Background/Aims: Neonates and infants whose mothers have Graves’ disease (GD) may suffer from central hypothyroidism (CH) after recovery from transient hyperthyroidism. Fetal and neonatal TSH producing cells are presumably suppressed under mothers’ GD in gestational GD-related CH (gG-CH). This suppression is due to thyrotoxicosis due to the transfer of TSH-receptor stimulating antibody through the placenta. However, little research has considered how long fetal TSH producing cells are suppressed by thyrotoxicosis in gG-CH. The present review was designed to identify the duration of fetal TSH suppression, which could lead to the development of gG-CH. Methods: Meta-analysis including our own case was done. Using 31 previously reported gG-CH cases, we estimated the duration of fetal hyperthyroidism, which led to TSH suppression.

Results: The shortest duration of thyrotoxicosis after 22weeks of GA was 5-7weeks and the longest one was 18weeks. Conclusion: Our results suggest that fetuses with TSH suppression duration of more than 5-7weeks from 22GA may be at risk for developing gG-CH.

Keywords: gestational graves’ disease, central hypothyroidism, fetal pituitary-thyroid axis, thyrotoxicosis

GD, graves’ disease; CH, central hypothyroidism; gG-CH, gestational GD-related CH; TSH, hyroid stimulating hormone

Neonates born to mothers with Graves’ disease (GD) may present with various thyroid dysfunctions, including transient hyperthyroidism and hypothyroidism.^1‒8 Thyroid dysfunctions may be due to the placental transfer of thyroid stimulating hormone (TSH)-receptor stimulating antibody and anti-thyroid agents. A rare condition, gestational GD-related central hypothyroidism (gG-CH), could develop after transient hyperthyroidism, which is known to be due to the transfer of TSH-receptor stimulating antibody through the placenta.⁹ At least two factors may contribute to the development of gG-CH: 1) high TSH-receptor stimulating antibody titers (with or without high thyroid hormone levels in the mother), leading to the transfer of these antibodies through the placenta, and 2) fetal and neonatal TSH suppression, which leads to a blunted ability to establish the negative feedback system of the pituitary-thyroid axis in the fetus, neonates, and infants.¹⁰

Based on clinical knowledge, it is clear that not all neonates born to gestational mothers with GD will develop gG-CH. Therefore, we hypothesized that certain duration of fetal hyperthyroid environment and its subsequent TSH suppression may be necessary for TSH to remain suppressed, even after the remission of hyperthyroidism in the newborns. To test this hypothesis, the present study evaluated the duration of fetus hyperthyroidism in reported patients with gG-CH.

The purpose of this study was to determine the minimum duration of fetal hyperthyroidism, which could lead to fetal TSH suppression, for the development of gG-CH by examining previously reported patients.

Data collection and meta-analysis

“PubMed” and “Google Scholar” databases were searched for reported cases of gG-CH. Using the keywords “maternal hyperthyroidism/GD and central hypothyroidism,” or “thyrotoxicosis/GD and central hypothyroidism”. This search resulted in 51 articles. Based on initial assessment, 24 of the identified 51 articles were subsequently screened for the potential cases, which were confirmed by the two authors. Cases were included if they met both of the following criteria: (1) Diagnosis of maternal GD, defined as undetectable levels of TSH with elevated fT3 and fT4 concentrations in addition to positive TSH-receptor stimulating antibody values at any time during pregnancy, (2) Diagnosis of CH after birth, defined as fT4 concentrations <1.0ng/dl in combination with TSH levels <10µIU/ml without the use of anti-hyperthyroid therapy during the neonatal period or infancy. L-thyroxine was required in the cases since fT4 levels were low. The threshold for TSH levels was used to exclude cases with primary hypothyroidism, particularly those related to anti-thyroid drug use.

Based on the inclusion criteria, 31 cases from seven references^11‒19 were evaluated. Based on the timing of the mothers’ diagnosis of GD, cases were divided into three groups (A, B, and C). For cases in Groups A (n=12) and B (n=9), mothers received a diagnosis of GD before and during their pregnancy, respectively. For cases in Group C (n=10), mothers were diagnosed during the postpartum period. Overall, 21 of the included 31 cases were reported in one paper,¹¹ 9 of the remaining 10 cases were reported from seven previous papers (including three Japanese journals),^12‒17 and one case was from our facility. The study protocol was approved by the Ethics Committee of Tokyo Metropolitan Children Medical Center.

Characteristics of included patients

Patient characteristics in Group A, B, and C are shown in Tables 1‒3, respectively. CH was diagnosed for a variable length of time after birth, ranging from 2 to 425days after birth, but the time of 425 days was exceptionally long compared to the others (Table 2).

The GA of delivery ranged across Groups A-C from 27 to 40weeks, with an average of 35.9weeks GA. Preterm deliveries (i.e., at less than 37weeks) represented 91.6%(11 cases) in Group A and 77.7%(7cases) in Group B, suggesting a tendency for premature labor under conditions reflecting poor thyroid function in these two groups.²⁰

Definition of duration of fetal hyperthyroidism during pregnancy

The duration of fetal hyperthyroidism during pregnancy was defined for each group using the following criteria.

Group A: All 12 cases in group A had histories of either poor control or absence of treatment for GD. The hyperthyroid state had started prior to pregnancy. Pituitary negative feedback has been reported to establish in the fetus at 22weeks GA^21,22as discussed later. Based on this timing, we used 22weeks as the initial point at which fetal TSH was suppressed by high thyroid hormones associated with elevated TSH-receptor antibody. Duration between 22weeks GA and the GA of delivery were subsequently calculated for each patient. For example, case 1 was delivered at 27weeks. Therefore, by subtracting 22 from 27weeks, the duration of hyperthyroidism was 5weeks.

Group B: For all cases in Group B, onset of fetal hyperthyroidism was defined as the GA at which maternal GD was diagnosed for the first time. Then, we calculated the duration of fetal hyperthyroidism by subtracting the GA of Graves’ disease diagnosis from the GA of delivery. For example, the GA of the delivery was at 37weeks and diagnosis of GD was given at 31weeks in case 13. Therefore, the duration of fetal hyperthyroidism was 6weeks. If GA of GD diagnosis was earlier than 22weeks of GA as in case 20, we assumed 22weeks was when suppression of fetal TSH began to occur, as explained for Group A.

Group C: Given that thyroid function was not measured during pregnancy, we could not estimate the starting point of thyrotoxicosis for patients in Group C. Based on the estimate of 22weeks as the first time when fetal TSH began to be suppressed as discussed above, we estimated duration of thyrotoxicosis during pregnancy by subtracting 22weeks from the GA of the delivery.

The calculated duration of hyperthyroidism during pregnancy ranged from 5-7weeks to 18weeks among the patients. Given that TSH suppression was estimated to begin at 22(see Methods and discussed later), earlier GA of delivery was associated with a shorter duration of hyperthyroidism in Group A. The shortest duration was observed in case 1. Across all groups, the longest duration was observed in case 30 and 31, and was 18weeks. No included cases of gG-CH were exposed to less than five weeks of hyperthyroidism. Observed exposure durations were 5-7weeks for 6 cases, 8-10weeks for 4 cases, 11-13weeks for 5 cases, and more than 14weeks for 16cases. In short, exposure to maternal thyrotoxicosis for 5-7weeks after 22weeks of GA could result in gG-CH.

Our results suggest that thyrotoxicosis during pregnancy for 5-7weeks after 22weeks of GA might lead to gG-CH. This is the first study paper to evaluate a link between duration of thyrotoxicosis during pregnancy and risk of gG-CH. Five weeks of exposure to thyrotoxicosis was the shortest period observed in the included cases.

Excessive thyroid hormones due to high TSH-receptor stimulating antibody transferred to the fetus through the placenta are necessary for fetal TSH levels to be suppressed. The presence of high TSH-receptor stimulating antibody titers in mothers appears to be more essential for the development of gG-CH than high thyroid hormone levels in mothers. This is based on the fact that a neonate born to his/her mother with euthyroid throughout pregnancy suffered from gG-CH.⁶ Research indicates that elevated levels of maternal TSH-receptor stimulating antibody titers are a risk factor for fetal hyperthyroidism^2,7,23,24 and are associated with the development of neonatal hyperthyroidism,²⁵ which could, in turn, result in developing gG-CH. In line with this notion, we found that high TSH-receptor stimulating antibody titers were overtly high in the mothers of all included cases (data not shown).

Several lines of evidence support the notion that TSH levels can be suppressed as late as 22weeks of GA in the fetus of gestational GD. First, IgG transfer from mother to fetus begins as early as 13weeks.²⁶ In particular, transplacental passage of TSH-receptor antibody was confirmed as early as 21weeks of GA.^17,27,28 Second, fetal Graves’ disease presented with undetectable TSH and remarkably elevated thyroid hormones in a patient of 20weeks of GA²⁹ Finally, an intra-amniotic thyroxine treatment for fetal hypothyroidism was successful with fetal TSH suppression at 22weeks of GA.^30,31 If fetal negative feedback was instead established at 20weeks GA, our results estimating the duration of hyperthyroidism during pregnancy would be extended by 2weeks.

It is reasonable to speculate that a certain minimum duration is needed to lead to the development of gG-CH. However, babies affected by this disorder could have a shorter duration of the exposure of fetal hyperthyroidism than that reported here. Unreported gG-CH cases in which thyrotoxicosis duration was less than 5weeks might exist.

Other limitations of this study warrant mention. First, this study was based on the assumption that fetal TSH negative feedback is established in 22weeks of GA as discussed above. Second, some cases with gG-CH that received treatment to combat hyperthyroidism may have been missed, given that neonates with this condition could recover spontaneously while tapering the dose of anti-thyroid drugs. This form of gG-CH is presumably self-limiting. On the other hand, we could emphasize that we have succeeded in answering to our initial clinical question raised, or how long fetal TSH producing cells are suppressed in gG-CH, by scrutinizing previous cases reported to have that condition.

Our results suggest that fetal TSH suppression for 5-7weeks after 22weeks GA could lead to the development of central hypothyroidism in babies born to mothers with uncontrolled gestational Graves’ disease during pregnancy.

We would like to thank Enago (www.enago.jp) for the English language review.

The authors declare no conflict of interest.

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