Clinical features of neonatal Graves’ disease revealed by twelve cases that require- antithyroid therapy

Abstract

Neonatal Graves’ disease (GD) is rare and serious condition with a complicated clinical course, its details of the clinical features have not been clarified. This study aimed to clarify the clinical course of neonatal GD cases requiring anti-thyroid treatment. We retrospectively analyzed records from 12 neonates (7 males) diagnosed with GD from 2012 to 2021. All neonates had maternal histories of GD, with significantly elevated TRAb levels (≥ 19 IU/L) observed during the second or third trimester of pregnancy. At birth, TRAb levels were elevated in all neonates (≥ 17.4 IU/L). Thiamazole (MMI) was given to 11 neonates, with additional potassium iodide (KI) and/or β-blockers in 10 cases; one received only KI and a β-blocker. Notably, maternal TRAb levels during late pregnancy were significantly correlated with neonatal TRAb levels at birth (R² = 0.8454, p = 0.027), and neonatal TRAb levels at birth were significantly associated with the duration of MMI treatment (R² = 0.750, p = 0.002). Secondary central hypothyroidism was observed in 33% of cases (4/12), with unmeasurably low TSH levels at birth (< 0.01 μIU/mL) as a significant risk factor for its development (p < 0.03). These findings suggest that maternal TRAb levels significantly influence neonatal TRAb levels at birth, and neonatal TRAb levels may predict the duration of anti-thyroidal treatment.

Highlight

● Maternal TRAb levels were significantly associated with neonatal TRAb levels.

● Neonatal TRAb levels at birth serve as a predictor of treatment duration.

● Undetectable TSH at birth have a higher risk of secondary central hypothyroidism.

Introduction

Graves’ disease (GD) is an autoimmune disease characterized by hyperthyroidism caused by thyroid-stimulating hormone (TSH) receptor antibodies (TRAb) that belong to the immunoglobulin class G (IgG). As IgG crosses the placenta (1, 2), maternal TRAb can cause overstimulation of the fetal and neonatal thyroid gland, leading to neonatal hyperthyroidism, namely neonatal GD (2,3,4,5,6). Neonatal GD occurs in approximately 1 to 5 percent of infants born to mothers with GD, and based on the prevalence of GD in pregnant women (7, 8), neonatal GD is expected to occur in approximately 1:25,000–50,000 neonates with both sexes equally affected (3, 4, 9, 10). Despite its self-limited nature, neonatal GD is one of the most serious conditions in neonates with a mortality of up to 20% (11,12,13), and may have deleterious effects on neural development (14).

As antithyroid drugs cross the placenta (15), the clinical course and severity of neonatal GD depend on the balance between the transmitted TRAb and the antithyroid drug administered to the mother (2). The plasma levels of anti-thyroid drugs decrease with time according to their clearance. The duration of antithyroid action is 36 to 72 h for thiamazole (MMI) (16). In contrast, the half-life of IgG in the serum is longer, approximately 12 d (17) and a median TRAb elimination is 20 d (5). Therefore, neonates from a mother whose thyroid function is normally controlled by MMI, typically are euthyroid to mildly hyperthyroid at birth, and, within a week after birth, develop hyperthyroidism that persists for several weeks (18).

In addition to hyperthyroidism, some neonates develop secondary central hypothyroidism after the disappearance of TRAb from the plasma (19, 20). This condition is presumably caused by long-term exposure to TRAb during fetal life, shifting the set-point of TSH secretion in the negative feedback loop of thyroid releasing hormone (TRH)-TSH-triiodothyronine (T3)/thyroxine (T4) (2, 19, 21, 22). Appropriate and prompt levothyroxine (LT4) replacement is essential to ensure normal development and growth. Secondary central hypothyroidism is transient and usually resolves between the ages of 3 and 19 mo. There are several opinions on weaning and ceasing LT4 replacement, and some physicians advise continuing the treatment until 3 yr of age (2). Furthermore, no biomarkers have been identified to predict secondary central hypothyroidism.

In this study, we analyzed the clinical courses of twelve neonatal GD cases that required anti-thyroidal treatment, providing insights into the clinical characteristics of neonatal GD.

Subjects and Methods

Ethics

The study protocol of the present study was approved by the Ethics Committee of Tokyo Medical and Dental University (M2020-011).

The subjects

Twelve neonates (male: 7; female: 5) with GD required anti-thyroidal treatment and diagnosed between 2012 and 2021 in a neonatal care unit were included in this study. None of the subjects had any comorbidity other than fetal-neonatal hyperthyroidism and its related clinical symptoms. A retrospective analysis based on medical records was performed (Table 1).

Table 1. Maternal and neonatal data of the 12 cases with neonatal Graves’ disease.

Collecting sample

Neonatal thyroid function (TSH, free-T4 (fT4), free-T3 (fT3)), TRAb, and TSAb levels at birth were measured using cord or vein blood collected within 24 h after delivery. Maternal thyroid function and TRAb levels were represented by the data obtained from the second to third trimester of the pregnancy. Due to limited number of the data, we excluded TSAb for further analysis

The basic principles of the clinical management

All neonates born to mothers with GD or high TRAb values had their TRAb and thyroid function measured, and those with elevated TRAb levels had their thyroid function measured regularly.

When the neonates developed elevated thyroid hormone levels, fT4 levels more than 2.0 ng/dL, or fT3 levels more than 5.0 pg/mL, or an apparent increase in fT4 levels with extremely low levels of TSH (< 0.1 IU/mL), treatment with MMI was initiated. MMI was introduced during the first week of life except in one case in which only potassium iodide (KI) was used as an antithyroid drug. The MMI dose was adjusted according to the fT4 and fT3 levels. KI was added to the initial treatment and continued until when the MMI dose reached its peak.

Maternal thyroid function was considered poorly controlled when high fT4 levels (> 2.0 ng/dL) were documented in the second trimester. The criterion for secondary central hypothyroidism was low TSH levels (< 1.0 μIU/mL), even when the fT4 levels were below 1.0 ng/dL. LT4 was administered to patients with secondary central hypothyroidism and their thyroid function was repeatedly evaluated.

Assay

The electrochemiluminescent immunoassay (ECLIA) Elecsys1 anti-TSH-R method with the human monoclonal TSH receptor stimulating autoantibody, M22, was employed for the third generation TRAb assay. For the second generation assay, the DYNOtest TRAb human kit (TRAb-Dyno) (Yamasa Corporation, Tokyo, Japan©) was used (23, 24). The precise relationship between the second generation TRAb (TRAK) and third generation TRAb (Elecsys TRAb) was examined by the samples obtained from 68 patients with GD, 18 with destructive thyroiditis patients, and two with subacute thyroiditis (25), yielding a correction formula of “y (Elecsys TRAb) = 1.020x (TRAK) –0.224”. The values of TRAK were converted according to this formula.

In our cohort, two measuring systems, electrochemiluminescence immunoassay (ECLIA, Roche Diagnostics)(Case #1–8) and chemiluminescent immunoassay (CLIA, Abbott Japan)(Case #9–12), were used for TSH, fT4 and fT3. Due to inter-assay variability, we employed conversion formulas according to the previous study in which 165 euthyroid samples were verified (26). The conversion formulas were y = 0.79x–0.00, y = 0.61x+0.25, and y = 0.54x+0.65 for TSH, fT4, and fT3, respectively [Abbott’s CLIA method (y) and Roche’s ECLIA method (x)].

Statistical analysis

All analyses were performed using a statistical software, JMP®Pro 15.1.0 (SAS Institute Inc., Cary, NC, 1989–2023). For analyses depicted in two or more variables and those with a single variable, regression without intercept analyses and Mann-Whitney analysis were used, respectively. Fisher’s test was used to examine the risk of low TSH levels of the neonates in the development of secondary central hypothyroidism.

Results

The maternal and neonatal TRAb levels were significantly associated

In all cases, maternal GD was diagnosed before delivery and maternal TRAb levels were above the normal range. TRAb was elevated in all neonates (≥ 17.4 IU/L). The average gestational age and birth weight of the neonates was 37.4 wk (range: 34–41 wk) and 2,800 grams (range: 1,752–3,388 g), respectively. We confirmed the normal distribution of both gestational age (p = 0.9259) and birth weight (p = 0.6168) by Shapiro-Wilk test (p > 0.05). Intrauterine growth failure with birth weight less than –2SD were not observed (Table 1). Eleven neonates were administered MMI (Table 1) due to increased levels of both fT3 and fT4 (#1–3, 5–7, 11, 12) or increased levels of either of them (#8–10) (Table 1, Supplementary Table 1). One patient (#4) developed slowly progressive hyperthyroidism that was treated solely using KI without MMI. Additional treatment with KI and/or a β-blocker was performed in eleven subjects. One neonate was treated with KI and a β-blocker without MMI (Table 1). We did not treat the mother of #5 because the levels of fT3 and fT4 did not elevate. The mother of #7 was diagnosed with Graves’ disease just before the delivery.

We assessed the relationship between maternal TRAb levels in the third trimester of pregnancy and neonatal TRAb levels at birth. TRAb of some samples was measured after dilution, resulting in values higher than the maximum limit of the assay systems. While, values exceeding the measurable range of the assay and samples collected in the second trimester were excluded. Although the sample size was small (n = 5), a significant correlation (n = 5, R2 = 0.8454, p = 0.027) was observed. The regression line was defined as y = 0.4662x. (Fig. 1A)

Fig. 1.

A: Scatter plots and regression lines of the relationship between maternal (3^rd trimester) and neonatal TRAb levels. Maternal TRAb levels were significantly associated with neonatal TRAb levels. (R2 = 0.8454, p = 0.027) B, C: Scatter plots and regression line of the relationship between neonatal TRAb values and duration (B) / maximum dose of MMI (C). Neonatal TRAb levels were significantly associated with the duration of MMI treatment (B) (R² = 0.750; p = 0.002), but not with the maximum dose of MMI (R² = 0.313; p = 0.092) (C).

The TRAb values were significantly positively correlated with the duration of MMI treatment for the neonates (n = 9, R² = 0.750, p = 0.002), and the regression line was defined as y = 1.1746x (Fig. 1B). On the contrary, the maximum dose of MMI was not significantly associated with the TRAb levels (Fig. 1C). During the MMI treatment for the neonates, no major adverse effects, such as agranulocytosis, were documented.

Subsequently, we examined whether maternal control during pregnancy affected the severity of neonatal hyperthyroidism. We compared the highest fT3 and fT4 levels and the lowest TSH levels in neonates between the controlled and poorly controlled groups and found no significant differences (Fig. 2). We also evaluated the association between maternal TRAb levels and the severity of hyperthyroidism, i.e., the highest fT3/fT4 levels, and the lowest TSH levels in neonates, although no significant association was observed (data not shown).

Fig. 2.

Neonatal hyperthyroidism was not affected by the control of maternal thyroid function during pregnancy. When fT4 levels were more than 2.0 ng/dL in the second trimester, maternal thyroid function was considered to be poorly controlled. P, Properly controlled; W, Worse controlled.

Neonates with measurable TSH at the age of 0 d would not develop secondary central hypothyroidism

Four neonates (33%, 4/12) developed secondary central hypothyroidism that required LT4 replacement (Table 1). In all the cases, the required LT4 replacement was transient, and after treatment cessation, hypothyroidism was not documented on repeated thyroid function screening.

The average age at the time of introduction of LT4 replacement was 38.0 d (range: 17–60 d). To identify the risks factors for secondary central hypothyroidism, we evaluated neonatal factors: MMI treatment (maximum dosage, duration, and d of age at introduction of the therapy) and TSH and TRAb at birth, and maternal factors: TRAb (second-third trimester), fT4, and fT3 levels. As a result of this evaluation, the neonatal TSH level was significantly lower in the group that developed secondary central hypothyroidism than in the non-affected group (p = 0.030, one-sided Mann-Whitney U test). This suggests that low neonatal TSH may be an early risk indicator for subsequent central hypothyroidism. (Fig. 3A). Furthermore, neonates with unmeasurably low TSH levels, < 0.01 μIU/mL, had significantly greater chances of developing secondary hypothyroidism (Fig. 3B).

Fig. 3.

Box-and-whisker plot comparing neonatal TSH levels (log₁₀-transformed) between the group that developed secondary central hypothyroidism (case group) and the non-affected group (control group). TSH levels at birth were significantly lower in the case group (n = 4) compared to the control group (n = 8) (p = 0.030, one-sided Mann–Whitney U test). Boxes indicate the interquartile range (IQR), horizontal lines within boxes represent medians, and whiskers extend to the most extreme values within 1.5 × IQR from the quartiles. No outliers were detected.(A). Fisher’s test, with the cut off value of TSH at 0.01 μIU/mL, confirmed that unmeasurably low TSH levels are significantly the risk for secondary hypothyroidism (B). The TSH values of TRH stimulating tests performed at 1 and 2 yr of life in a case with secondary central hypothyroidism (C). At the age of 1 yr, the TSH secretion of the patient was severely reduced with a peak level of 0.294 μIU/mL. However, at the age of 2 yr, the peak value recovered to 14.3 μIU/mL (within the normal range).

In one case (#2), hypothyroidism lasted for a year and we repeated TRH stimulation tests at the ages of one and two years, revealing an apparent recovery in TSH secretion (Fig. 3C). TRH stimulation tests were performed with the administration of LT4. After the discontinuation of LT4, the patient did not exhibit hypothyroidism. Currently, the patient is 5 yr old, and neurodevelopmental complications have not been identified yet. The clinical course of the cases with secondary central hypothyroidism is illustrated in Supplementary Fig. 1.

Discussion

Our cohort study highlights five clinical points: (a) Maternal TRAb levels in the second or third trimester are significantly associated with neonatal TRAb levels at birth, (b) Neonatal TRAb values at birth approximately predict the duration of required MMI treatment, (c) The severity of hyperthyroidism in neonates cannot be predicted by maternal control of thyroid function during pregnancy nor by the TRAb levels of the neonates, (d) Neonates with secondary central hypothyroidism accounted for 33% of neonatal hyperthyroidism cases, (e) unmeasurably low TSH levels at birth are a risk factor for the development of secondary central hypothyroidism.

It has been reported that maternal TRAb levels are useful for predicting the development of neonatal hyperthyroidism, and potential correlations between maternal and neonatal TRAb levels have been documented (27, 28). The ratio between maternal-neonatal IgG is variable according to an antibody (29, 30), and the details of the relationship between the two parameters were not clarified yet. One reason for this is that first-generation TRAb assays are competition-based and potentially unsuitable for determining the precise relationship between maternal and neonatal TRAb levels (31, 32). Our present study was based on the second- and third-generation TRAb assays, which enabled us to determine the relationship. Although the ratio between maternal and neonatal IgG varies by its antigen (29, 30), the ratio determined in the present study (0.4073) seems to be within the previously reported range for other IgGs (29, 30).

We presume that the maternal and neonatal IgG ratio of 0.4662 is legitimate, considering previous reports of the maternal TRAb cutoff value for the risk of neonatal GD. A study of 47 newborns of mothers with measurable TRAb levels revealed that a maternal serum TRAb level of more than 5 IU/L predicted neonatal hyperthyroidism with 100% sensitivity and 43% specificity [33]. Among Japanese Graves’ Deiease patients (n = 145) who conceived within two years after RAI therapy, the cutoff TRAb value in the third trimester for predicting neonatal Graves’ disease was 9.7 IU/L (34). Similarly, a recent systematic review revealed that the lowest maternal TRAb level leading to neonatal thyrotoxicosis was 4.4 IU/L (35). An IgG ratio of 0.4662 predicts that the cutoff value of the neonate for hyperthyroidism is approximately 2.0–2.5 IU/L, typically identical to the upper limit of the normal range of TRAb.

GD duration has been suggested to depend on the initial TRAb level at birth, with neonatal GD generally resolving by 6 mo after birth (2, 33, 36). Our study revealed an association between the required MMI treatment duration and TRAb levels in neonates at birth. In contrast, the maximum dose of MMI was not associated with neonatal TRAb levels. It indicates that the therapeutic intensity was not determined by only MMI due to co-administration with other anti-thyroidal agents, KI.

The severity of hyperthyroidism in neonates cannot be predicted by maternal thyroid function during pregnancy. The impact of maternal thyroid function on neonatal thyroid function is minor because the placental transmission of TSH and thyroid hormones is limited. Neonatal TRAb levels were not associated with the severity of hyperthyroidism, such as maximum values of fT3 and fT4, suggesting that the severity of hyperthyroidism is determined by other factors, probably intervention. The finding implies that, even in neonates with high TRAb levels, appropriate intervention can prevent the development of severe neonatal hyperthyroidism.

As the severity of hyperthyroidism in neonates, our study revealed that the timing of treatment initiation among cases was various. In cases #3, #4, #8, and #10, the timing of treatment was delayed from 6–10 d, compared to those # 1, #9, and #11, from 1–3 d. Our analysis did not identify the factors that predict the timing of developing hyperthyroidism. We presume that the timing may be influenced by individual pharmacokinetics which affect the duration of the antithyroid drug’s effect, maternal thyroid function control status, and TRAb levels. These factors may have contributed to differences in the timing of neonatal hyperthyroidism onset.

Our study revealed that one-third of neonates with GD which required anti-thyroidal treatment developed secondary central hypothyroidism. Although secondary central hypothyroidism has been recognized as a major complication of neonatal GD (2, 19, 21, 22), data demonstrating its precise prevalence among neonates treated with anti-thyroid treatment are limited. Additionally, our study revealed that neonates with unmeasurably low TSH levels at birth are at risk of secondary central hypothyroidism. Unmeasurably low TSH levels is the consequence of massive exposure to transmitted TRAb during the fetal period. Neonates with low TSH levels at birth should be monitored repeatedly after the resolution of hyperthyroidism. Although recovery from hypothyroidism is usually observed between 3 and 19 mo of age (21, 37), there is no standardized approach for evaluating recovery from secondary central hypothyroidism (2, 21). As observed in case #7, premature birth would affect the recovery form secondary central hypothyroidism, although limited number of our cohort leave it inconclusive. Based on our study, repeated TRH stimulation tests would be one of the options to evaluate the recovery in regions where recombinant TRH is available.

The mother of case #2 was post-thyroidectomy, and her TRAb levels remained high, leading to neonatal GD despite euthyroid. Likely, the suppression lasted longer than in neonates whose mothers were treated with antithyroid drugs, potentially having deteriorated secondary central hypothyroidism. In such cases, a treatment has been proposed to prevent fetal GD by orally administering ATD to the mother with simultaneous administration of L-T4. Although no specific fetal abnormalities were documented in this case, it is possible that characteristic signs were not adequately assessed during pregnancy. Recent reports have emphasized the importance of careful fetal monitoring in pregnancies complicated by elevated maternal TRAb levels—even in euthyroid women following total thyroidectomy (38,39,40). Typical findings suggestive of fetal Graves’ disease include persistent fetal tachycardia, advanced bone maturation, and intrauterine growth restriction (IUGR). Among these, fetal tachycardia (heart rate >160 bpm) is considered the earliest and most sensitive marker, and its detection may serve as a trigger for timely maternal ATD therapy (38). Therefore, in similar cases, strict monitoring of maternal TRAb levels and serial fetal ultrasound examinations are warranted to enable early diagnosis of fetal thyroid dysfunction and consideration of preventive treatment strategies, ultimately improving neonatal outcomes (39, 41).

Another point highlighted by our present study is the clinical significance of the extremely low levels of TSH at birth. For late-onset hypothyroidism, timely intervention is required. It is challenging to determine whether extremely low levels of TSH in cord blood are from transient thyrotoxicosis or from underlying central hypothyroidism, and vigilant follow-up with continuous endocrinological monitoring is essential for neonates whose TSH level is extremely low at birth.

Our study has several limitations. First, the population of our cohort was small, this may have prevented the identification of biomarkers for predicting the severity of hyperthyroidism and secondary central hypothyroidism in neonates. Second, TRAb values that were higher than the measurement ranges were not included in the analysis, and this may have affected the results. Third, we were unable to evaluate the functional activity of the thyroidal antibody, such as TSAb, because of data unavailability. Fourth, long-term outcomes, including neurodevelopmental problems, were not examined in our study, and the long-term comorbidities of neonatal hyperthyroidism remain unclear.

In summary, we analyzed a cohort of twelve neonatal GD cases to reveal the clinical features of neonatal GD. The significant association between maternal and neonatal TRAb levels would enable us to estimate the neonatal TRAb level based on the maternal value. Furthermore, early monitoring and intervention in collaborating with an obstetrician and endocrinologist are essential for preventing severe neonatal hyperthyroidism. Unmeasurably low TSH levels, less than 0.01 μIU/mL at birth may be a risk for secondary central hypothyroidism. Our analysis provides insights for further improvements in the clinical management of neonatal hyperthyroidism.

Conflict of interests

All authors have no conflicts of interest to declare.

Data availability statements

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.