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.
1. Danzi S, Klein I. Thyroid hormone and blood pressure regulation. Curr Hypertens Rep 2003;5:513–20.
2. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344:501–9.
3. Sheffield JS, Cunningham FG. Thyrotoxicosis and heart failure that complicate pregnancy. Am J Obstet Gynecol 2004;190:211–7.
4. Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, et al.. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 2006;295:1033–41.
5. Dorr M, Wolff B, Robinson DM, John U, Ludemann J, Meng W, et al.. The association of thyroid function with cardiac mass and left ventricular hypertrophy. J Clin Endocrinol Metab 2005;90:673–7.
6. Duan Y, Peng W, Wang X, Tang W, Liu X, Xu S, et al.. Community-based study of the association of subclinical thyroid dysfunction with blood pressure. Endocrinology 2009;35:136–42.
7. Volzke H, Ittermann T, Schmidt CO, Dorr M, John U, Wallaschofski H, et al.. Subclinical hyperthyroidism and blood pressure in a population-based prospective cohort study. Eur J Endocrinol 2009;161:615–21.
8. Liu D, Jiang F, Shan Z, Wang B, Wang J, Lai Y, et al.. A cross-sectional survey of relationship between serum TSH level and blood pressure. J Hum Hypertension 2010;24:134–8.
9. Imaizumi M, Akahoshi M, Ichimaru S, Nakashima E, Hida A, Soda M, et al.. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab 2004;89:3365–70.
10. Volzke H, Robinson DM, Schminke U, Ludemann J, Rettig R, Felix SB, et al.. Thyroid function and carotid wall thickness. J Clin Endocrinol Metab 2004;89:2145–9.
11. Walsh JP, Bremner AP, Bulsara MK, O'Leary P, Leedman PJ, Feddema P, et al.. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med 2005;165:2467–72.
12. Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, et al.. Impaired endothelium-dependent vasodilation in subclinical hypothyroidism: Beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab 2003;88:3731–7.
13. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al.. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549–55.
14. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, et al.. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999;50:149–55.
15. Abbassi-Ghanavati M, Casey BM, Spong CY, McIntire DD, Halvorson LM, Cunningham FG. Pregnancy outcomes in women with thyroid peroxidase antibodies. Obstet Gynecol 2010;116:381–6.
16. Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, et al.. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005;105:239–45.
17. Casey BM, Dashe JS, Wells CE, McIntire DD, Leveno KJ, Cunningham FG. Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol 2006;107:337–41.
18. Casey BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, Cunningham GF. Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol 2007;109:1129–35.
19. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, Sullivan L, Canick J, Porter TF, et al.. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 2008;112:85–92.
20. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf) 2003;59:282–8.
21. Mannisto T, Vaarasmaki M, Pouta A, Hartikainen AL, Ruokonen A, Surcel HM, et al.. Perinatal outcome of children born to mothers with thyroid dysfunction or antibodies: a prospective population-based cohort study. J Clin Endocrinol Metab 2009;94:772–9.
22. Mannisto T, Vaarasmaki M, Pouta A, Hartikainen AL, Ruokonen A, Surcel HM, et al.. Thyroid dysfunction and autoantibodies during pregnancy as predictive factors of pregnancy complications and maternal morbidity in later life. J Clin Endocriniol Metab 2010;95:1084–94.
23. Stagnaro-Green A, Chen X, Bogden JD, Davies TF, Scholl TO. The thyroid and pregnancy: a novel risk factor for very preterm delivery. Thyroid 2005;15:351–57.24.
24. Haddow JE, McClain MR, Palomaki GE, Neveux LM, Lambert-Messerlian G, Canick JA, et al.. Thyroperoxidase and thyroglobulin antibodies in early pregnancy and placental abruption. Obstet Gynecol 2011;117(2 Pt 1):287–92.
25. Alexander JM, McIntire DD, Leveno KJ, Cunningham FG. Selective magnesium sulfate prophylaxis for the prevention of eclampsia in women with gestational hypertension. Obstet Gynecol 2006;108:826–32.
26. Ness RB, Roberts JM. Epidemiology of pregnancy-related hypertension. In: Lindheimer MD, Roberts JM, Cunningham FG, editors. Chesley's hypertensive disorders in pregnancy. San Diego (CA): Elsevier; 2009. p. 37–50.
27. Hubel CA, Roberts JM. Metabolic syndrome and preeclampsia. In: Lindheimer MD, Roberts JM, Cunningham FG, editors. Chesley's hypertensive disorders in pregnancy. San Diego (CA): Elsevier; 2009. p. 105–28.
28. Fletcher AK, Weetman AP. Hypertension and hypothyroidism. J Hum Hypertension 1998;12:79–82.
29. Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB, et al.. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 2010;165:2460–6.
30. Davis LE, Lucas MJ, Hankins GD, Roark ML, Cunningham FG. Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 1989;160:63–70.
31. Kriplani A, Buckshee K, Bhargava VL, Takkar D, Ammini AC. Maternal and perinatal outcome in thyrotoxicosis complicating pregnancy. Eur J Obstet Gynecol Reprod Biol 1994;54:159–63.
32. Mestman JH. Hyperthyroidism in pregnancy. Clin Obstet Gynecol 1997;40:45–64.
33. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002;12:63–8.
34. Leung AS, Millar LK, Koonings PP, Montoro M, Mestman JH. Perinatal outcome in hypothyroid pregnancies. Obstet Gynecol 1993;81:349–53.
35. Dashe JS, Casey BM, Wells CE, McIntire DD, Byrd EW, Leveno KJ, et al.. Thyroid-stimulating hormone in singleton and twin pregnancy: importance of gestational age-specific reference ranges. Obstet Gynecol 2005;106:753–7.
36. Taylor RN, Davidge ST, Roberts JM. Endothelial cell dysfunction and oxidative stress. In: Lindheimer MD, Roberts JM, Cunningham FG, editors. Chesley's hypertensive disorders in pregnancy. San Diego (CA): Elsevier; 2009. p. 143–68.
37. Maynard SE, Karumanchi SA. Angiogenic factors and preeclampsia. Semin Nephrol 2011;31:33–46.
38. Cornelis T, Odutayo A, Keunen J, Hladunewich M. The kidney in normal pregnancy and preeclampsia. Semin Nephrol 2011;31:4–14.
39. Davison JM, Lindheimer MD. Pregnancy and chronic kidney disease. Semin Nephrol 2011;31:86–99.