A variety of endocrine disorders can complicate pregnancy and vice versa. Diabetes mellitus is the most prevalent and is discussed in Chapter 52. Thyroid disorders are also common, and a number of less common endocrinopathies—for example, pheochromocytoma—can have devastating effects on pregnancy outcome. The pathogenesis of many endocrinopathies is disordered autoimmunity. And as with most organ-specific autoimmune disorders, clinical manifestations of endocrinopathies result from a complex interplay among genetic, environmental, and endogenous factors that activate the immune system against target cells (Weetman, 2004). In many cases, a nonspecific event such as a viral infection initiates an organ-specific response with subsequent immune-mediated glandular destruction. Also, studies implicating cells transferred between mother and fetus during pregnancy in development of autoimmune disease decades later represent a new investigative frontier (Muraji and associates, 2008; Rust and Bianchi, 2009).
Taken in aggregate, thyroid disorders are common in young women. There is an intimate relationship between maternal and fetal thyroid function, and drugs that affect the maternal thyroid also affect the fetal gland. Thyroid autoantibodies have been associated with increased early pregnancy wastage, and uncontrolled thyrotoxicosis and untreated hypothyroidism are both associated with adverse pregnancy outcomes (Männistö and colleagues, 2009). Finally, there is evidence that the severity of autoimmune thyroid disorders is ameliorated during pregnancy, only to be exacerbated postpartum.
Thyroid Physiology and Pregnancy
The impact of pregnancy on maternal thyroid physiology is substantial. Changes in the structure and function of the gland sometimes cause confusion in the diagnosis of thyroid abnormalities. These are discussed in greater detail in Chapter 5, Endocrine System, and normal hormone level changes are found in the Appendix. Maternal serum concentration of thyroid-binding globulin is increased concomitantly with total or bound thyroid hormone levels (Fig. 5-16). Thyrotropin, or thyroid-stimulating hormone (TSH), currently plays a central role in screening and diagnosis of many thyroid disorders. Serum thyrotropin levels in early pregnancy decrease because of thyroid stimulation from the weak TSH effects of human chorionic gonadotropin (hCG) (Grossman and associates, 1997). TSH does not cross the placenta. At the same time, hCG serum levels are maximal for the first 12 weeks, free thyroxine levels increase to suppress pituitary thyrotropin secretion (Fig. 53-1). Accordingly, thyrotropin-releasing hormone (TRH) is undetectable in maternal serum. Fetal serum TRH is detectable beginning at midpregnancy, but does not increase.
Gestational age-specific values for serum thyroid-stimulating hormone (TSH) levels (black lines) and free thyroxine (T4) levels (blue lines). Data were derived from 17,298 women tested during pregnancy. For each color, the dark solid lines represent the 50th percentile, whereas the upper and lower light lines represent the 2.5th and 97.5th percentiles, respectively. (Data from Casey and colleagues, 2005; Dashe and co-workers, 2005.)
Throughout pregnancy, maternal thyroxine is transferred to the fetus (Calvo and associates, 2002; Vulsma and colleagues, 1989). Maternal thyroxine is important for normal fetal brain development, especially prior to development of fetal thyroid gland function (Bernal, 2007). And even though the fetal gland begins concentrating iodine and synthesizing thyroid hormone after 12 weeks, maternal thyroxine contribution remains important. In fact, maternal thyroxine accounts for 30 percent of thyroxine in fetal serum at term (Thorpe-Beeston and colleagues, 1991; Vulsma and co-workers, 1989). Developmental risks associated with maternal hypothyroidism after midpregnancy remain poorly understood (Morreale de Escobar and colleagues, 2004).
Autoimmunity and Thyroid Disease
Most thyroid disorders are inextricably linked to the presence of autoantibodies to various cell components. A number of these antibodies variably stimulate thyroid function, block function, or cause thyroid inflammation that may lead to follicular cell destruction. Oftentimes, these effects overlap or even coexist.
Thyroid-stimulating autoantibodies, also called thyroid-stimulating immunoglobulins (TSI), bind to the thyrotropin receptor and activate it, causing thyroid hyperfunction and growth. Although these antibodies are identified in most patients with classic Graves disease, simultaneous production of thyroid-stimulating blocking antibodies may blunt this effect (Weetman, 2000). Thyroid peroxidase antibodies, previously called thyroid microsomal autoantibodies, have been identified in 5 to 15 percent of all pregnant women as shown in Figure 53-2 (Casey and colleagues, 2007; Kuijpens and co-workers, 2001). These antibodies have been associated with early pregnancy loss (Abramson and Stagnaro-Green, 2001). Conversely, women with antibodies identified in the first half of pregnancy did not have increased rates of poor pregnancy outcomes (Casey and colleagues, 2008). These women are, however, at high risk for postpartum thyroid dysfunction and at lifelong risk for permanent thyroid failure (Hidaka and associates, 1994; Premawardhana and co-workers, 2000).
Incidence of antithyroid peroxidase antibodies in women who are euthyroid; in those with isolated maternal hypothyroxinemia (IMH), defined by a normal serum thyroid-stimulating hormone (TSH) value and serum free thyroxine (T4) level < 0.86 ng/dL; in those with subclinical hypothyroidism (SH), defined as serum TSH value ≥ 3.0 mU/L with a normal reference range serum free T4 level; and in those with overt hypothyroidism defined by an abnormally high serum TSH value with an abnormally low serum free T4 level. (Data from Casey and associates, 2007.)
Autoimmune thyroid disease is much more common in women than in men. One intriguing explanation for this disparity is fetal-to-maternal cell trafficking. When fetal lymphocytes enter the maternal circulation, they can live for more than 20 years. Stem cell interchange also seems likely with engraftment in a number of maternal tissues to include the thyroid (Bianchi and Romero, 2003; Khosrotehrani and associates, 2004). Such maternal microchimerism with male fetuses has been identified in some women who have the SRY sex-determining gene. Up to a third of women who have borne a ...