Elizabeth N. Pearce

Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum

Pregnancy has a profound impact on the thyroid gland and thyroid function. The gland increases 10% in size during pregnancy in iodine-replete countries and by 20%– 40% in areas of iodine deficiency. Production of thyroxine (T4) and triiodothyronine (T3) increases by 50%, along with a 50% increase in the daily iodine requirement. These physiological changes may result in hypothyroidism in the later stages of pregnancy in iodine-deficient women who were euthyroid in the first trimester. The range of thyrotropin (TSH), under the impact of placental human chorionic gonadotropin (hCG), is decreased throughout pregnancy with the lower normal TSH level in the first trimester being poorly defined and an upper limit of 2.5 mIU/L. Ten percent to 20% of all pregnant women in the first trimester of pregnancy are thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody positive and euthyroid. Sixteen percent of the women who are euthyroid and positive for TPO or Tg antibody in the first trimester will develop a TSH that exceeds 4.0 mIU/L by the third trimester, and 33%–50% of women who are positive for TPO or Tg antibody in the first trimester will develop postpartum thyroiditis. In essence, pregnancy is a stress test for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency, and postpartum thyroiditis in women with underlying Hashimoto’s disease who were euthyroid prior to conception. Knowledge regarding the interaction between the thyroid and pregnancy/the postpartum period is advancing at a rapid pace. Only recently has a TSH of 2.5 mIU/L been accepted as the upper limit of normal for TSH in the first trimester. This has important implications in regards to interpretation of the literature as well as a critical impact for the clinical diagnosis of hypothyroidism. Although it is well accepted that overt hypothyroidism and overt hyperthyroidism have a deleterious impact on pregnancy, studies are now focusing on the potential impact of subclinical hypothyroidism and subclinical hyperthyroidism on maternal and

Environmental pollutants and the thyroid.

Common environmental exposures may affect thyroid function in humans. Foetuses and infants are most vulnerable to these effects because they need thyroid hormone for normal neurodevelopment. Perchlorate, thiocyanate and nitrate are all competitive inhibitors of the sodium/iodine symporter (NIS) in pharmacologic doses, but their effects on human thyroid function at environmental exposure levels remain unclear. Many compounds, including polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs), bisphenol-A (BPA) and triclosan, may have direct actions on the thyroid hormone receptor, but these effects are complex and are not yet well understood. Isoflavones inhibit thyroperoxidase (TPO) activity, and, therefore, may cause goitre and hypothyroidism if ingested at high levels, particularly in iodine-deficient individuals. Organochlorine pesticides and dioxins may decrease serum T(4) half-life by activating hepatic enzymes. Additional studies are needed to further elucidate the risk posed by these and other potentially thyroid-disrupting compounds.

Neonatal Thyroxine, Maternal Thyroid Function, and Child Cognition

CONTEXTnThyroid hormone is essential for normal brain development. Limited data are available regarding whether thyroid function in neonates influences later cognitive development.nnnOBJECTIVEnOur objective was to study associations of newborn T4 levels with maternal thyroid function and childhood cognition.nnnDESIGN AND SETTINGnWe studied participants in Project Viva, a cohort study in Massachusetts.nnnPARTICIPANTSnWe studied a total of 500 children born 1999--2003 at 34 wk or more.nnnMAIN OUTCOME MEASURESnWe determined cognitive test scores at ages 6 months and 3 yr.nnnRESULTSnMean newborn T4 at a mean age of 1.94 d was 17.6 (sd 4.0) microg/dl, and levels were higher in girls [1.07 microg/dl; 95% confidence interval (CI) 0.38, 1.76] and infants born after longer gestation (0.42 microg/dl; 95% CI 0.17, 0.67 per wk). Newborn T4 levels were not associated with maternal T4, TSH, or thyroid peroxidase antibody levels. On multivariable linear regression analysis, adjusting for maternal and child characteristics, higher newborn T4 was unexpectedly associated with poorer scores on the visual recognition memory test among infants at age 6 months (-0.5; 95% CI -0.9, -0.2), but not with scores at age 3 yr on either the Peabody Picture Vocabulary Test (0.2; 95% CI -0.1, 0.5) or the Wide Range Assessment of Visual Motor Abilities (0.1; 95% CI -0.2, 0.3). Maternal thyroid function test results were not associated with child cognitive test scores.nnnCONCLUSIONSnNewborn T4 concentrations within a normal physiological reference range are not associated with maternal thyroid function and do not predict cognitive outcome in a population living in an iodine-sufficient area.

ASSOCIATION OF FIRST-TRIMESTER THYROID FUNCTION TEST VALUES WITH THYROPEROXIDASE ANTIBODY STATUS, SMOKING, AND MULTIVITAMIN USE

OBJECTIVEnTo determine first-trimester thyroid function values and associations with thyroperoxidase antibody (TPO-Ab) status, smoking, emesis, and iodine-containing multivitamin use.nnnMETHODSnWe collected information by interview, questionnaire, and blood draw at the initial obstetric visit in 668 pregnant women without known thyroid disease. We compared thyroid-stimulating hormone (TSH), total thyroxine (T4), and free T4 index (FT4I) values by TPO-Ab status. Multiple regression was used to identify characteristics associated with thyroid function values.nnnRESULTSnThe following median (range containing 95% of the data points) thyroid function test values were obtained in 585 TPO-Ab-negative women: TSH, 1.1 mIU/L (0.04-3.6); FT4I, 2.1 (1.5-2.9); and T4, 9.9 microg/dL (7.0-14.0). The following median (range containing 95% of the data points) thyroid function test values were obtained in 83 TPO-Ab-positive women: TSH, 1.8 mIU/L (0.3-6.4) (P<.001); FT4I, 2.0 (1.4-2.7) (P = .06); and T4, 9.3 microg/dL (6.8-13.0) (P = .03) (P values denote statistically significant differences between TPO-Ab-positive and negative participants). Among TPO-Ab-negative participants, TSH level was not associated with use of iodine-containing multivitamins, smoking, or race. TSH increased 0.03 mIU/L for every year of maternal age (P = .03) and decreased by 0.3 mIU/L for every increase in parity (P<.001). T4 decreased 0.04 microg/dL for every year of maternal age (P = .04). Mean FT4I was 2.05 in smokers and 2.20 in nonsmokers (P<.01). There were no relationships between T4 or FT4I and parity, race, or iodine-containing multivitamin use.nnnCONCLUSIONnTPO-Ab status of pregnant women should be considered when constructing trimester-specific reference ranges because elevated serum TPO-Ab levels are associated with higher TSH and lower T4 values.

Treatment options for Graves disease: a cost-effectiveness analysis.

BACKGROUNDnFirst-line treatment for Graves disease is frequently 18 months of antithyroid medication (ATM). Controversy exists concerning the next best line of treatment for patients who have failed to achieve euthyroidism; options include lifelong ATM, radioactive iodine (RAI), or total thyroidectomy (TT). We aim to determine the most cost-effective option.nnnSTUDY DESIGNnWe performed a cost-effectiveness analysis comparing these different strategies. Treatment efficacy and complication data were derived from a literature review. Costs were examined from a health-care system perspective using actual Medicare reimbursement rates to an urban university hospital. Outcomes were measured in quality-adjusted life-years (QALY). Costs and effectiveness were converted to present values; all key variables were subjected to sensitivity analysis.nnnRESULTSnTT was the most cost-effective strategy, resulting in a gain of 1.32 QALYs compared with RAI (at an additional cost of 9,594 US dollars) and an incremental cost-effectiveness ratio of 7,240 US dollars/QALY. RAI was the least costly option at 23,600 US dollars but also provided the least QALY (25.08 QALY). Once the cost of TT exceeds 19,300 US dollars, the incremental cost-effectiveness ratio of lifelong ATM and TT reverse and lifelong ATM becomes the more cost-effective strategy at 15,000US dollars/QALY.nnnCONCLUSIONSnThis is the first formal cost-effectiveness study in the US of the optimal treatment for patients with Graves disease who fail to achieve euthyroidism after 18 months of ATM. Our findings demonstrate that TT is more cost effective than RAI or lifelong ATM in these patients; this continues until the cost of TT becomes > 19,300 US dollars.

Assessment of thyroid function and urinary and breast milk iodine concentrations in healthy newborns and their mothers in Tehran

Objectiveu2003 To measure breast milk iodine (MI) and urinary iodine (UI) concentrations in healthy newborns and their nursing mothers from an iodine‐sufficient region to determine adequacy and to relate these parameters to thyroid function tests in mothers and infants.

Thyroid dysfunction in perimenopausal and postmenopausal women.

Thyroid dysfunction is common, especially among women over the age of 50. In caring for peri- and post-menopausal women, it is important to recognize the changing clinical manifestations of thyroid disease with age. Postmenopausal women are at increased risk of both osteoporosis and cardiovascular disease, and untreated thyroid disease may exacerbate these risks. Screening for thyroid dysfunction in asymptomatic individuals is controversial, but aggressive case-finding should be pursued, especially in older women. Women with overt thyroid dysfunction should be treated. Therapy for women with subclinical thyroid dysfunction is more controversial, although women with levels of thyroid stimulating hormone (TSH) ≥10 mU/L should be treated, and treatment may be considered in symptomatic women with subclinical hypothyroidism and TSH values <10 mU/L, and in women with subclinical hyperthyroidism who have TSH values consistently <0.1 mU/L. In women who are treated with thyroxine, careful dose titration and monitoring are required in order to prevent the adverse consequences of iatrogenic subclinical hyperthyroidism or hypothyroidism. Finally, caution is required in diagnosing and treating thyroid dysfunction in women who are taking oral estrogens or selective estrogen receptor modulators.

What Do We Know about Iodine Supplementation in Pregnancy

Despite major progress over the last four decades, iodine deficiency remains the leading preventable cause of mental retardation. It has been estimated that 20% of the 2 billion individuals worldwide currently at risk for iodine deficiency disorders reside in Europe (1). The study of Velasco et al. (2), published in this issue of JCEM, demonstrated that infants of Spanish mothers who had received oral 300 g potassium iodide (KI) supplements daily during pregnancy and lactation had higher Bayley Psychomotor Development scores at 3–18 months of age than infants whose mothers did not receive iodine supplements. A strength of the study was the authors’ ability to collect trimester-specific urinary iodine concentrations (UIC) and thyroid function data, cord blood thyroid function studies, infant UIC, breast milk iodine concentrations, and infant neurocognitive data in a majority of the treatment group; this was a heroic feat. The major limitation of the study is the fact that it was not rigorously controlled. Apparently this was not by choice. The authors note that “the Ethics Committee . . . did not authorize the inclusion of a control group without treatment.” The authors selected a group of 61 untreated women to serve as controls. Because they were enrolled in the eighth month of pregnancy, thyroid function and urinary iodine measurements were not obtained in these women before the third trimester. Another 31 untreated women who experienced miscarriage at wk 8–12 were recruited to provide only UIC. Although there was no difference between treated and untreated groups in infant birth weights, Apgar scores, maternal age, frequency of prematurity, frequency and duration of breastfeeding, or parental education, neurodevelopment is an extremely complex process, and there are many potential confounders that could have contributed to the apparent difference in infant development between the study groups. Was the decision of the Ethics Committee appropriate? It would clearly be unethical to withhold iodine supplementation from pregnant women known to be severely iodine deficient. A blinded, placebo-controlled clinical trial begun in the 1960s in Papua, New Guinea, demonstrated that preconception supplementation of severely iodine-deficient women (median UIC 20 g/liter) with iodinated oil eliminated the risk for cretinism and improved offspring cognitive function and survival (3). These findings have subsequently been replicated in many regions of the world (4). A meta-analysis of Chinese studies suggests that iodine supplementation in severely iodinedeficient regions may increase the average child IQ by 12.5 points (5). The women in the Velasco study, however, were moderately but not severely iodine deficient at baseline. Although sample sizes were small, in the two untreated control groups, the median UIC were 69 and 88 g/liter—both below the optimal range of 150–249 g/liter as defined by the World Health Organization (6), and similar to the UIC of 84 g/liter previously reported for third-trimester pregnant women from Andalusia (7). What is known about the effects of iodine supplementation in pregnant women with this moderate degree of iodine deficiency? Seven previous controlled trials of iodine supplementation in moderately iodine-deficient pregnant European women have been published, although doses and timing of iodine supplementation varied, and only one previous trial examined effects on offspring development.

Iodine in Pregnancy: Is Salt Iodization Enough?

Iodine deficiency affects more than 2.2 billion individuals worldwide (38% of the world’s population). Decreases in maternal T4 associated with even mild iodine deficiency may have adverse effects on the cognitive function of offspring (1,2), and iodine deficiency remains the leading cause of preventable mental retardation worldwide. It has recently been suggested that mild iodine deficiency may also be associated with attention-deficit and hyperactivity disorders in offspring (3).

Urine test strips as a source of iodine contamination.

In the course of conducting an analysis in a subset of the controlled antenatal thyroid screening study (1) samples, we recently noted that some urine samples from pregnant women in Wales, a region known to be iodine deficient, had urinary iodine concentrations in excess of 500mg=L. We suspected contamination from urine test strips. We obtained Combur Test D urine test strips (Roche Diagnostics, Mannheim, Germany), as were used in the Welsh study. We also obtained Multistix 10 SG urine test strips (Bayer Health Care, Elkhart, IN), used in our clinic, for comparison. Iodine was not mentioned in the package insets for either test strip. Two urine samples were obtained from healthy volunteers. Total urinary iodine concentrations were measured both spectrophotometrically by a modification of the method of Benotti et al. (2) and by mass spectroscopy. Measurements were obtained at baseline, after placing each test strip in the urine for 1 second, and again after placing each test strip in the urine for 30 seconds (Table 1). To determine which individual tests contained iodine, the test strips were cut into separate pieces for each test, and urine iodine concentrations were remeasured after placing individual pieces in a separate urine sample for 30 seconds. Iodine was present in the tests for glucose and blood in the Combur Test D and only in the Multistix test for glucose. The test strips for glucose rely on sequential reactions. First, glucose oxidase catalyzes the aerobic oxidation of glucose to gluconic acid and hydrogen peroxide. Second, in the presence of iodide, hydrogen peroxide oxidizes the iodide to free iodine, producing a color change in the indicator. The color change produced indicates the amount of hydrogen peroxide present, and therefore the glucose content of the urine. Although previously reported by Chanoine et al. (3) over 20 years ago, the contamination of urine with iodine by test strips is not well known. Since Combur and Multistix test strips still contain iodine as a reagent for blood and glucose testing, urine iodine concentrations should be assessed before test strip measurements. This is important in evaluating populations for iodine sufficiency. References