring free T4 levels in all pregnant women? No, we are not there yet. Although an association between both early and late pregnancy high-normal free T4 and lower birth size has been demonstrated, we are far from showing causality or a strength of association that merits action. First, errors in the measurement of free T4 must be overcome. The gold standard measures are not used in studies estimating association between thyroid dysfunction and adverse pregnancy outcomes, and free T4 immunoassays are prone to interference by changes in thyroid hormone binding protein concentrations during pregnancy (1–3). There is little correspondence between the free T4 immunoassay results and those from the gold standard method, although both express the typical pattern of pregnancy-related changes in thyroid function (6, 7). If we assume that the immunoassays are reliable (although not valid), each study is comparing an internal laboratory standard “high” to “low,” but results are not comparable across studies. We cannot rationally discuss changing the ranges for pregnancy without better basic data. Second, we are limited by a lack of information on the dynamic changes in free T4 in relation to fetal growth. Free T4 levels increase during early pregnancy and decrease afterward with a large range of expected decrease (1.7–33.3%) (8). It is therefore plausible that women with high-normal free T4 levels in early pregnancy could have normal levels later or women with normal free T4 early in gestation do not exhibit the typical decrease later in pregnancy. We do not know whether isolated incidences of high-normal free T4 levels are associated with lower birth size or whether a more constant elevation leads to this adverse outcome. With respect to mechanisms, the association between overt maternal hyperthyroidism and low birth weight is well-established (1–3) and might be due to the passage of maternal free T4 through the placenta, leading to thyrotoxicosis and a catabolic state in the fetus. Indeed, healthy infants of women with thyroid hormone resistance during pregnancy had lower birth weight and low cord blood TSH levels indicating thyrotoxicosis, possibly due to high maternal free T4 expression in pregnancy without symptoms of hyperthyroidism (9). Whether high-normal free T4 levels have the ability to produce fetal thyrotoxicosis remains unknown. Given the lack of data on mechanisms as well as the concerns about measurement and timing of high levels, lowering the free T4 reference intervals in pregnant women or screening all pregnant women for free T4 cannot be recommended. We are accumulating evidence on defining normal TSH levels during pregnancy, but even there we have many unanswered questions, especially regarding the treatment of subclinical hypothyroidism in preventing adverse pregnancy and neonatal outcomes (1–3). The current study by Medici et al. (4) is an important step in building an evidence base for defining “normal” free T4 levels during pregnancy, but we need to do more. There is an urgent need for randomized and even observational studies that begin before pregnancy and collect longitudinal serum samples during pregnancy. We need to do a better job of defining normal thyroid function during gestation and need more data to determine the optimal treatment for women with thyroid dysfunction during pregnancy. Screening all women for TSH and possibly for free T4 could lead to substantial benefits if poor fetal growth can be prevented, but we can't move forward on clinical recommendations without better evidence.