In this study, THOP and control groups of newborns who had been matched according to their gestational age were compared. Low birth weight, SGA and CHD were found to be as independent risk factors. These three risk factors are not affected by the gestational age, the severity of the illness and the medical and clinical treatment practices applied. It is already shown in the literature that the frequency of hypothyroxinemia changes in proportion to gestational age (18).
THOP and SGA
In our study, interestingly although THOP group had similiar gestational age with the control group, had a low birth weight in THOP group. Consequently in this study, incidence of SGA was higher in the THOP group and increased the risk of the THOP 5.3 times, one hundred gram increase in BW reduced the THOP risk by 20%. We speculate that being SGA may result in further deficit in storage and adaptive mechanisms. A recent study by Chunhua et al, supported our results that SGA in preterms may be associated with thyroid dysfunction (19). A comprehensive study by Bagnoli et al showed that similar to our results, preterm SGA neonates had lower FT4 compared to preterm AGAs and TSH levels were similar (20). It is generaly accepted that hypothyroxinemia is usually transient in preterm SGAs and is caused by placental hypoxia and delayed maturation of the thyroid gland (21). In addition, some studies underlined that hypothyroxinemia in preterm SGAs might be attributed to nutritional deficiency and might be reversible with the regulation of nutrition (22,23). Similar to the literature, the results of our study suggested that thyroid function tests should be followed more closely in both preterm and SGA newborns.
THOP and CHD
It is well known that thyroid and cardiac disorders can be associated. Congenital heart diseases (5.5%) are frequently associated with congenital hypothyroidism sugggesting common genetic mechanisms involved in thyroid and heart development (24). The association of CHD and thyroid disorder in Down syndrome, which is a genetic disorder, has been well defined (25). In the recent study of HJ Lee et al., it was found that the coexistence of CHD and transient thyroid disorders is approximately 50% (26). In a study with 76 preterm infants hospitalized in neonatal units, cardiovascular disease was significantly higher in THOP (27). In a comprehensive study by Sadia Malik et al., evaluating the relationship between SGA and CHD, it was found that the risk of being SGA was twice as high as in the control group (28). Decreased birth weight, SGA and CHD may have common pathogenetic mechansims that are associated with THOP. Similarly, in this study, hypothyroxinemia was found with a higher rate in preterms with SGA and CHD. It is well known in the literature that the combination of CHD and SGA increases mortality and morbidity (29). Therefore, close follow-up of thyroid function tests is more important in preterms with CHD and SGA.
THOP and prenatal-postnal conditions
Some studies have shown that in preterms thyroid functions are affected by postpartum drugs and some perinatal conditions. Drugs frequently used in premature infants (dopamine, dexamethasone), respiratory distress syndrome, infections, disorders such as necrotizing enterocolitis, patent ductus arteriosus, malnutrition, chorioamnionitis, iodine deficiency or overload may suppress thyroid functions (11, 30-33). It should be noted that gestational age is inversely correlated with the severity of problems in the prematüre newborns which may be associated with more intense medical and invasive treatments. Thus, it is difficult to evaluate whether a risk factor is the consequence of immaturity or the medical treament. Previous studies reported that surfactant, dopamine, glucocorticoids and erythrocyte transfusion increase the risk of THOP (34-37). Most of these studies evaluating the risk factors for hypothyroxinemia belong to the past years and are studies with a smaller number of cases compared to our study.
The medications are used widely as gestational age decrease and severity of the disorder increase. In a study of very low birth weight newborns, it was shown that the negative effect of dopamine and dobutamine use on thyroid function rapidly resolved after treatment was discontinued (38). There are some studies showing that the suppression of thyroid functions has decreased in parallel with the decrease in RDS severity due to the development of prenatal care and neonatal units, especially the widespread use of antenatal steroids and early surfactant treatment in recent years (11). In a study by Lay et al. In recent years, no relationship was shown between THOP and PDA, IVH, antenatal steroid use, ROP, Apgar scores, and sepsis (39). In different pathologies like respiratory distress syndrome, PDA, sepsis, intracranial hemorrhage and necrotizing enterocolitis, it is claimed that their effects on serum thyroid hormone levels are mediated in part by acute inflammatory cytokines (11). In our study, differently from previous studies RDS, PDA, sepsis, IVH, dopamine, dobutamine and erythrocyte suspension transfusion were not found to be the risk factors for THOP. The reason for these different results in our study, may be due to less needed treatments and their temporary effects with the widespread use of surfactants and antenatal steroids in recent years and the decrease in the severity of diseases in neonatal units.
In this study, serum TFT results between ten and twenty days of life were evaluated according to the postnatal and gestational age reference values, which were generally accepted in the literature and in the largest study on this subject (1). However, there is no TFT level defined as "low or normal" and there is no consensus on the timing of measurements. The strength of this study is that it is one of the few studies (7, 10, 34-38) evaluating so many parameters affecting thyroid functions in premature newborns. On the other hand our study have some limitations as being it is a single center and retrospective study. A multi center and prospective study could create more meaningful results.
In conclusion increase in premature births, improvement of intensive care conditions and survival of these newborns increase the frequency of THOP. There are different recommendations in different studies regarding the frequency and follow-up of THOP. Preterm babies with CHD and SGA could have more risk for THOP. However, prospective studies with broad participation evaluating the prenatal, natal and postnatal risk factors of THOP are needed.