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Editorial |
Associate Editor
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Figure. Catherine Y. Spong, MD Associate Editor
Thyroid disease in pregnancy is a hot topic in public and medical forums, with philosophical differences between medical endocrinologists and obstetricians. Both groups accept that women with known hypo- or hyperthyroidism should be treated and symptomatic women should be evaluated, screened, and treated if overt disease is identified. However, since 1999, the identification, diagnosis, and management of subclinical hypothyroidism during pregnancy have been brought to the forefront, and the implications and optimal management are now openly debated. Subclinical hypothyroidism is defined as an elevated thyroid-stimulating hormone (TSH) level with a normal circulating thyroxine (free T4).
Recent work has raised concern that subclinical hypothyroidism during pregnancy results in intellectual impairment of the child. Two studies have shown that low thyroid hormone concentrations can be associated with significant decrements of the intelligence quotient (IQ) of the children. These studies are complicated by the inclusion of women with overt hypothyroidism, women taking suboptimal doses of thyroid medication, and women with subclinical hypothyroidism, with the conclusions being that all of these groups should be treated.
It has been shown that it is the maternal free T4 that is critical for fetal brain development and maturation, regardless of the TSH.1,3 The fetus begins to produce thyroid hormones at around 12 weeks of gestation. Before this time, the maturing fetal brain is dependent on the circulating maternal free T4. Given that free T4 is the critical component, it is not clear how subclinical hypothyroidism, where there is normal thyroxine, impairs fetal brain development, although it is suggested that these women may require higher levels than normal. Importantly, other studies have identified that excessive thyroxine may be detrimental to the fetus.4
Position statements from major societies range from those mandating that "Serum thyrotropin testing should be done in all women considering pregnancy"5 to those recommending that "Routine serum TSH testing early during pregnancy is reasonable but should be left to the judgment of the physician, in consultation with the patient." The current American College of Obstetricians and Gynecologists (ACOG) recommendations are to perform indicated testing of thyroid function in women with a personal history of thyroid disease or symptoms of thyroid disease.8 Two national meetings were held in 2004 to address these issues among the experts (American Thyroid Association. Impact of maternal thyroid disease on the developing fetus: implications for diagnosis treatment and screening. January 12–13, 2004; Atlanta, Georgia, and American Thyroid Association, The American Association of Clinical Endocrinologists. Impact of maternal thyroid status on pregnancy and fetal and childhood development; April 2, 2004; Alexandria, Virginia).9 The summary of both meetings maintained that there is not enough evidence to determine whether screening and treatment for subclinical hypothyroidism before or during pregnancy in the asymptomatic woman is warranted or necessary. The first meeting outlined major research gaps, including that data relating adverse outcome for subclinical hypothyroidism need to be substantiated, and if positive, an effective treatment needs to be identified. The participants considered it both ethical and critical to conduct a randomized controlled trial in women with subclinical hypothyroidism because the outcomes and benefits of treatment are uncertain.
The relationship between subclinical hypothyroidism and impairment of the child's neurodevelopment has not been proven to be causal, and there is no evidence that treatment with thyroxine will alter the outcome. The studies to date are noninterventional or retrospective. Prior to this issue's study by Casey et al,10 there were no large prospective studies on an unselected population to define the extent of the condition in pregnancy and whether there were associated adverse obstetric complications with subclinical hypothyroidism. Interestingly, despite the dearth of evidence regarding treatment of subclinical hypothyroidism in pregnancy, there is a chasm in the medical field, with many medical endocrinologists recommending routine screening of all pregnant women and treatment of subclinical disease and obstetricians recommending screening only for symptoms.
The study by Casey et al10 is a step forward for this controversial issue. Over a nearly 30-month period, all women (n = 25,756) presenting for prenatal care underwent thyroid screening in a central laboratory. Of these, 17,298 (67%) were at less than 20 weeks of gestation and were further studied. Those with elevated TSH levels were screened for free T4, and those with overt disease were treated. Euthyroid women and women with subclinical hypothyroidism comprised the study population and did not receive an intervention. Pregnancy outcomes were compared between women with the laboratory diagnosis of subclinical hypothyroidism and those with normal thyroid function. In their population, 0.2% were identified to have overt hypothyroidism and 2.3% were identified to have subclinical hypothyroidism, consistent with other studies that have identified prevalence for subclinical hypothyroidism of 2–5%. Casey et al10 found an association between subclinical hypothyroidism and preterm delivery, suggesting in part that some of the difference in long-term outcome may be related to the prematurity rather than directly to the thyroid hormone abnormalities.
Certainly the implications of routine universal screening and treatment would be a major public health undertaking and require an evidence base. This study provides data that will be useful for future research in this hotly debated area of clinical obstetric medicine. Additional information is needed for clarity, including replication of the findings, if possible, by another group; large unselected population-based normal ranges for thyroid levels across gestation; an interventional trial to determine if indeed replacement therapy with thyroxine is beneficial for pregnant women with subclinical hypothyroidism; and research into the mechanism, including the evaluation of the role of thyroid antibodies and confounding autoimmune disorders. In the meantime, given that we do not have known appropriate therapies, routine screening of all pregnant women remains unwarranted.
Footnotes
Any opinions expressed in this editorial do not necessarily represent those of the National Institutes of Health or the U.S. Department of Health and Human Services.
doi:10.1097/01.AOG.0000153143.89006.ac
REFERENCES
1. Morreale de Escobar G, Obregon MJ, Escobar del Ray F. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 2000;85:3975–87.
2. 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.
3. 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.[Medline]
4. Anselmo J, Cao D, Karrison T, Weiss RE, Refetoff S. Fetal loss associated with excess thyroid hormone exposure. JAMA 2004;292:691–5.
5. The Endocrine Society. The Endocrine Society issues recommendations in response to major hypothyroidism study—ES position paper. Available at: http://www.endo-society.org/news/press/1999/199908181.cfm. Retrieved November 30, 2004.
6. The American Thyroid Association Public Health Committee. Haddow study of maternal hypothyroidism during pregnancy and subsequent childhood neuropsychological development. Thyroid 1999;9:971–2.
7. Gharib H, Cobin RH, Dickey RA. Subclinical hypothyroidism during pregnancy: position statement from the American Association Of Clinical Endocrinologists. Endocr Pract 1999;5:367–8. Available at: http://www.aace.com/clin/guidelines/pregnancy.pdf. Retrieved November 30, 2004.
8. Thyroid disease in pregnancy. ACOG Practice Bulletin No. 37. American College of Obstetricians and Gynecologists. Obstet Gynecol 2002;100:387–96.[Medline]
9. A Symposium of the American Thyroid Association and The American Association of Clinical Endocrinologists. Impact of maternal thyroid status on pregnancy and fetal and childhood development; April 2, 2004; Alexandria, Virginia. Available at: http://www.blueskybroadcast.com/Client/ATA_4.2.04/. Retrieved November 30, 2004.
10. Casey BM, Dashe JS, Wells CE, McIntire D, Byrd W, Leveno KJ, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2004;105:239–45.
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