The one salient finding of this study that included nearly 25,000 pregnant women was that those identified to have subclinical hypothyroidism had a significantly increased risk for development of severe preeclampsia when compared with euthyroid women. This association is particularly strong because its significance persisted after adjustment for factors known to increase preeclampsia risks, such as age, parity, race, and weight.26,27 There are a number of observations that support the biological plausibility of this association. These include the cardiovascular effects of abnormal concentrations of thyroid hormones, the adverse pregnancy outcomes reported for women with overt hypothyroidism, other vascular-related pregnancy complications that have been linked to subclinical hypothyroidism, and, finally, endothelial cell activation from abnormal amounts of thyroid hormones.
Regarding the first observation, there are well-documented widespread cardiovascular effects in nonpregnant women who secrete abnormal amounts of thyroid hormones. Those that are genomically mediated include transcription of structural and regulatory proteins within myocytes that stimulate cell growth.1 Nongenomic direct T4 actions include increased cardiac contractility and decreased systemic vascular resistance. Also, with prolonged exposure to either abnormally excessive or decreased amounts of hormone, ventricular hypertrophy can lead to heart failure.1,2,28 Up to one fourth of overtly hypothyroid individuals are hypertensive, with a decreased pulse pressure, slowed diastolic filling, decreased ventricular filling and contractility, and increased systemic vascular resistance.1,2 Although less well-studied, there is evidence that subclinical hypothyroidism in some, usually older, patients can cause hypertension, heart failure, and atherosclerotic vascular disease.1,6,8,29 Finally, subclinical hypothyroidism has been shown to cause endothelial cell dysfunction characterized by diminished nitric oxide production with impaired vasorelaxation.12
A second observation that strengthens the biological plausibility of a link between subclinical hypothyroidism and preeclampsia is that adverse outcomes are increased in pregnant women with overt thyroid disorders. A number of investigators have reported that pregnancies in women with untreated or poorly controlled thyrotoxicosis have increased incidences of cardiovascular and related complications such as preeclampsia, placental abruption, and heart failure.3,30 – 34 Similarly, reports of pregnant women with untreated overt hypothyroidism describe inordinately high rates of preeclampsia, placental abruption, and heart failure.30,33,34
The third link is derived from large prenatal screening studies designed to ascertain normal serum levels of thyroid-related analytes, as well as to study adverse pregnancy outcomes caused by thyroid disorders.19,21,35 Although in none of these was an association found between subclinical hypothyroidism or hyperthyroidism and preeclampsia, in one study pregnant women with subclinical hypothyroidism had a significant association with placental abruption, which is another vascular-related complication. In this study, such women were observed to have a significant threefold increased risk for placental abruption compared with euthyroid pregnant women.16 Additionally, in two of these large population-based studies, a significantly increased twofold to threefold risk for placental abruption was reported in women who had abnormally elevated serum antithyroid antibody levels.15,16
The unifying theme of these cited studies is that abnormal levels of thyroid hormones can lead to long-term cardiovascular sequelae that are mediated in part by chronic endothelial cell damage. In this regard, preeclampsia is thought to be a syndrome characterized by multiorgan involvement that results from endothelial cell activation.36 Thus, it seems reasonable to posit that abnormal levels of thyroid hormones are additive or synergistic toward the development of preeclampsia in women genetically predisposed.37 As such, the effects of subclinical hypothyroidism are similar to those observed in other maternal conditions characterized by chronic endothelial activation with an increased risk for preeclampsia. Some of these underlying conditions include obesity and the metabolic syndrome, chronic hypertension, diabetes, and renal disease.27,37 – 39
The strengths of this study are principally related to the number of women enrolled. Specifically, even after adjusting for maternal age, race, parity, and weight, the association of subclinical hypothyroidism and severe preeclampsia remains significant. Conversely, there are three weaknesses that are apparent. One is that the majority of women are of Hispanic heritage, and thus our observations may not be applicable in other ethnic populations. A second is that our database precluded identification of women with chronic hypertension or other such risk factors that are known to increase the risk for preeclampsia. Finally, because height was not recorded for all women enrolled in the first part of the study, we adjusted using weight as a continuous variable instead of body mass index, which many consider to be a more accurate indicator of obesity.
What are the implications of this persistent association between subclinical hypothyroidism and severe preeclampsia? We are of the opinion that our findings are more biologically significant than clinically relevant. Our observations add to accruing data that subclinical hypothyroidism, a relatively common finding in women of childbearing age, may be associated with some adverse perinatal outcomes. Nonetheless, we remain convinced that routine prenatal screening for thyroid disorders should not be implemented until clear benefit is established. The Eunice Kennedy Shriver National Institute of Child Health and Human Development–sponsored randomized intervention trial of women identified to have subclinical thyroid disorders currently being conducted by the Maternal-Fetal Medicine Units Network may provide such data.
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