Mild Hypothyroidism in Childhood

Who, When, and How Should Be Treated?

Maria Cristina Vigone; Donatella Capalbo; Giovanna Weber; Mariacarolina Salerno

Disclosures

J Endo Soc. 2018;2(9):1024-1039. 

In This Article

Mild Hypothyroidism in Neonates

In the neonatal period, mild hypothyroidism can be defined by the presence of a TSH value between 6 and 20 mIU/L and normal FT4 levels.[2] Mild congenital hypothyroidism (CH) can be transient or permanent. Over the past years, the increased sensitivity in the TSH assay, the use of lowered TSH cutoff values, and an increased survival rate of a growing number of preterm babies have resulted in a progressively increased incidence of mild and potentially transient forms of CH.[8–11]

CH and, in particular, mild CH are more common in some risk categories such as preterm or ill neonates,[12] small for gestational age infants,[13] children born after in vitro fertilization (IVF),[14] and in multiple pregnancies.[15] In these categories of neonates, the initial screening tests may be inappropriate or provide normal results, and therefore the European Society for Pediatric Endocrinologist (ESPE) guidelines[2] suggest a strategy of second screening, at about 2 weeks of age or 2 weeks after the first screening test. Other risk factors that should be taken into account in the decision to perform the second screening test are the presence of chromosopathies, malformations, steroid treatment during pregnancy or in the neonatal period, and maternal thyroid dysfunction.

The optimal management of neonates with a mild isolated increase in TSH levels is still debated and should be individualized. Moreover, due to the potential neurodevelopmental impairment, each case of mild CH should be carefully monitored.

In the next subheadings, the peculiarity of each category of at-risk neonates and the management of mild hypothyroidism in the neonatal period are discussed.

Maternal Autoimmune Thyroid Disease

Autoimmune maternal thyroiditis is the most frequent cause of hypothyroidism during pregnancy. It could be related either to the presence of thyroid peroxidase antibodies or, rarely, TSH receptor antibodies (rTSH-Abs). Moreover, newborns of mothers treated with thionamide during pregnancy could develop a transient form of mild hypothyroidism because these antithyroid drugs are able to cross the placenta.[16]

In newborns of mothers affected by autoimmune thyroiditis, there is no consensus on whether to repeat thyroid function evaluation during the first month of life in addition to the first neonatal screening. Rovelli et al.[17] suggested to retest thyroid function between days 15 and 30 because they found a mild TSH increase in ~28% of a neonatal cohort. However, replacement therapy was not necessary in the majority of these patients (93.3%),[17] and they all presented a transient form of hypothyroidism (unpublished data). On the contrary, according to a more recent study from McGovern et al.,[18] the first neonatal screening seems to be able to identify all cases of mild hypothyroidism, and further thyroid function tests are not necessary.[18] In conclusion, further studies are required to clarify whether a second screening is needed for all newborns of mothers affected by autoimmune thyroiditis.

In addition to thyroid peroxidase antibodies, rTSH-Abs should be tested in case of neonatal hypothyroidism with autoimmune maternal thyroid disease and/or other siblings affected with transient CH.[2] The transplacental passage of TSH receptor-blocking antibodies is responsible for 2% of cases of CH in North America, with an incidence of 1:180,000 healthy children.[19] The alterations in neonatal thyroid function are usually transient as rTSH-Abs are cleared from the neonatal circulation in 3 to 4 months.[20] Nevertheless, replacement treatment should be started in some cases.[21] Moreover, the presence of blocking antibodies could also interfere with the scintigraphic iodine uptake of a normal eutopic gland.[22]

Prematurity and Low-birthweight Infants

Preterm and low-birthweight (LBW) neonates are at risk for hypothalamic-pituitary immaturity, premature loss of the contribution of transplacental T4 and iodine, limited thyroid gland reserve, immaturity of the mechanism of thermogenesis mediated by brown adipose tissue, persistent fetal thyroid hormone metabolism, and a high morbidity predisposing to euthyroid sick syndrome.[23] Moreover, the administration of certain drugs (dopamine, caffeine, phenobarbital, etc) can cause alterations of thyroid function.

Therefore, premature and LBW babies may face variable degrees of thyroid dysfunction such as CH, SH, hypothyroxinemia, euthyroid sick syndrome, and delayed TSH rise. However, prematurity seems to be associated with transient rather than permanent thyroid failure.[24]

Woo et al.[25] showed that CH with a delayed TSH elevation occurred in 1 in 58 extremely LBW and 1 in 95 very LBW (VLBW) infants, in comparison with only 1 in 30,329 infants weighing ≥1500 g (P < 0.0001). In the study by Cavarzere et al.,[26] 57.5% of LBW newborns presented CH with delayed TSH elevation and required L-T4 treatment, whereas the remaining infants presented SH (21.25%) or normal thyroid function (21.25%).

Although the effect of transient hypothyroxinemia of prematurity on the neurologic outcome has been extensively studied,[27–30] the impact of persistent SH on the neurologic development of preterm infants has not been adequately investigated. Woo et al.[25] showed that the developmental outcomes at 18-month corrected age in preterm infants with delayed TSH elevation were similar to control infants. However, this study was limited by the small sample size.

In conclusion, thyroid function should be carefully monitored in preterm and LBW infants. In a recent systematic review, Hashemipour et al.[12] recommend repeating the screening test in preterm, LBW, and VLBW infants at the age of 2, 6, and 10 weeks by measuring TSH and FT4 levels simultaneously and considering TSH of 10 mIU/L as the cutoff level for positive and suspicious cases.

According to ESPE guidelines,[2] we suggest a strategy of second screening at ~2 weeks of age in all preterm or LBW neonates and in neonates admitted to neonatal intensive care units. A strategy of an additional screening at 4 to 6 weeks of age might be considered in case of severe prematurity, VLBW, and critically ill neonates.

Twins

Recent studies reported a high incidence of CH with eutopic thyroid in multiple pregnancies. The incidence is nearly double in twin births compared with singletons and even higher with multiple births.[15,31] Data from the Italian National Registry of infants with CH have also shown a high frequency of twins that is threefold higher in the CH population (3.5%) than in the Italian general population (1.1%).[15] A high prevalence of twins among infants affected by transient hypothyroidism has also been reported.[15]

This increased CH risk in multiple pregnancies has important implications in terms of public health given the high number of induced pregnancies in Italy as well as in other Western countries.[32]

Twins born monozygotic usually show a delayed TSH rise, and thus rescreening at 2 to 4 weeks should be recommended.[2]

IVF

Onal et al.[14] showed a high prevalence of SH in IVF babies, being diagnosed in ~10% of the IVF neonates at postnatal ages of 2 weeks to 1 month. In addition, Sakka et al.[33] demonstrated a significantly higher prevalence of SH in children aged 4 to 14 years, conceived after IVF than in the control group, in the absence of detectable thyroid antibodies. A possible explanation provided by the authors was an epigenetic developmental abnormality in the set point of TSH sensitivity related to the preimplantation manipulation of the embryo.[33]

Currently, IVF neonates are not considered a special risk category by the screening programs. However, in view of the documented increased risk to develop SH, these patients should be carefully monitored.

Genetic Mutations

Even though CH is more frequently a sporadic disease, evidence has been provided that the CH population is significantly enriched with rare/low-frequency alleles in the CH related genes (NKX2-1, FOXE1, PAX8, GLIS3, JAG1, TSHR, SLC26A4, DUOX2, DUOXA2, TPO, TG), and the frequency of multiple gene involvement is two- to fourfold higher than in the control population.[34] Congenital thyroid dysfunction may also arise in the context of other complex disorders, such as Alagille syndrome type 1 due to JAG1 mutations (ALGS1)[35] and hepatic or parotid massive hemangiomas, which may produce the thyroid hormone–inactivating enzyme type 3 iodothyronine deiodinase.[36,37]

So far, only a few studies have focused on the incidence and/or the evolution of SH in these genetic forms, except for those related to mutations of DUOX2 and TSH receptor (TSHR) genes.

Loss-of-function variants of the TSHR are the most frequent causes of TSH resistance (RTSH) (OMIM 275200), causing various clinical phenotypes depending on the degree of the impairment of the TSHR function.[38,39] In case of biallelic variants, patients can have complete RTSH, resulting in severe hypothyroidism. Patients with monoallelic mutations have a partial RTSH, which results in nonautoimmune SH.[40] To date, at least 68 loss-of-function mutations of the TSHR have been described[39] with a variable prevalence (11% to 29%) depending on the population tested.[38,41–44] Most carriers have a positive family history for thyroid diseases.

The long-term follow-up of pediatric patients with SH due to RTSH showed a favorable clinical outcome with regular growth, normal metabolic profile and bone density, and normal intellectual outcome.[45]

The DUOX2 and DUOXA2 genes are the principal elements generating the hydrogen peroxide needed for TPO function.[46] Defects in DUOX2/DUOXA2 genes lead to partial dyshormonogenic defects. Monoallelic DUOX2 mutations are associated with transient CH, whereas biallelic DUOX2 mutations can lead to transient or permanent CH, with a highly variable intra- and interfamilial phenotype, suggesting a role of genetic/environmental modulators.[46]

Patients with DUOX2 variants usually show borderline blood spot TSH levels at first neonatal screening and subsequently high serum TSH at confirmatory tests (TSH >100 mIU/L) with low FT4, higher thyroglobulin (Tg) levels, and hyperplastic thyroid gland at birth.[47]

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