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ORIGINAL RESEARCH |
From the University of Iowa Hospitals and Clinics, Iowa City, Iowa; and Poriya Government Hospital, Lower Galilee, Israel.
Address reprint requests to: David Peleg, MD, Poriya Government Hospital, Department of Obstetrics and Gynecology, Lower Galilee 15208, Israel; E-mail: peleg123{at}hotmail.com.
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ABSTRACT |
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METHODS: The records of pregnant women undergoing testing for thyroid-stimulating immunoglobulin over a 10-year period were analyzed. Neonatal thyrotoxicosis was defined as the presence of tachycardia, goiter, hydrops, tremulousness, voracious appetite, irritability, cardiomegaly, or congestive heart failure, with elevated thyroid hormone levels. The relationship between maternal thyroid-stimulating immunoglobulin values and the development of thyrotoxicosis was examined. The sensitivity, specificity, and positive and negative predictive values were calculated using an arbitrarily chosen cutoff for thyroid-stimulating immunoglobulin.
RESULTS: Twenty-nine women with a history of Graves disease and positive thyroid-stimulating immunoglobulin values were available for analysis. Of the 35 live births, there were six cases of neonatal thyrotoxicosis (17.1%). A maternal thyroid-stimulating immunoglobulin value at least 5 index units predicted neonatal thyrotoxicosis with a sensitivity of 100%, specificity of 76.0%, positive predictive value of 40.0%, and negative predictive value of 100%.
CONCLUSION: Pregnancies complicated by high values of maternal thyroid-stimulating immunoglobulin appear to be at risk of developing neonatal thyrotoxicosis.
Thyrotoxicosis complicates one in 500 pregnancies.1 The usual cause of thyrotoxicosis is Graves disease. Although the etiology of Graves disease is not clearly defined, it appears to be a combination of genetics, autoimmunity, and environment.2 Autoimmune dysfunction results in the synthesis of thyroid-stimulating immunoglobulin. This immunoglobulin binds to the TSH receptor and stimulates the thyroid gland. Thyroid-stimulating immunoglobulin is found in 71–100% of Graves patients depending upon the review.3
Transplacental passage of maternal thyroid-stimulating immunoglobulin was first noted in 1956.4 This immunoglobulin was termed "long-acting thyroid stimulator." Long-acting thyroid stimulator was assayed by in vivo stimulation of the mouse thyroid. This was replaced by an assay in cell culture that measures the net immunoglobulin-stimulating effect.
Thyroid-stimulating immunoglobulin, like other antibodies, may cross the placenta. Fetal effects may be noted after 20 weeks’ gestation when the fetal thyroid can respond to stimuli.5 Effects on the fetus and newborn include tachycardia, intrauterine growth restriction, cardiomegaly, failure to thrive, and stillbirths.1,6–8 Some have suggested that the presence of maternal thyroid-stimulating immunoglobulin is an indication for cordocentesis to evaluate fetal thyroid status.9 Others have indicated that a critical level of maternal thyroid-stimulating immunoglobulin is necessary to affect the fetus.10–13 This study reviews pregnancy outcomes in women with Graves disease with measurable thyroid-stimulating immunoglobulin to determine whether maternal values correlate with the risk of developing neonatal thyrotoxicosis.
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MATERIALS AND METHODS |
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The decision of if and when to assay for thyroid-stimulating immunoglobulin was at the discretion of the patient and attending physician. All thyroid-stimulating immunoglobulin samples were assayed in the same laboratory. Immunoglobulin G from the patient’s serum was incubated with cells from a stable Fischer rat thyroid cell line. The thyroid-stimulating immunoglobulin binding to (or near) the TSH receptor causes the conversion of adenyl cyclase to cyclic adenosine monophosphate. The amount of cyclic adenosine monophosphate generated was then measured by a radioimmunoassay.14 One index unit represents the mean value obtained from a normal pooled population. A value less than or equal to 1.3 index units (representing less than a 130% response) was considered normal as designated by the core laboratory.
A cutoff for maternal thyroid-stimulating immunoglobulin values was made arbitrarily, separating healthy neonates from those with thyrotoxicosis. Statistical evaluation included determination of sensitivity, specificity, and positive and negative predictive values using this cutoff.
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RESULTS |
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The 29 women had 35 pregnancies resulting in live births. Two women had previous miscarriages. During the 35 pregnancies resulting in live births, 11 women were taking propylthyrouracil; eight, thyroxine (seven had histories of previous radioactive iodine or surgical correction with resultant hypothyroidism); and six, both propylthyrouracil and thyroxine. Ten were untreated throughout pregnancy. Thyroid-stimulating immunoglobulin was measured during the second trimester in all 35 pregnancies (range 14–26 weeks). Of the 35 live births, there were nine (25.7%) who delivered preterm (less than 37 weeks), three (8.6%) complicated by preterm rupture of membranes (less than 37 weeks), and six (17.1%) with intrauterine growth restriction (less than 10th percentile).
Seven women consented to cordocentesis (performed at 24–35 weeks’ gestation) for evaluation of fetal thyroid hormone levels. Three were taking thyroxine, two, propylthyrouracil, and three, both. One woman (thyroid-stimulating immunoglobulin 8.5 index units) had a previous neonate with thyrotoxicosis. The fetal thyroid function tests were abnormal, and the infant was born 4 weeks later with neonatal thyrotoxicosis. Three fetuses (maternal thyroid-stimulating immunoglobulin 3.9, 6.0, 8.0 index units) had elevated free thyroxine (T4) and depressed TSH. Two of these had the maternal doses of propylthyrouracil increased and were delivered 4 and 5 weeks later; the third was delivered soon after the procedure. All three neonates showed no signs or symptoms of thyrotoxicosis. The results of the remaining three cordocenteses (maternal thyroid-stimulating immunoglobulin 3.3, 8.7, 15.0 index units) were normal. One of these neonates (maternal thyroid-stimulating immunoglobulin 15.0 index units), delivered 3 weeks later, developed neonatal thyrotoxicosis. Delivery was spontaneous vaginal in 22 (62.9%) women, instrumental in seven (20.0%), and abdominal in six (17.1%).
There were six cases of neonatal thyrotoxicosis (17.1%) from four women. During pregnancy, one woman was taking thyroxine, and two were taking propylthyrouracil. One infant was growth restricted. The characteristics of these neonates are shown in Table 1
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. Among the six neonates with thyrotoxicosis, the mothers of four had values greater than 5 index units. Six women who delivered normal infants had thyroid-stimulating immunoglobulins values greater than 5 index units. The 19 women with thyroid-stimulating immunoglobulin values less than 5 index units all delivered infants with no evidence of thyrotoxicosis. A thyroid-stimulating immunoglobulin of at least 5 index units was able to predict neonatal thyrotoxicosis with a sensitivity of 100% (95% confidence interval [CI] 39.8, 100), specificity of 76.0% (95% CI 54.9, 90.7), positive predictive value of 40.0% (95% CI 12.2, 73.8), and negative predictive value of 100% (95% CI 82.4, 100).
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DISCUSSION |
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The disease in the neonate usually abates after approximately 3 months with the clearance of the maternal antibodies. Diagnosis is based on determination of levels of thyroid hormones, and antithyroid medications (thionamides, ß blockers, and iodine) form the basis of treatment. These agents must be used with caution during pregnancy because of the ease in which they cross the placenta and the risk of in utero hypothyroidism. The long-term prognosis of neonates with thyrotoxicosis has not been well documented.
We recommend that all women with a history of Graves disease undergo thyroid-stimulating immunoglobulin testing. Our results have shown that critical values (at least 5 index units) of maternal thyroid-stimulating immunoglobulin are needed to place the fetus and neonate at risk of developing thyrotoxicosis. This has been previously suggested by others.10–13,18 Unfortunately, there is no standard test for thyroid-stimulating immunoglobulin, and each performing laboratory needs to establish normal values. The development of neonatal thyrotoxicosis in the absence of thyroid-stimulating immunoglobulin is much less common. Cordocentesis has been suggested by some for determination of fetal thyroid status,9 especially if the mother is on antithyroid medication. However, cordocentesis for suspected thyrotoxicosis is probably unnecessary and should not be considered in the absence of clinical signs and low or absent maternal thyroid-stimulating immunoglobulin values. On the other hand, the presence of high values of maternal thyroid-stimulating immunoglobulin should alert the perinatologist to the possibility of fetal thyrotoxicosis, and cordocentesis should be considered. In these cases, the neonatologist should be notified of the possibility of impending thyrotoxicosis, even after maternal antithyroid medication has been cleared from the circulation.
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Footnotes |
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Received July 24, 2001. Received in revised form January 14, 2002. Accepted January 31, 2002.
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REFERENCES |
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2. Akamizu T, Mori T, Nakao K. Pathogenesis of Graves disease: Molecular analysis of anti-thyrotropin receptor antibodies. Endocr J 1997;44:633–46.[Medline]
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6. Nutt J, Clark F, Welch RG, Hall R. Neonatal hyperthyroidism and long-acting thyroid stimulator protector. Br Med J 1974;4:695–6.
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8. Utiger RD. Recognition of thyroid disease in the fetus. N Engl J Med 1991;324:559–61.[Medline]
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11. Tamaki H, Amino N, Aozasa M, Mori M, Iwatani Y, Tachi J, et al. Universal predictive criteria for neonatal overt thyrotoxicosis requiring treatment. Am J Perinatol 1988;5:152–8.[Medline]
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14. Vitti P, Rotella CM, Valente WA, Cohen J, Aloj SM, Laccetti P, et al. Characterization of the optimal stimulatory effects of Graves monoclonal and serum immunoglobulin G on adenosine 3',5'-monophosphate production in fRTL-5 thyroid cells: A potential clinical assay. J Clin Endocrinol Metab 1983;57:782–91.[Abstract]
15. Major CA, Nageotte MP. Thyroid disease. In: James DK, Steer PJ, Weiner CP, Gonik B, eds. High risk pregnancy. 2nd ed. London, UK: WB Saunders; 1999:709–16.
16. Davis LE, Lucas JM, Hankins GD, Roark ML, Cunningham FG. Thyrotoxicosis complicating pregnancy. Obstet Gynecol 1989;160:63–70.
17. Polak M. Hyperthyroidism in early infancy: Pathogenesis, clinical features and diagnosis with a focus on neonatal hyperthyroidism. Thyroid 1998;8:1171–7.[Medline]
18. Clavel S, Madec AM, Bornet H, Deviller P, Stefanutti A, Orgiazzi J. Anti TSH-receptor antibodies in pregnant patients with autoimmune thyroid disorder. Br J Obstet Gynaecol 1990;97:1003–8.[Medline]
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