Intraventricular hemorrhage (IVH) often occurs in preterm infants and is an important cause of brain damage in the infants. Although its incidence has decreased, IVH remains a significant complication in the survival of preterm infants. One of the predisposing factors is thyroid function. The aim of the present study was to evaluate the effects of thyroid hormones T4 and thyroid-stimulating hormone (TSH) on risk of IVH in Iranian preterm infants. We designed a cross-sectional study, and the population includes fifty preterm infants admitted in the neonatal intensive care unit (NICU) ward of Ali Asghar Hospital, Tehran, Iran, during the period of 2017 to 2018. Cranial sonography at the 5th and 30th day after birth was performed to evaluate the IVH and thyroid function tests were conducted on blood samples using radioimmunoassay. Results of IVH prevalence and grading indicated that 5th day IVH occurs in 38% and 30th day IVH occurs in 28% of infants. There is no statistically significant correlation between T4 and TSH with 5th day IVH but there is a significant statistical relationship between T4 and TSH levels and IVH on the 30th day after birth. Thyroid function hormones could be used as markers to predict the risk of IVH in preterm infants. Larger sample size can help to obtain more validated results.
Bleeding in the germinal matrix, which is often ruptured into the lateral ventricle by appendicitis, is referred to as intraventricular hemorrhage (IVH) . IVH occurs predominantly in preterm infants, and its incidence increases with decreasing gestational age and birth weight. IVH often occurs in infants born before the 32nd week of pregnancy or birth weight of less than 1500 g . IVH is an important cause of brain damage in preterm infants. Although its prevalence has decreased in the last decades, IVH remains a significant problem in the survival of preterm infants [3, 4]. Neuropathological studies indicate that bleeding is primarily within the capillary network, which is freely associated with the venous system, despite bleeding may also occur from the arterial circulation. The vessels in this area occupy the borderline region between the cerebral arteries and the area of deep vein collection and are more permeable when exposed to hypoxia and/or increased venous pressure . The exact nature of the IVH is still unknown. Although some studies have suggested that the capillaries in the germinal matrix could not easily be torn apart, others have suggested that this could occur, since the vessels have immature membrane proteins. The immature brain is exposed to blood pressure fluctuations, due to limitations in auto-regulation of cerebral blood flow. This is especially true for preterm infants and could be a cause of IVH [6, 7]. There are several risk factors for IVH in preterm infants, including prenatal factors, neonatal conditions, and genetic and metabolic risk factors. One of the most important involved conditions is congenital hypothyroidism, a deficiency of thyroid function at birth or before birth. Thyroid function abnormalities are among the most important endocrine and metabolic complications, which might progress to neurodevelopmental disorders [8, 9].
Rapid diagnosis is critical because delay in treatment can lead to irreversible brain damage or cretinism. However, there are rare signs of overt hypothyroidism at birth, and 95% of affected neonates are asymptomatic . Thyroxin (T4) is an important hormone for normal development of the brain and nervous system. Low total T4 levels in preterm infants have been reported to be associated with increased risk of neonatal mortality and IVH . The aim of the present study was to evaluate the levels of T4 and TSH hormones in preterm infants admitted in the neonatal intensive care unit (NICU) ward of Ali Asghar Hospital, Tehran, Iran, in the period of 2017 to 2018 and the association of thyroid function tests with IVH.
Materials and Methods
Study Design and Patients
The present study is a descriptive cross-sectional study. Study population includes fifty preterm infants (with less than 34 weeks of gestational age) in the NICU ward of Ali Asghar Hospital, Tehran, Iran, during the period of 2017 to 2018. The sampling method was non-random. All parents provided written informed consents according to the ethical rules of Iran University of Medical Sciences adhering to the Declaration of Helsinki, 2008. Those whose parents declared their discontent for participating in our study, history of thyroid hormone consumption, major congenital anomalies, and blood transfusion/exchange were excluded from the study. If indicated, pregnant mothers received single dose of corticosteroids about their delivery and none of the neonates had treatment with corticosteroids.
All the infants underwent cranial sonography at the 5th day of birth using standardized coronal and sagittal images through an anterior fontanel sonographer to evaluate IVH. Cranial sonography was performed at the end of the 1st month after the birth to evaluate IVH at 30th day in infants.
Grading of IVH was performed based on the grading system stated in a study performed before .
Main birth-related variables include gestational age; weight of infant; and appearance, pulse, grimace, activity, and respiration (APGAR) scores and its relation with IVH for all infants.
Thyroid Function Tests
T4 and TSH levels were assessed at 5th, 14th, and 28th days after the birth via the radioimmunoassay technique to evaluate thyroid function of infants and its relation with IVH. T3 level and anti-TPO antibodies were not measured. A mentioned standard cut-off level for thyroid hormones in neonatology references was used.
Data was first analyzed by SPSS v.20 program. Chi-square test, T test, and Mann-Whitney U test were used to demonstrate differences between observed variables. Furthermore, a P value < 0.05 was considered statistically significant.
Gender, gestational age, weight, and APGAR scores were collected in infants.
Fifty preterm infants (all infants were less than 34 weeks) were enrolled in this study with a mean gestational age of 29.18 weeks. The results of other factors are listed in Table 1.
Prevalence of IVH in the 5th day and 30th day after birth was evaluated. IVH was evaluated via cranial sonography for all infants in the 5th day and at the end of the first month after birth. Prevalence of IVH is shown in Table 2. Results indicated that IVH has not occurred in the majority of infants in both times of investigation.
Grading of IVH was performed using grading system I–V. Results of grading are displayed in Figs. 1 and 2. The results revealed that grades 1 and 2 are the most common grades in the 5th and 30th days after birth in IVH respectively.
Correlation Between Study Variables and IVH
The relation of IVH with gender in infants has been investigated, and the results showed there was no statistically significant relation between gender and IVH at 5th and 30th days after birth (P value = 0.87 and 0.1, respectively).
Evaluation of correlation between birth-related factors (such as gestational age, weight at birth, APGAR score) and IVH at 5th and 30th days after the birth was performed (Table 3). Results indicated that all these birth-related factors are significantly related to IVH except APGAR 1 with 30th days IVH.
Thyroid Function Tests
Correlation Between Thyroid Function Tests with IVH
Table 4 indicates the comparison between thyroid variables in two groups of infants (with or without bleeding) at the 5th day of birth. Results revealed that there are no statistically significant differences between T4 and TSH at the 5th day IVH.
Table 5 shows the comparison between thyroid variables in two groups of infants (with or without IVH) at the 30th day of birth. Results showed there are significant statistical differences between all the variables listed in Table 5 with those of the IVH at the 30th day after birth.
Table 5 shows the most valuable results of this study, showing that infants positive for IVH have a lower T4 and TSH level.
IVH in preterm infants usually originates from the germinal matrix and is almost common in infants who are prematurely born or have low birth weight . In premature infants, the more common cause of IVH is the change in the permeability of the subtle structures of the cell in the developing brain. Reducing blood flow to the brain leads to cell death, followed by a failure in the vasculature, resulting in bleeding. Majority of IVH occur within the first 72 h after birth [5, 14].
The occurrence of IVH reduces maturation of oligodendrocyte progenitors cells (OPCs) that leads to insufficient myelination of the white matter of the brain. IVH reduces deiodinase2 and increases deiodinase3 enzyme levels in the brain region adjacent to the ventricle that finally leads to decreasing T3 content in the neural cells . Accordingly, T4 treatment in preterm rabbits enhances proliferation and maturation of OPCs, and promotes myelination and neurological recovery .
In the present study, IVH grading was assessed in preterm infants at the 5th and 30th days after birth. The most frequent grades at the 5th and 30th days were grade 1 and grade 2, respectively. These results are in consistence with other similar studies. In the study of Bolisetty et al., IVH and its effects on brain development in 426 premature infants were investigated. The results indicated that 296 infants had grade 1 and 2 hemorrhages, and in these newborns, there was an increased risk of mild to moderate impairment in the nervous system. In neonates with grade 1 and 2 hemorrhages, the delayed brain development was the most common symptom . The results of this study are in agreement with our study in view of the prevalence of low-grade neonates in infants. In another study, Abdi et al. examined the incidence of IVH among 641 premature infants. The incidence of IVH among infants was 28%. The most common type of IVH was reported for grade 1 (37.5%) and the lowest incidence of bleeding for grade 4 (3.7%) .
One of the important variables in the severity of the premature infant is the age of the embryo during delivery, known as the gestational age. In the present study, the mean gestational age in fifty preterm infants was 29.19 weeks. The minimum and maximum weeks in the neonates were 25 and 34 weeks. In the case of infants who had IVH at the 5th day, the gestational age was 27.80 and 27.90, respectively. Various studies have been conducted on the association between premature infant age and the possibility of IVH. In a cohort study by Lee et al., 1074 premature infants were examined in South Korea. In this study, several risk factors have been investigated regarding the effect of IVH on preterm infants. The results of this study indicate that many risk factors, including the sex of the infant, the number of previous pregnancies, in vitro fertilization, and delivery method, have no significant effect on IVH, but the gestational age is considered as an effective factor .
The main objective of the present study was at investigating the relationship between T4 and TSH levels with IVH in preterm infants admitted to NICU in Ali Asghar Hospital during the years 2017 to 2018. In this study, 50 preterm infants were studied. Evaluation of T4 and TSH levels in infants and its relation with IVH at the 5th day after birth showed that there was no significant relationship between T4 and TSH levels with bleeding. In the case of T4 and TSH hormones, the average of these hormones at days 5, 14, and 28 was lower than the normal range, and the levels of hormones T4 and TSH at days 5, 14, and 28 have showed a significant relationship with IVH at the 30th day of birth. The level of thyroid hormones in the group of infants who had bleeding at the 30th day showed a statistically significant difference compared with the group of infants who did not have bleeding. Interestingly, the lack of correlation between levels of T4 and TSH at the 5th day with 5th day IVH versus its significant correlation with IVH on the 30th day could be due to the difference between the causes of IVH in these two times. In other words, bleeding at the 30th day is more related to the internal and metabolic problems of the infant, as the age increases. In a similar study, Dilli et al. examined the serum thyroid hormone levels in preterm infants and the association of transient hypothyroidism with postpartum characteristics in 200 infants in the NICU. T4 and T3 values steadily increased from weeks 1 to 3, while free T4 did not significantly change. The amount of TSH decreased steadily from week 1 to weeks 3–4. The prevalence of transient hypothyroidism decreased from 1 week to 3 weeks in all newborns . The results of this study showed an important difference with our study in infants who have had IVH, the amount of TSH hormone does not decrease with increasing age and shows a slight increase, and this increase is significant in comparison with non-bleeding infants. In another study, Kantor et al. measured the association between thyroid hormones levels with IVH and death in premature infants. The results of this study showed that the levels of these two hormones in infants who had severe IVH significantly decreased compared with those who did not have bleeding .
In the present study, the levels of T4 and TSH were measured in preterm infants. The results revealed that the level of T4 and TSH hormones in preterm infants is lower than the normal range of infants. Moreover, there was a statistically significant correlation between the lower level of thyroid hormones and IVH at the 30th day of life. We have concluded an association between lower levels of thyroid function hormones and IVH and it may be a consequence more than a cause of IVH. Thyroid function hormones could be used as markers to predict risk of IVH in preterm infants.
It is suggested that this study be conducted with a larger number of newborns to increase the validity and accuracy of the results. Eventually, it could be useful to design a prospective cohort study to evaluate the effects of thyroid hormones on IVH and brain growth and development in preterm infants.
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The authors would like to thank the Vice Chancellor in charge of the research, Iran University of Medical Sciences and Health Services, all the patients who participated in this study, and our colleagues at the NICU ward of Ali Asghar Hospital.
Ethics Approval and Consent to Participate
All parents of infants provided written informed consents and the project was approved by the Local Committee on Health Research Ethics (Iran University of Medical Sciences and Health Services).
The authors declare that they have no competing interests.
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Khosravi, N., Chobdar, F.A., Mazouri, A. et al. Effects of Thyroid Hormones on Risk of Intraventricular Hemorrhage in Preterm Infants. SN Compr. Clin. Med. 2, 158–163 (2020). https://doi.org/10.1007/s42399-019-00200-3
- Intraventricular hemorrhage
- Preterm infants
- Thyroid-stimulating hormone