The neonatal screening and early treatment of congenital primary hypothyroidism (CH) patients has successfully improved the prognosis and the management of this disorder.

CH is a heterogeneous disorder related to dyshormonogenesis or defect in thyroid gland development. Congenital central hypothyroidism is a very rare form of CH and not screened in most countries.

Long term health and socio-educational attainment

The prevention of neurological deficits through the early initiation of treatment during the neonatal period is one of the chief justifications for the screening of newborns and has greatly modified disease prognosis. With early and adequate treatment, intellectual disability has largely become a thing of the past and mean IQ is now about 20 points higher than in patients born before the screening area [1]. However, several studies of patients born since the introduction of screening have reported subtle neurological deficits in some patients, reflecting subnormal cognitive and motor development during childhood and into early adulthood. Some children of school age have displayed minor deficits in psychomotricity, reaction time, memory and attention, and a delayed acquisition of language, but have nevertheless progressed normally through the school system  [2-6]. By contrast, others have achieved lower levels of educational attainment during childhood and adulthood, mostly due to CH severity and treatment inadequacy [7-12]. A subtle social disadvantage has been described in early adulthood. However, this impairment has been found to have little impact from a public health standpoint, as most patients are well integrated into society [11].

The impact of CH is clearly not uniform, and decisions about the support required during childhood and adulthood should therefore take into account a broader range of relevant indicators, including CH severity, associated comorbidity and treatment adequacy, together with the socio-educational status of the parents [13]. A recent study of patients displaying a more rapid normalization of thyroid function during the neonatal period than reported during the first two decades following the introduction of screening showed normal intellectual and motor development in young adult, with no subtle deficit [14].

In our French nationwide study of 1202 young adult patients, we showed that, at a median age of 23.4 years, a significantly larger proportion of the CH population than of the general population reported having hearing impairment (9.5 vs. 2.5%) and that the risk of developing hearing impairment was more than three times higher in these patients than in the reference population [11, 15]. Hearing loss was associated with the severity of CH at diagnosis during the neonatal period. Parents, patients and primary care providers should be aware of this risk, as early diagnosis and intervention could improve the long-term prognosis of these patients. Early and regular evaluations of hearing acuity, beginning before the child starts school and continuing throughout childhood and early adulthood should be recommended [13].

Patients with CH have a higher risk of being overweight and, thus, of metabolic complications, than the general population. In addition to the higher risk of congenital heart malformations, young adults with CH have a slightly higher cardiovascular risk, which may be related to inadequate treatment. Lifestyle interventions, including diet and exercise, should be encouraged in individuals with CH [11,13,16,17].

Optimization of treatment/management during childhood and adulthood

In our observational study, we showed that about only 70% of patients with CH have adequate treatment in early adulthood. This inadequacy of treatment, with non-optimal follow-up or poor compliance with treatment in young adults, is reflected in uncontrolled hypothyroidism or, less frequently, subclinical hyperthyroidism. Slightly negative consequences for the patients’ health-related quality of life, with concerns about mental performance and “vitality”, have been reported for young adult patients with inadequate treatment [11]. This is an important point, given that abnormal thyroid function can influence mood, emotional and/or behavioral functioning, neurosensory, metabolic and cardiovascular functions, thereby having a long-term effect on health and social functioning [18].

It should also be borne in mind that thyroid hormone requirements increase during pregnancy, and most women on levothyroxine treatment therefore require an increase in the dose administered during early pregnancy. It is widely accepted that the optimal treatment of maternal hypothyroidism is important for successful pregnancy outcomes and good neurodevelopment outcomes in the offspring. These findings for patients highlight the need for more appropriate thyroid disease management and for vigilant monitoring and adherence to treatment, to decrease the impact of the disease on both mother and child [19,20]. We recently reported the first cohort study on pregnancy outcome in the CH patients who were treated early. We found that these patients had a higher risk of gestational hypertension, emergency cesarean delivery, induced labor for vaginal delivery and preterm delivery than the reference population [21]. Disease etiology and severity were not associated with a higher risk of adverse outcomes. We also demonstrated that, although thyroid hormones requirements and levothyroxine dose increased during pregnancy, serum TSH concentration was high (TSH ≥ 5 mIU/L) in the first or second trimester in 40% of the pregnancies for which TSH assays were carried out. Moreover, in the same cohort, about half the patients reported no TSH test results at any time during pregnancy, suggesting that follow-up was non-optimal or that compliance with treatment was poor in these women. High serum TSH concentrations (TSH ≥ 10 mIU/L) during the first three to six months of pregnancy were associated with a higher risk of preterm delivery and fetal macrosomia [21]. Slight adverse effects on some developmental milestones in the child at one year of age, particularly for children born to mothers with CH and with uncontrolled hypothyroidism have been demonstrated [22].

The genetic counselling should include explaining the inheritance and the risk of recurrence of the patient’s primary or central form of CH, based on the CH subtype, the family history and, if known, the genetic cause [23,24]. Any syndromic association should be studied genetically.

Permanent versus transient form of CH

Over the years, lower cutoff points for TSH levels have been adopted in screening programs, to make it possible to detect additional mild forms of the disease, essentially with the gland in situ, with a view to potentially preventing poorer neurodevelopmental outcomes and this has led to an increase in the reported incidence of CH [25]. However, we recently demonstrated, in a nationwide study in France, that the increase in the incidence of CH with a eutopic gland includes not only mild cases, but also more severe CH phenotypes, suggesting that shifts in diagnostic criteria, with a decrease in TSH cutoff, were not the only reason for the observed increase in incidence [26]. According to current guidelines, children with CH and a eutopic gland should undergo a re-evaluation of thyroid function at or before the age of three years, to distinguish between cases of transient and permanent CH [13]. We recently reported that about half of these patients had transient CH and stopped treatment at a median age of 1.5 years [27]. Patients with transient CH had lower L-T4 dose requirements than those with permanent CH, with an optimal cutoff dose of 3.2 µg/kg/d at 6 months of age, with values below this threshold considered predictive of transient CH. A positive first-degree family history of CH significantly increased the risk of permanent CH. These findings highlight the need for appropriate and vigilant clinical and biological monitoring in these children with CH and eutopic gland to prevent unnecessary long-term treatment during childhood [27]. However, the natural course of thyroid function of patients with transient CH during early childhood remains to be determined, and it is unknown whether these patients need to resume L-T4 treatment later in life during times of increased thyroxine need due to increases in metabolism, such as puberty and pregnancy, warranting the careful long-term follow-up of this population.

In conclusion

The successful newborn screening program for CH introduced 40 years ago has been shown to be the best way to prevent the deleterious impact of thyroid hormone deficiency on the developing brain of affected individuals, and should be implemented worldwide. Prompt optimal treatment and management involving regular medical follow-up throughout the patient’s life, identification and management of potentially associated medical conditions related to disease severity, and better educational strategies to improve compliance with treatment, particularly during infancy, adolescence, the transition from pediatric to adult services and during pregnancy, are required to ensure long-term health.

Conflict of interests

The author declares no conflict of interests related to this article.

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