There was some speculation on a possible seasonal variation in the incidence of CH. However, this topic is still under debate. Studies demonstrating an increase in CH in the winter months have been conducted in Japan, Finland, Iran, and USA [33–36], indicating this is an effect that is observed globally in geographic areas with varying climates. In Japan, sex-specific seasonal patterns of incidence have been also found [37]. However, similar variations have not been confirmed in other parts of the world [27, 38–40].

The increase of the CH incidence has been attributed to the widespread shift from primary T4 to primary TSH screening strategies and to the reduction of TSH cutoff [41, 42]. With increasing accuracy of TSH measurements on the small volume of blood available in the dried blood specimens obtained for screening, several programs employing a primary T4 test switched to a primary TSH test. Currently, most newborn screening programs around the world employ a primary TSH strategy, the exceptions being some state programs in the United States, Israel, the Netherlands, and some programs in Japan measuring free T4 and TSH simultaneously [43].

Data from the literature have shown that the impact of lowering TSH cutoff on the incidence of CH has resulted in a significant rise of the incidence with an increased detection of milder cases of CH [44]. As shown in Table 6.1 when the TSH cutoff was lowered from a range of >20–25 mU/L to >10 mU/L (whole blood), a doubling of the incidence of CH confirmed at birth was generally observed. An exception was represented by Quebec where the CH incidence increased less. It was 1:2,850 in the period 1990–2000 and 1:2,450 in the period 2001–2009. This lower increase can be at least partially explained by the fact that the reduction of the TSH cutoff (from 15 to 5 mU/L) only concerned the second (recall) test, which is performed when the result of the first screening test (at 3–5 days of life with a cutoff of 15 mU/L) is positive [13].

An important clinical question is whether these milder cases of CH are transient or require permanent treatment. In our previous study conducted on the data of the INRICH, we have demonstrated that in the period 2000–2006 21.6 % of the Italian population of babies with permanent CH had a milder increase of TSH at screening (≤15.0 mU/L whole blood), whereas in the group of infants with transient hypothyroidism this percentage was 54 % [45]. In another Italian study conducted on a group of 84 Italian children with eutopic thyroid glands and mild CH, results of the reevaluation of the diagnosis after the age of 3 years showed that 35 % of these children had abnormal TSH elevations after thyroxine withdrawal and 27 % had persistent hyperthyrotropinemia (TSH 5–10 mU/L). A minority of cases had mutations in the genes commonly linked to mild forms of CH [46]. Taken together, these data suggest that newborns with mild abnormalities on neonatal screening have a significant risk of permanent CH that may become more severe in the future. Furthermore, babies with thyroid dysgenesis may have a mild increase of TSH at screening. In our more recent study conducted on 4,195 babies with a diagnosis of CH confirmed at birth and recruited in the INRICH, it was found that 8.7 % of infants with thyroid dysgenesis had a TSH at screening <15.0 mU/L whole blood. This finding can explain the slight increase (+8.0 %) of CH incidence due to thyroid dysgenesis observed in our analysis (from 1:4,000 live-borns in the period 1987–90 to 1:3,300 in the period 2007–08) [30]. Such a result was not found in other studies conducted in countries where screening programs adopted higher TSH cutoff or used T4 as the primary screening test [13, 28].

Thyroid dysfunction is frequently observed among comorbidities associated with prematurity. The most common pattern of thyroid dysfunction seen in preterm infants is transient hypothyroxinemia of prematurity (low T4 with normal TSH) which is observed in up to 50 % of infants born before 28 weeks [47]. In addition to transient hypothyroxinemia of prematurity, preterm babies have a higher incidence of primary CH, mostly with eutopic thyroid [48]. It has been reported that VLBW babies have a risk of CH about 14-fold higher than that of normal birth weight babies (1:250) [49]. Moreover, about two thirds of VLBW infants with CH detected on newborn screening show a delayed TSH rise [49, 50]. The timing of this elevation generally occurs between 2 and 4 weeks of age. According to recent guidelines [6, 7], NBS programs in the USA and Europe now collect a second specimen at 2–4 weeks of life in special categories of at-risk neonates, including babies born preterm [28–30, 51, 52].

Preterm babies show a high risk of both permanent and transient CH. In the Italian population of infants with CH recorded in the INRICH between 1987 and 2008, the frequency of preterm babies was 12.4 % among infants with permanent CH and 30.7 % among babies with transient hypothyroidism ascertained by reevaluation of the diagnosis. These frequencies were significantly higher than the 6.5 % observed in the Italian newborn population in the same period [30]. Improvements in perinatal and neonatal care have increased the survival rate of a growing number of preterm babies [53]. Therefore, with improved survival rates more preterm and LBW infants, who would previously have died in the newborn period, now have a greater potential to be tested and confirmed to have CH. This fact has been confirmed by a recent analysis conducted on data of the INRICH demonstrating that about 50 % of the increased incidence of CH observed in Italy between 1987 and 2008 (from 1:3,000 to 1:1,940 live-borns) was attributable to preterm babies, including those with low TSH at birth who have been identified by means of a low TSH cutoff and special procedures for at-risk newborns (resampling at 2–4 weeks of life) [30]. Another factor which can affect the frequency of preterm babies with CH is the iodine nutritional status. Because the ability to escape from the Wolff-Chaikoff effect does not mature until 36 weeks, preterm babies are at risk of hypothyroidism from excess iodine exposure due to topical application of iodine antiseptics [41]. However, as preterm infants have lower iodine stores and greater iodine requirements than term infants, they are also at risk of thyroid hypofunction due to iodine deficiency. This risk is particularly high in hospitalized preterm infants. In fact, it has been demonstrated that a hypothetical 1 kg preterm infant would receive less than the recommended 30 μg/kg/day with any standard nutritional regimen (enteral and parenteral nutrition) [54].

As regards twins, recent decades have seen a major increase in multiple birth rates globally, given the increasing use of techniques of assisted reproduction and drugs inducing ovulation [55, 56]. In our previous study conducted on the INRICH data, a risk of CH occurrence was found threefold higher in twins than in single deliveries. The estimated CH incidence was 10.1 per 10,000 live births in multiple deliveries and 3.2 per 10,000 live births in single deliveries [57]. Moreover, the analysis of reevaluated infants with high suspicion of transient hypothyroidism recorded in the INRICH has also shown a twin prevalence of 1.9 % among infants who resulted affected by permanent CH and 13.2 % in those with final diagnosis of transient CH. Taken together, these findings have demonstrated an increased risk for both permanent and transient CH in multiple than in single pregnancies.

Changes in the ethnic composition of the population have been also reported as a potential cause of the worldwide rise in CH incidence, as different ethnic groups may have a different risk for CH. In the USA, white newborns have been reported to have a higher risk of CH than black infants. Moreover, between 1991 and 2000, the highest incidence rate of CH in the USA was found in Hispanic newborns, and this rate was associated with a high percentage of Hispanic births in that period [58]. In another study conducted in New Zealand, it was found that the rate of dyshormonogenesis in hypothyroid cases was associated with higher birth rates among Asian and Pacific populations [27]. Beside the ethnicity and the fertility rate of a population, the prevalence of consanguinity among parents is an important factor that can help to explain certain differences in CH incidence rates. In our recent study conducted on the data of the INRICH between 1999 and 2008, consanguinity was found to be significantly higher among African (24 %), Asian (13 %), and Hispanic CH babies (9.0 %) than Caucasian CH babies (Italian 2.0 % and East-European 1.6 %). Moreover, in the same period, the group of babies born to consanguineous parents showed a significantly higher frequency of normal/hyperplastic thyroid than of thyroid dysgenesis (65 % vs 35 %, P < 0.05), suggesting a high occurrence of genetically determined dyshormonogenesis among babies born to consanguineous parents [30].