Introduction into clinical practice of extremely sensitive assays for serum levels of thyrotropin, or thyroid stimulating hormone (TSH), have made it possible to identify both subclinical hypothyroidism and hyperthyroidism. Although usually representing normal biological variations, these biochemically defined extremes may herald the earliest stages of thyroid disease. Subclinical hyperthyroidism is defined by a serum TSH level that is below the statistically defined lower limit along with a serum free thyroxine (fT4) level within the normal reference range.1 Its prevalence is higher in iodine-insufficient areas, and although it increases with age, it still is relatively common in women of childbearing age. Over the past 20 years, information has accrued suggesting that subclinical hyperthyroidism probably has long-term adverse sequelae that include osteoporosis, cardiovascular morbidity, and progression to overt thyrotoxicosis or thyroid failure.2,3
Overt hypothyroidism and thyrotoxicosis have well-documented adverse impacts on pregnancy outcomes.4–8 Similarly, subclinical hypothyroidism has been significantly linked with placental abruption and preterm delivery, and preliminary observations suggest a possible association with impaired fetal neurological development.9,10 We designed the present study of a large cohort of pregnant women who underwent prenatal TSH screening to establish the prevalence and impact of subclinical hyperthyroidism.
MATERIALS AND METHODS
Parkland Health and Hospital System is a tax-supported institution serving the medically indigent in Dallas County. Faculty of the Department of Obstetrics and Gynecology at the University of Texas Southwestern Medical School supervise the delivery of all obstetric care at Parkland Hospital, including 8 prenatal clinic sites throughout Dallas County. All women who present for prenatal care, regardless of gestational age, undergo same-day prenatal laboratory testing that includes serum screening for rubella antibody. With the approval of the institutional review boards at the University of Texas Southwestern and Parkland Hospital, excess serum from blood tested for rubella antibody was delivered to an immunochemistry research laboratory for thyroid studies that included a chemiluminescent assay for TSH and fT4, using an Immulite 2000 Analyzer (Diagnostic Products Corporation, Los Angeles, CA). The analytical sensitivity or detection limit of the TSH assay was 0.002 mU/L, and its coefficient of variation was 3.8% within a run and 4.6% between runs using specimens in the normal range. The detection limit for fT4 was 0.18 ng/mL, with a within-run coefficient of variation of 7.1% and between-run coefficient of variation of 6.4%.
Serum samples from 2,000 women screened during a 1-month period (October 2000) were analyzed to determine that the 5th percentile value for TSH was 0.2 mU/L when not corrected for gestational age. The 5th percentile was chosen to ensure that all women with overt hyperthyroidism, as determined by fT4 levels, were identified. As has previously been reported, serum from women tested November 1, 2000, to April 14, 2003, that had an abnormal TSH value was reflexively assayed for free thyroxine.9 Those women with both an abnormally low TSH level and a high fT4 level (> 2.0 ng/dL) were contacted for referral to a special obstetric clinic for evaluation and treatment. Free triiodothyronine (T3) levels were not performed during thyroid screening. The institutional review boards at the University of Texas Southwestern and Parkland Hospital approved this identification and referral process for women with laboratory values indicating overt hyperthyroidism.
Women who were screened and delivered of a singleton infant weighing 500 g or more during the screening period were analyzed. For the purposes of this study, women with TSH values at or below the 2.5th percentile for gestational age whose serum fT4 levels were 1.75 ng/dL or less were identified as having subclinical hyperthyroidism. The TSH thresholds, according to week of gestation and the fT4 threshold were derived by using a previously described subset of these women.11 The 2.5th percentile for TSH at each week of gestational age varied between 0.008 and 0.668 mU/L. The fT4 threshold of 1.75 ng/dL represents the 97.5th percentile of available fT4 values and was not adjusted for gestational age. Pregnancy outcomes in women identified with subclinical hyperthyroidism were compared with those in women whose TSH values were between the 5th and 95th percentiles.
Selected obstetric and neonatal outcomes for all women delivering infants at Parkland Hospital are routinely entered into a computerized perinatal database. Nurses attending each delivery complete an obstetric data sheet and research nurses assess the data for consistency and completeness before electronic storage. Data on infant outcomes are abstracted from discharge records. Results from thyroid function studies (TSH and fT4) were electronically stored and linked to the perinatal and infant databases.
Gestational age was established using the obstetric estimate recorded at delivery. This age in weeks is based on a last menstrual period (LMP), with sonography performed if the LMP was uncertain or to resolve discrepancies between fundal height and LMP. This method of gestational age determination has been found to correlate well with sonographic and pediatric estimates in our obstetric population.12 Gestational hypertension was defined as a blood pressure of 140/90 mm Hg or greater. Severe preeclampsia was diagnosed in hypertensive women who had at least one of the following: blood pressure greater than 160/110 mm Hg, serum creatinine greater than 1.0 mg/dL, platelet count less than 100,000/μL, serum aspartate aminotransferase level at least twice the upper normal value, persistent headache or scotomata, 2+ or greater dipstick proteinuria, or more than 2 g of protein excreted in 24 hours.13 Infants with major malformations included those with aneuploidy, an identifiable syndrome, and those with an anomaly involving a principal organ system.14
Pearson χ2 and Student t test were used for univariate 2-group comparisons. Logistic regression was applied to examine the significance for gestational hypertension adjusted for race and parity. The Hosmer-Lemeshow statistic was used to examine the goodness-of-fit for the logistic regression model.15 Statistical computations were performed with SAS 8.2 (SAS Institute, Cary, NC). Two-sided P values less than .05 were judged statistically significant and were not adjusted for multiple testing.
Between November 1, 2000, and April 14, 2003, a total of 25,765 women who underwent thyroid screening were delivered of singleton infants at Parkland Hospital. Ninety-three women were found to have overt hyperthyroidism based on a high free thyroxine level during screening. (Fig. 1) These women were referred for follow-up testing. Three women had histories of thyroid disease, and 9 others were confirmed to have high free thyroxine levels and were treated. These 12 women represent a hyperthyroidism rate of 0.5/1,000, which is consistent with prior studies at our institution.8 Applying previously established gestational age–specific TSH thresholds,11 there were 433 (1.7%) women in this cohort with an abnormally low TSH and a fT4 level of 1.75 ng/dL or lower (97.5th percentile) who were considered to have subclinical hyperthyroidism for the purpose of this analysis. Serum TSH values for these 433 women ranged from 0.002 to 0.668 mU/L, and fT4 levels ranged from 1.75 to 0.68 ng/dL.
Shown in Table 1 are maternal characteristics of women identified to have subclinical hyperthyroidism compared with 23,124 control women whose TSH levels were between the 5th and 95th percentiles for gestational age. Women identified with subclinical hyperthyroidism were more likely African American, were more likely to be parous, and had a lower mean body mass index (BMI) than women with normal TSH values. Listed in Table 2 are pregnancy outcomes in these 2 groups of women. The incidence of gestational hypertension was significantly lower in women identified with subclinical hyperthyroidism (6.0% versus 8.8%, P = .04). This difference persisted after adjustment for race and parity (odds ratio 0.66, 95% confidence interval 0.44–0.98; Hosmer-Lemeshow goodness-of-fit, P = .16). Severe preeclampsia was not significantly different between the subclinical hyperthyroid and euthyroid groups (3.5% versus 5.3%, P = .09). There were no significant differences in infant outcomes (Table 3).
Using a contemporaneous definition for subclinical hyperthyroidism, we found its prevalence to be 1.7% in 25,765 pregnant women. Another 0.4% of these women had an elevated concomitant serum fT4 level and were referred for evaluation and treatment. The observed prevalence of subclinical disease in these pregnant women with a mean of age of 25 years is similar to that reported for nonpregnant individuals.16 A greater proportion of African-American women had subclinical hyperthyroidism than did Hispanic women (3% versus 1.6%, P < .001). This may be explained by the fact that TSH and human chorionic gonadotropin (hCG) levels are inversely related, and black women have higher serum levels of hCG than white or Hispanic women.17 We observed that subclinically hyperthyroid women were also more likely to be parous than women with a normal TSH (72% versus 64%, P < .001). This finding is possibly related to autoimmune thyroiditis from persistent maternofetal microchimerism after a previous pregnancy.18,19 We also identified that women with subclinical hyperthyroidism were less likely to be obese than women with TSH values between the 5th and 95th percentile. This positive relationship between TSH values and BMI has previously been reported and is hypothesized to represent an altered energy balance due to increased thermogenesis in obese women.20
The most important finding in this prospective study is that subclinical hyperthyroidism was not associated with any of a number of adverse pregnancy outcomes. In fact, we found subclinical hyperthyroidism may have a protective effect against development of hypertension during pregnancy. Although this finding may seem paradoxical, studies in animals and humans have shown a vasodilatory effect for thyroid hormone.21,22 Also, studies in pregnant women have shown a further reduction in systemic vascular resistance with thyrotoxicosis.8,23
Presently, there is no convincing evidence that subclinical hyperthyroidism should be treated in nonpregnant individuals, and our results indicate that treatment during pregnancy is also unwarranted.24 Indeed, it should be considered contraindicated because maternal antithyroid drugs cross the placenta and may cause fetal thyroid suppression.25 Further studies are necessary to ascertain any adverse long-term effects of maternal subclinical hyperthyroidism. Because of possible long-term sequelae, women identified with subclinical hyperthyroidism should undergo confirmatory testing and, if positive, may benefit from surveillance later in life.3,26,27
Some have recommended that all pregnant women undergo TSH screening to detect those with hypothyroidism with the intention of preventing subnormal neurologic development in the offspring.10,28 Such screening would also identify almost 2% with subclinical hyperthyroidism. Our results indicate that this diagnosis does not adversely affect pregnancy outcome and should not be considered as a justification for universal TSH screening during pregnancy.
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