Thyroid Function of Infants Breastfed by Mothers with Graves Disease Treated with Inorganic Iodine: A Study of 100 Cases.

CONTEXT: We previously reported that inorganic iodine therapy in lactating women with Graves disease (GD) did not affect the thyroid function in 25 of 26 infants despite their exposure to excess iodine via breast milk. OBJECTIVE: To further assess thyroid function in infants nursed by mothers with GD treated with inorganic iodine. DESIGN: Case series. SETTING: Tajiri Thyroid Clinic, Japan. PARTICIPANTS: One hundred infants of lactating mothers with GD treated with potassium iodide (KI) for thyrotoxicosis. MAIN OUTCOME MEASURES: Infant blood thyrotropin (TSH) and free thyroxine (FT4) levels were measured by the filter paper method. Subclinical hypothyroidism was defined as TSH ≥10 µIU/mL and ≥5 µIU/mL in infants aged <6 and ≥6 months, respectively. RESULTS: Overall, 210 blood samples were obtained from 100 infants. The median infant age was 5 (range, 0-23) months; median maternal KI dose, 50 (4-100) mg/day; median blood TSH level, 2.7 (0.1-12.3) µIU/mL; and median blood FT4 level, 1.04 (0.58-1.94) ng/dL. Blood TSH level was normal in 88/100 infants. Twelve infants had subclinical hypothyroidism; among them, blood TSH levels normalized after maternal KI withdrawal or stopping breastfeeding in 3 infants. In 7 infants, blood TSH levels normalized during KI administration without stopping breastfeeding. Two infants could not be followed up. CONCLUSION: In Japan, inorganic iodine therapy for lactating women with GD did not affect thyroid function in most of the infants. Approximately 10% of infants had mild subclinical hypothyroidism, but blood TSH level normalized during continued or after discontinuing iodine exposure in all followed up infants.

Effects of Inorganic Iodine Therapy Administered to Lactating Mothers With Graves Disease on Infant Thyroid Function.

CONTEXT: The effects of maternal inorganic iodine therapy on infant thyroid function are not well known. OBJECTIVE: This study investigated the effects on infant thyroid function of maternal inorganic iodine therapy when administered to lactating mothers with Graves disease. DESIGN AND SETTING: This study was a prospective case series performed at the Tajiri Thyroid Clinic, Kumamoto, Japan. PARTICIPANTS: Subjects were 26 infants of lactating mothers with Graves disease treated with potassium iodide (KI) for postpartum thyrotoxicosis. MAIN OUTCOME MEASURES: Infant blood levels of thyroid-stimulating hormone (TSH) and free thyroxine were measured using the dried filter-paper method. Iodine concentrations in breast milk and infant urine were measured on the same day. Subclinical hypothyroidism was defined as a blood TSH level of ≥10 or ≥5 µIU/mL in <6-month-old and 6- to 12-month-old infants, respectively. RESULTS: The median age of the infants was 3 months (range, 0 to 10 months). The median KI dose was 50 mg/d (range, 10 to 100 mg/d). High median iodine concentrations were detected in breast milk (15,050 µg/L; range, 831 to 72,000 µg/L) and infant urine (15,650 µg/L; range, 157 to 250,000 µg/L). Twenty-five of 26 infants had normal thyroid function. Although one infant had subclinical hypothyroidism (blood TSH, 12.3 µIU/mL), the TSH level normalized to 2.3 µIU/mL at 2 months after KI discontinuation. CONCLUSION: In Japan, where iodine intake is sufficient, administration of inorganic iodine to lactating mothers with Graves disease did not affect thyroid function in most infants despite high levels of exposure to iodine via breast milk.

Antenatal management of recurrent fetal goitrous hyperthyroidism associated with fetal cardiac failure in a pregnant woman with persistent high levels of thyroid-stimulating hormone receptor antibody after ablative therapy.

High titer of maternal thyroid-stimulating hormone receptor antibody (TRAb) in patients with Graves' disease could cause fetal hyperthyroidism during pregnancy. Clinical features of fetal hyperthyroidism include tachycardia, goiter, growth restriction, advanced bone maturation, cardiomegaly, and fetal death. The recognition and treatment of fetal hyperthyroidism are believed to be important to optimize growth and intellectual development in affected fetuses. We herein report a case of fetal treatment in two successive siblings showing in utero hyperthyroid status in a woman with a history of ablative treatment for Graves' disease. The fetuses were considered in hyperthyroid status based on high levels of maternal TRAb, a goiter, and persistent tachycardia. In particular, cardiac failure was observed in the second fetus. With intrauterine treatment using potassium iodine and propylthiouracil, fetal cardiac function improved. A high level of TRAb was detected in the both neonates. To the best of our knowledge, this is the first report on the changes of fetal cardiac function in response to fetal treatment in two siblings showing in utero hyperthyroid status. This case report illustrates the impact of prenatal medication via the maternal circulation for fetal hyperthyroidism and cardiac failure.

[Management of Graves' disease and hypothyroidism in pregnancy].

In the treatment of pregnant patients with Graves' disease, propylthiouracil is preferred over methimazole in early pregnancy because of a possible teratogenicity of methimazole. Methimazole is preferable to propylthiouracil in other time of pregnancy on the basis of severe liver dysfunction occasionally caused by propylthiouracil. Fetal hypothyroidism can be avoided when maternal free T4 levels are maintained at or above the upper normal limit for non-pregnant subjects. However, maternal free T4 should be kept normal for pregnant reference range when pregnancy complications develop. Fetal hypothyroidism in this setting will not affect the infant's development as long as mothers are euthyroid and the infants recover from hypothyroid state within a short time after birth. In hypothyroid women, 1-T4 dose often needs to be increased in pregnancy. Maternal T4 deficiency in early pregnancy has been suggested to affect normal brain development in the offspring. However, it has recently been shown in iodine rich area that no adverse effect on neuropsychological development was seen irrespective of the severity of maternal T4 deficiency. Insufficient iodine intake in the mother can cause low T4 in pregnancy and also inadequate production of T4 in breast-fed infants when sufficient T4 is essential for normal brain development.

Neurodevelopment in children born to hypothyroid mothers restored to normal thyroxine (T4) concentration by late pregnancy in Japan: no apparent influence of maternal T4 deficiency.

CONTEXT: The importance of maternal T4 for brain development prior to the onset of fetal thyroid function has been suggested in basic studies, and a correlation between mild maternal T4 deficiency in early gestation and disturbance of neurodevelopment in progenies has been shown in large case-control studies. These findings suggest that maternal T4 deficiency in early pregnancy potentially affects neurointellectual development. On the other hand, no apparent adverse effect in children born to mothers with overt hypothyroidism in Japan has been reported where maternal T4 had been restored to normal by late pregnancy. OBJECTIVE: We report five cases in Japan showing no apparent effect of maternal T4 deficiency on neurodevelopment in progenies where low T4 levels had been corrected by late pregnancy. METHODS: Five women with overt hypothyroidism detected at 6-16 wk gestation initiated T4 treatment. Four women restored euthyroidism by the 20th week. One remained in a subclinical hypothyroid state. Developmental scores of their children were evaluated between 25 months and 11 yr of age by either the Tsumori-Inage Infant's Developmental Test or the Wechsler Intelligence Scale for Children-Third Edition and compared to those of corresponding siblings with no exposure to maternal hypothyroidism. RESULTS: The development scores of all the children turned out to be either normal or advanced. CONCLUSIONS: In iodine-sufficient areas, maternal T4 deficiency in early pregnancy does not necessarily affect neurodevelopment. Therefore, other potential factors altering neurodevelopment, such as iodine deficiency, must be investigated.

Persistent high TRAb values during pregnancy predict increased risk of neonatal hyperthyroidism following radioiodine therapy for refractory hyperthyroidism.

Serum levels of TSH receptor antibody (TRAb) often increase after radioiodine treatment for Graves' disease, and high-serum levels of maternal TRAb in late pregnancy indicate a risk of neonatal hyperthyroidism. The aim of this retrospective study is to investigate the characteristics of Graves' women who had a history of radioiodine treatment for intractable Graves' disease, and whose neonates suffered from hyperthyroidism. The subjects of this study were 45 patients with Graves' disease who became pregnant during the period from 1988 to 1998 after receiving radioiodine treatment at Ito Hospital. 25 of the 45 subjects had had a relapse of hyperthyroidism after surgical treatment for Graves' disease. 19 pregnancies were excluded because of artificial or spontaneous abortion. In the remaining 44 pregnancies of 35 patients, neonatal hyperthyroidism developed in 5 (11.3%) pregnancies of 4 patients. Serum levels of TRAb at delivery were higher in patients whose neonates suffered from hyperthyroidism (NH mother) than those of patients who delivered normal infants (N mother). Furthermore, serum levels of TRAb in NH mother did not change during pregnancy, although those of 4 patients of N mother, in which serum levels of TRAb before radioiodine treatment were as high as in NH mother, decreased significantly during pregnancy. In conclusion, women who delivered neonates with hyperthyroidism following radioiodine treatment seem to have very severe and intractable Graves' disease. Persistent high TRAb values during pregnancy observed in those patients may be a cause of neonatal hyperthyroidism.

[Current problems in the treatment of Graves' disease in pregnancy and in lactation].

In Graves' patients complicated by pregnancy, both maternal and fetal problems related to the disease can be reduced or avoided by controlling hyperthyroidism. However, optimal treatment for mothers may exert detrimental effects on fetuses. Methimazole may cause "methimazole embryopathy". Antithyroid drug doses that maintain mothers in euthyroid status are sometimes excessive fetuses. Furthermore, successful treatment with surgery or radioiodine occasionally may result in fetal hyperthyroidism due to TSH receptor antibody(TRAb). There are approaches to manage these problems. Propylthiouracil is chosen in treating Graves' disease in early pregnancy. In later pregnancy, maternal free thyroxine is maintained near or somewhat above normal. Ablative therapy is not recommended in women whose TRAb levels are extremely high from the standpoint of fetal thyroid state.

Ratio of serum free triiodothyronine to free thyroxine in Graves' hyperthyroidism and thyrotoxicosis caused by painless thyroiditis.

The serum T3 to T4 ratio is a useful indicator for differentiating destruction-induced thyrotoxicosis from Graves' thyrotoxicosis. However, the usefulness of the serum free T3 (FT3) to free T4 (FT4) ratio is controversial. We therefore systematically evaluated the usefulness of this ratio, based on measurements made using two widely available commercial kits in two hospitals. Eighty-two untreated patients with thyrotoxicosis (48 patients with Graves' disease and 34 patients with painless thyroiditis) were examined in Kuma Hospital, and 218 patients (126 with Graves' disease and 92 with painless thyroiditis) and 66 normal controls were examined in Ito Hospital. The FT3 and FT4 values, as well as the FT3/FT4 ratios, were significantly higher in the patients with Graves' disease than in those with painless thyroiditis in both hospitals, but considerable overlap between the two disorders was observed. Receiver operating characteristic (ROC) curves for the FT3 and FT4 values and the FT3/FT4 ratios of patients with Graves' disease and those with painless thyroiditis seen in both hospitals were prepared, and the area under the curves (AUC), the cut-off points for discriminating Graves' disease from painless thyroiditis, the sensitivity, and the specificity were calculated. AUC and sensitivity of the FT(3)/FT(4) ratio were smaller than those of FT(3) and FT(4) in both hospitals. The patients treated at Ito hospital were then divided into 4 groups according to their FT4 levels (A: < or =2.3, B: >2.3 approximately < or =3.9, C: 3.9 approximately < or =5.4, D: >5.4 ng/dl), and the AUC, cut-off points, sensitivity, and specificity of the FT(3)/FT(4) ratios were calculated. The AUC and sensitivity of each group increased with the FT4 levels (AUC: 57.8%, 72.1%, 91.1%, and 93.4%, respectively; sensitivity: 62.6%, 50.0%, 77.8%, and 97.0%, respectively). The means +/- SE of the FT3/FT4 ratio in the Graves' disease groups were 3.1 +/- 0.22, 3.1 +/- 0.09, 3.2 +/- 0.06, and 3.1 +/- 0.07, respectively, versus 2.9 +/- 0.1, 2.6 +/- 0.07, 2.5 +/- 0.12, and 2.3 +/- 0.15, respectively, in the painless thyroiditis groups. In the painless thyroiditis patients, the difference in the FT3/FT4 ratio between group A and group D was significant (p<0.05). Thus, the FT3/FT4 ratio in patients with Graves' disease likely remains unchanged as the FT4 level rises, whereas this ratio decreases as the FT4 level rises in patients with painless thyroiditis. In conclusion, the FT3/FT4 ratios of patients with painless thyroiditis overlapped with those of patients with Graves' disease. However, this ratio was useful for differentiating between these two disorders when the FT4 values were high.

Stimulation of thyroid-stimulating hormone (TSH) receptor antibody production following painless thyroiditis.

OBJECTIVE: Development or recurrence of Graves' disease (GD) following painless thyroiditis (PT) has been documented. Therefore, we measured titres of TSH receptor antibodies (TSHR Ab) using a novel sensitive TSHR Ab assay in patients with PT to determine whether PT enhances TSHR Ab production, possibly triggering the development or recurrence of GD. DESIGN AND MEASUREMENTS: Ninety-two patients who developed PT were studied. Group G consisted of 40 patients with a history of GD (19 patients in remission, 21 who had stopped taking antithyroid drugs during pregnancy). Group P consisted of 52 patients with no history of GD. Serum thyroid hormone levels, thyroid autoantibodies including TSHR Ab, and 123I uptake at 24 h (RAIU) were measured in these patients at the time of PT onset. TSHR Abs were measured by radioreceptor assay using porcine TSH receptors (pTBII) or human TSH receptors (hTBII). RESULTS: There were no significant differences in serum thyroid hormone levels or pTBII values between groups G and P. Nor was there any significant difference between p- and h-TBII values in group P. There was also no significant difference in pTBII levels before, compared to at the time of PT onset in group G patients. However, hTBII values at the PT onset were significantly higher in the group G than in the group P (7.7 +/- 9.8%vs. 1.4 +/- 5.4%, P = 0.0014). The rate of hTBII positivity was also significantly higher in group G than in group P (12/40 vs. 3/52, P = 0.002). Furthermore, the RAIU in group G patients was significantly higher than that in group P patients (2.8 +/- 2.4%vs. 1.3 +/- 0.9%, P = 0.0002). GD recurrence was observed in seven patients in group G, whose hTBII levels were significantly higher than those of other patients in this group (17.0 +/- 11.8%vs. 5.7 +/- 8.2%, P = 0.02). Of these seven with relapses, five had hTBII values exceeding 15%. CONCLUSIONS: TBII elevation at the onset of PT in patients with a history of GD was detected by a sensitive hTBII assay. Destruction of the thyroid by PT may trigger GD recurrence in patients with a history of GD.