One of the most frequent bases of the newborn’s thyroid abnormalities is in the mother’s endocrine disorder. The association between isolated maternal hypothyroxinemia and preterm birth is currently observed (21). In 2019 Korevaar et al. published a meta-analysis concerning the hypo- or hyperthyroidism of mother correlating with infant’s thyroid function and preterm birth. After including 19 cohorts with a population of 47 045 pregnant women, it was stated that patients’ subclinical hypothyroidism, isolated hypothyroxinemia and TPO antibody positivity directly affect higher risk of preterm birth (22). Maternal subclinical hypothyroidism is also associated with the lower birth weight as well as newborns small for gestational age (SGA), which explains the need for a careful therapy during pregnancy (23, 24). However, in 2018 Varner et al. conducted multi-center randomized, double-masked, placebo-controlled thyroxine replacement trials in pregnancies in order to assess the probable neonatal benefits of maternal subclinical hypothyroidism/hypothyroxinemia treatment. The conclusions stated no statistically relevant difference in infants’ TSH levels, which questions the value of prebirth pharmacotherapy (25). Contrary, current guidelines emphasize the importance of treating maternal overt hypo- and hyperthyroidism both during pregnancy and before the conception. What is more, the recommendations favor implementing targeted screening in case of high-risk pregnancies rather than universal screening for thyroid disorders before or throughout the pregnancy (26).

Maternal thyroid disorders not only affect the duration of pregnancy and labor, but also directly influence the newborn’s neuropsychological development. Studies show that low maternal free thyroxine concentrations may impair infant’s psychomotor and cognitive abilities leading to underperforming in school, learning difficulties or even behavioral and emotional disorders (27). Authors specifically examine Graves’s disease in mothers’ association with thyroid disfunction and SGA in neonates (3, 28). As the disorder not only remains the main cause of hyperthyroidism in pregnant women, but also bears risk of severe consequences, it needs to be diagnosed and adequately treated as soon as possible (29).

Preterm labors may occur as a result of placental abruption or insufficiency or other pregnancy-related complications, especially in hypo/hyperthyroid women (30, 31). Endangered pregnancies have been identified as a significant factor in preterm neonatal thyroid disorder. Pre-eclampsia carries a great risk of placental insufficiency, which may induce intrauterine hypothyroidism (32). It is also claimed that perinatal asphyxia results in lower TSH, T4, T3 and FT4 cord blood levels in newborns (33).

Generally, thyroid disorders in preterm newborns occur spontaneously or because of previously mentioned risk factors. Nevertheless, plenty of studies yield information about familial hypothyroidism with prevalence up to 2% (34). The genetic etiology of the disease seems to explain extrathyroidal malformations reported in some cases of CH with numerous candidate genes to possibly be responsible (34–36).

Mentioned thyroid morphological defects are known as a separate risk factor for congenital hypothyroidism in preterm newborns (37). Total or hemi agenesis, ectopy and hypoplasia are objectively diagnosed in up to 85% cases of thyroid dysgenesis (36).

Multiple medications implemented during pregnancy and in the postnatal stage have numerous diverse effects on infants. However, in most cases their usage is a necessity, thus possible consequences must be considered. Amiodarone, which is commonly used in pregnant women for treatment of maternal and fetal dysrhythmias, may cause infant’s hypothyroidism (38). The drug is rich in iodine and resembles thyroxine in structure, so its administration may alter thyroid function (39). In preterm newborns the impact of excess iodine from amiodarone on TH is linked to the disturbed Wolff-Chaikoff effect (40). In general, the oversupply of iodine inhibits not only its organification but also thyroglobulin proteolysis (41). Recent studies show that 18,2% of premature neonates administered with iodinated contrast media (ICM) had transient hypothyroidism (42, 43). Nevertheless, a trial by Rath et al. suggests that ICM may cause adverse thyroid effects only when its administration is not conducted carefully (44). Moreover, lower TH levels are observed in preterm breastfed infants after their lactating mothers had a CT scan with ICM (45). Bowden et al. described the inhibition of TSH release induced by glucocorticoids, somatostatin, and dopamine (46). However, Ekmen et al. suggests that TSH, T3 and T4 levels are not disturbed during dopamine infusions (47). Bearing in mind that dopamine is known to suppress thyrotropin release, there is an urgent need to conduct more trials concerning its impact on infant’s TH. Some studies emphasize the negative influence of glucocorticoids on TSH and thyroxine secretion. The trial by Shimokaze et al. suggests that very short-term glucocorticoid administration may cause marked changes in TH levels (48).

Considering the remarkable progress and innovations in modern medicine, the survival rate of preterm newborns is constantly escalating (58). Although proper neonatal care should enhance neonates’ healthy development, in many cases it is insufficient (59). Consequently, there is an increasing incidence of congenital hypothyroidism (60, 61). Despite its estimated prevalence between 1:2000 and 1:4000 in infants, there is evidence about epidemiological differences dependent on the geographic location (62).

Congenital hypothyroidism is a condition occurring in infants unable to produce a sufficient amount of thyroid hormone (thyroxine, T4), which is necessary for a normal metabolism, growth and brain development. The disorder develops sporadically and is rarely inherited.

Primary congenital hypothyroidism (PCH) is the most prevalent form of CH, because of which the serum T4 levels are low, whereas TSH levels are elevated (63). Moreover, it is not associated with neither prenatal nor risk factors. There are several types of primary CH, the most common form being caused by abnormal fetal development of the thyroid gland (36). Severe PCH entails the highest risk of neurodevelopmental impairment (64).

Permanent congenital hypothyroidism develops as a result of perpetual dyshormonogenesis or thyroid dysgenesis (65). Its risk factors are not fully analyzed yet (66). The prevalence in neonatal screenings is estimated at 1:748 (67). Surprisingly, it appears similarly in both pre- and term infants (68). As oppose to transient CH, it is said to occur more often in women than in men (69).

Transient congenital hypothyroidism (TCH) is more common in preterm neonates, with incidence of 1:1114 (67). The syndrome may develop as a result of maternal exposure to antithyroid medications or fetal exposure to maternal antithyroid antibodies (65, 70). What is more, the use of iodine-based skin disinfectants on premature infants can inhibit thyroxine production resulting in transient hypothyroidism (71). Untreated maternal hypothyroidism might lead to low fetal levels of thyroxine as well (71). TCH is characterized by decreased levels of thyroid hormones evaluated at birth which return to normal values after a few months or years of life (72).

Secondary or central congenital hypothyroidism (CHC) is observed in children after brain damage, intraventricular hemorrhage and in cases of an insufficiency of hypothalamus or/and pituitary gland (73). This disorder can only be diagnosed using screening tests detecting TSH and fT4 levels simultaneously or stepwise (74). As a matter of fact, CHC must be distinguished from T4-binding globulin deficiency (75).

In premature neonates, serum TSH, T4 and free T4 (fT4) concentrations tend to change dynamically according to their postmenstrual age (PMA). The initial high TSH values (with the peak at PMA=30 weeks) gradually decrease to reach the term infants’ level at PMA=38-40 weeks. Adequately, the T4 and fT4 levels are the lowest around PMA=26-27 weeks, only to also reach the norm at PMA=38-40 weeks (76, 77). Moreover, lower TGB concentrations are responsible for the decreased T4 serum levels.

Furthermore, some very low birth weight and extremely low birth weight premature neonates present delayed TSH elevation (dTSH), which is also known as “atypical hypothyroidism” (78–80). It occurs when second capillary screening at 1 month of age shows serum TSH concentrations higher than 20 mIU/L following a normal value below 15 mIU/L at first neonatal screening within first 4-6 days after birth (81). Woo et al. conducted a study to establish the prevalence of dTSH. The results identified the incidence of 1:58 in ELBW and 1:95 in VLBW infants. In comparison, it estimated 1:3029 in newborns with weight higher than 1500 grams, which proves dTSH dependence on low birth weight (82).

Transient hypothyroxinemia of prematurity is a term regarding the time of premature infant’s life with serum low thyroid hormone levels. The decreased values are suggested to originate from the immaturity of the hypothalamic-pituitary-thyroid axis (83). Studies mention various risk factors for this abnormality: lower gestational age, maternal pre-eclampsia, respiratory distress syndrome, mechanical ventilation, and dopamine infusions (32, 84, 85).

Although hypothyroxinemia of prematurity is a separate disorder, and not an additional form of congenital hypothyroidism, authors usually do not differentiate between them. Both conditions prevail because of preterm infants’ insufficient fetal thyroid evolution and multiple other risk factors described before (86). Clinical manifestations of the two diseases are very similar due to their strict origin from prematurity, thus it is almost impossible to classify them accordingly. Current guidelines do not specifically recommend treating hypothyroxinemia of prematurity with levothyroxine, unless TSH elevation is also observed (87). However, because of considerable difficulty in the exact diagnosis, it is usually treated as CH up to the necessary reevaluation after 6 months of life (5).

Iodine deficiency can be observed in preterm infants due to its insufficient amount in the parenteral nutrition and the rapid loss of maternal supply. It contributes to slow recovery from hypothyroxinemia of prematurity. Therefore, the newborn’s exposure to excess iodine, for instance iodine disinfectants or radiological contract infusions, leads to down-regulation of T4 and T3 levels, also known as Wolff-Chaikoff effect (71).

Levothyroxine is known to be the most effective drug in congenital hypothyroidism. The crucial part of the treatment is the exact time of its initiation. Guidelines recommend starting the therapy not later than on the 14^th day of life. SGA, VLBW and ELBW newborns have greater risk of CH and its consequences, thus the time of the effective drugs action is short-up to four weeks after labor. Guidelines suggest maintaining the fT4 and fT3 levels not later than in 1-2 weeks. The initial dose of L-T4 depends on the severity of the disease. In primary CH levothyroxine in tablet form starts from 10–15 μg/kg/day and increases in children with severe CH (5). Oral administration on an empty stomach at least 30 minutes before eating is recommended (95, 96). Levothyroxine in liquid form can be administered along with the meal and the dosage is evaluated the same or lower than in the tablet form (96–99). The target dose should be adjusted according to the serum levels of TSH and fT4 to ensure stable euthyreosis. In suspected central CH levothyroxine dose is estimated at 5-10 µg/kg/day and in diagnosed CHC at 1-2 µg/kg/day. Reevaluations beyond the first 6 months of life are crucial to assess the need or its absence for further therapy (5). TSH level should be within the range of the reference values for age, and fT4 in the upper half of them. It is worth mentioning that inappropriate dose of levothyroxine (both insufficient and excessive) may cause multiple adverse effects and disturb treatment’s effects (107). The check-ups should be performed within specific time spans and accordingly to the patient’s needs (5, 90).

Some studies correspond with guidelines and show that preterm infants supplemented with levothyroxine perform significantly better in both cognitive and motor functions (100–102). However, as the research on that topic had been gathering pace, more studies not correlating with neither the previous ones nor the recommendations had emerged (104–106) ( Table 1 ). In 2020 Ng et al. enrolled 153 infants before 28 weeks’ gestation to an explanatory double-blind, randomized, placebo-controlled trial. Children were supplemented with L-T4 or given the placebo until 32 weeks’ corrected gestational age. Neurodevelopmental outcomes after 42 months showed that the L-T4 supplemented group performed significantly better in motor, language, and cognitive function domains (100). Accordingly, in 2014 Noumra et al. showed that L-T4 supplementation prevents the developmental delay of extra low birth weight infants with transient hypothyroxinemia. Moreover, the trial proved the association of gestational age with serum levels of fT4 (101). The study by Suzumura et al. demonstrated that levothyroxine treatment in extremely preterm newborns initiated at the end of the first week of life could reduce the incidence of cerebral palsy (102). However, Van Wassenaer-Leemhuis et al. did not find any differences in mental or motor development and rates of cerebral palsy between the compared groups of infants born less than 28 gestational weeks, treated or not with levothyroxine (106). Van Wassenaer et al. reported there is no correlation between the initial plasma free thyroxine concentration and the effect of treatment. In the study 200 infants born before 30 weeks’ gestational age received orally L-T4 or placebo treatment for 6 weeks. The follow-up did not show any differences in mortality or morbidity between compared groups. In thyroxine-treated infants born before 27 weeks’ gestation the Mental Development Index measured at the age of 24 months was 18 points higher than in the placebo group, while among children born 27 weeks or later the same index was 10 points lower in the treated group than that of their counterparts (103). Hollanders et al. suggest no association between transient hypothyroxinemia of prematurity and neurodevelopmental outcome in young adulthood. The study was a part of 19 years follow-up project which included infants born very preterm and with very low birth weight. This long-time multicenter trial demonstrated no correlation of IQ score or motor function with hypothyroxinemia in preterm born children after adjustment for demographic and perinatal characteristics (105). Yoon et al. aimed to determine the incidence, etiology, and outcomes of the TSH elevation and its treatment in extremely low-birth-weight infants (ELBWIs). Indeed, the levothyroxine replacement therapy resulted in significantly higher TSH elevations, lower fT4 levels and significantly reduced mortality compared to untreated children. Nevertheless, according to the follow-up, the treatment had no significant effect on neurodevelopmental outcomes and growth (104).

Guidelines do not recommend the use of iodine in congenital hypothyroidism therapy (5, 90). However, some trials, regarding to iodine’s essential role in the synthesis of thyroid hormones, try to investigate whether its dietary supplementation affects thyroid function during the neonatal period. The meta-analysis performed by Walsh et al. did not show any effect of iodine intake on mortality or neurodevelopment in two-years follow-up. However, analyzed trials assessed the effect of prophylactic rather than therapeutic iodine supplementation (108). Further research conducted by Ares et al. revealed similar results. Ninety-four infants with very-low birth weight were enrolled to the trial and assigned into two groups. Children in the intervention group were treated everyday with iodine in oral drops, while the placebo group did not receive any supplements. Blood samples were collected for thyroid hormones and the neurodevelopment was assessed. The analysis showed a positive outcome on the blood levels of thyroid hormones. Infants in the supplemented group reached the recommended levels from the start of the trial. Nevertheless, positive neurodevelopmental effects of iodine intake were not found. The study suggest that preterm newborns are at high risk of iodine deficiency, thus their iodine intake should be monitored. Iodine supplementation should be considered if the intake is found to be insufficient (109).