The Association Between Hypoxic–Ischemic Encephalopathy and Thyroid Hormones

Abstract

We aimed to compare serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels in neonates with different hypoxic–ischemic encephalopathy (HIE) stages undergoing therapeutic hypothermia (TH), and to evaluate the TSH and fT4 levels in neonates with HIE/TH in comparison with a control group. This was a retrospective study conducted between January 2020 and December 2022. The neonates with HIE/TH constituted the study group and the neonates with transient tachypnea of the newborn (TTN) constituted the control group. The study group consisted of neonates with stage 2 and stage 3 HIE. Serum TSH and fT4 levels measured at postnatal fifth day were compared between the groups. Of the 202 (47.1%) neonates included in the study group, 144 (71.3%) had stage 2 HIE and 58 (28.7%) had stage 3 HIE. In the control group, there were 227 (52.9%) newborns. Serum TSH and fT4 levels were found to be lower in the newborns with stage 3 HIE compared with those with stage 2 HIE (p = 0.015, 0.002, respectively). Although the serum TSH level was higher in the newborns with HIE compared with the newborns with TTN, serum fT4 levels did not change between the groups (p = < 0.001, 0.14, respectively). When we made the analysis according to the reference intervals, HIE/TH was associated with higher rates of TSH elevation compared with TTN, and the difference was more pronounced in stage 2 HIE/TH (p < 0.001). Although stage 3 HIE/TH was significantly associated with higher rates of low fT4 compared with TTN (p = 0.006), this relationship was not significant between stage 2 HIE/TH and TTN. It would be reasonable to interpret thyroid function tests performed on the fifth day with caution in newborns with HIE/TH, because higher TSH and lower fT4 levels on the fifth day in this patient group may result in unnecessary repetition of tests.

Introduction

Hypoxic–ischemic encephalopathy (HIE) is an important cause of morbidity and mortality in newborns, and therapeutic hypothermia (TH) is the unique proven treatment that has been shown to decrease the mortality and neurologic sequelae rates in neonates who are diagnosed as having moderate and severe HIE (Jacobs et al., 2013; Kurinczuk et al., 2010).

Besides the central nervous system, hypoxia and ischemia can cause damage to all systems such as the cardiovascular, respiratory, gastrointestinal, urinary, hematological and endocrine systems (Akisu et al., 2018). Transient hypothyroxinemia (low free thyroxin [fT4] levels) (Sak et al., 2000; Tahirović, 1994), and/or transient peripheral hypothyroidism (high thyroid-stimulating hormone [TSH] levels) (Gemer et al., 2000; Kobayashi et al., 2018; Sak et al., 2000) at birth were reported in neonates with either low Apgar scores or cord blood acidemia in comparison with healthy controls. In addition, in neonates with HIE/TH, lower serum free triiodothyronine (fT3) and fT4 levels between 72 and 96 hours after birth were speculated to predict brain damage (Kobayashi et al., 2018). In addition, repeating TSH screening after TH was recommended, as TH might alter the thyroid function tests (Yazici et al., 2023).

There are not many studies investigating thyroid hormone levels in newborns with HIE/TH, and the results of the available literature regarding the effect of HIE and TH on thyroid hormones are conflicting (Gemer et al., 2000; Kobayashi et al., 2018; Sak et al., 2000; Tahirović, 1994; Yazici et al., 2023). Yazici et al. (2023) showed that neonates with stage 2–3 HIE/TH had higher rates of TSH elevation compared with the ones with stage 1 HIE who did not receive TH, but serum TSH and fT4 levels were similar after the fourth day in neonates diagnosed with stage 2–3 HIE/TH and neonates with stage 1 HIE who did not receive TH.

In addition to the literature that concluded that asphyxia does not affect thyroid functions after day 5, the results of Yazici et al.'s (2023) study suggested that TSH and fT4 levels in neonates with HIE were not affected by TH after day 4 (Franklin and O'Grady, 1985). The available literature is insufficient to show the exact timing of the peak, nadir, or plateau in TSH and fT4 levels after TH or hypoxic ischemic injury (Kobayashi et al., 2018; Yazici et al., 2023). On the contrary, our routine NICU protocol included evaluation of all neonates admitted to the NICU on day 5 for congenital hypothyroidism. Therefore, we primarily aimed to compare the fifth day TSH and fT4 levels in neonates with different HIE stages undergoing TH. We secondarily aimed to evaluate the fifth day TSH and fT4 levels in neonates with HIE/TH in comparison with a control group that included neonates with transient tachypnea of the newborn (TTN).

Materials and Methods

This was a retrospective cross-sectional study. Newborns, who received TH between January 2020 and December 2022 with the diagnosis of HIE, were included in the study as the study group. The neonates admitted to the NICU with the diagnosis of TTN between October 2022 and December 2022 were included in the study as the control group. The newborns who died without evaluation of thyroid function tests (before postnatal 120th hour) were excluded from the study.

TH was decided based on the Turkish Neonatal Society Guideline on neonatal encephalopathy (Akisu et al., 2018; Committee on Fetus and Newborn et al., 2014). The following treatment criteria were used: (1) newborns with a gestational age of ≥36 weeks and aged ≤6 hours; a pH value of ≤7.00 or base excess (BE) value of less than or equal to −16 mM in the blood sample collected from the cord or in the blood sample collected from the baby in the first hour of life; (2) a 10th minute Apgar score of <5 or persisting need for resuscitation; and (3) signs of moderate or severe encephalopathy on clinical evaluation. The following absolute contraindications for TH were used in this study: (1) babies who were aged over 12 hours; (2) babies under the gestational age of 34 weeks; (3) babies weighing <1800 g; (4) babies with major congenital anomalies; and (5) babies with very severe or diffuse parenchymal cranial hemorrhages or very severe life-threatening coagulopathy.

TH was applied using either the Tecotherm TS Med 200 N device (Inspiration Healthcare Ltd, Leicester, United Kingdom) or Arctic Sun 5000 Temperature Management System (Medivance, Inc., Louisville, CO). Cooling to a rectal temperature of 33.5°C ± 0.5°C was achieved in all infants within the postnatal 6 hours. Rewarming to 36.5°C was started following 72-hour cooling by elevating the temperature with a rate of 0.5°C per hour. The Sarnat and Sarnat staging system was used to determine the stage of HIE (stage 2/moderate or stage 3/severe HIE). The severity of HIE was defined daily during the first 72 hours of life, and the worse stage was recorded.

The diagnosis of TTN was made according to chest X-ray findings, after exclusion of other causes of respiratory distress in the newborns with respiratory difficulty (Alhassen et al., 2021). Inotropic treatment was started in the presence of low blood pressure, if low blood pressure was accompanied by signs of organ hypoperfusion in line with the Turkish Neonatal Society Guidelines (Akisu et al., 2018).

Early detection and prompt treatment of congenital hypothyroidism are essential to prevent future adverse consequences, including neurodevelopmental delay. Therefore, the first capillary blood sample is obtained from the heel in all NICU babies at the latest on the 48th hour of life for congenital hypothyroidism screening in our country (Özon et al., 2018). In addition, venous blood serum TSH and fT4 levels were routinely checked at the postnatal 120th hour in all babies admitted to our NICU, and the babies with abnormal TSH and/or fT4 levels were evaluated with pediatric endocrinologists, and TSH and fT4 follow-up schemes were planned.

Our thyroid hormone level follow-up scheme for the NICU babies was as follows: (1) If the serum fT4 concentration was below the reference range and the TSH concentration was clearly above the reference range, then LT4 treatment was started immediately. (2) If the serum TSH concentration was >20 μIU/mL at approximately the 2nd week of life, even if fT4 was normal, treatment was started. (3) If the TSH level was 6–20 μIU/mL, whereas the fT4 level was within the normal limits after the 21st day, the thyroid hormone tests were repeated 2 weeks later without initiating treatment. (4) If serum fT4 was low and TSH was low, normal or mildly elevated, levothyroxine (LT4) was started after the newborns were evaluated for accompanying adrenal insufficiency (Özon et al., 2018; van Trotsenburg et al., 2021).

As the rates of both iodine deficiency and transient TSH elevations were high in our country, we repeated testing fT4 and TSH levels in the first 2 weeks of life under the supervision of a pediatric endocrinologist before initiating LT4 treatment in line with our national guideline to avoid unnecessary treatment in cases of isolated TSH elevation (Özon et al., 2018). The TSH and fT4 concentrations were determined with electrochemiluminescence immunoassay on a Roche e601 analyzer (Roche Diagnostic GmbH, Mannheim, Germany). The normal reference intervals for the kits used in the study were 0.27–4.2 μIU/mL and 12–22 pmol/L for TSH and fT4, respectively. The TSH and fT4 levels of the patients were classified as normal, low, and high, and it was investigated whether there was a difference between the groups.

The patients' gestational ages, birth weights, sexes, modes of delivery, 1st and 5th-minute Apgar scores, cord blood pH and BE values, HIE stages, 120th-hour TSH and fT4 levels, use of inotropes, and outcomes including length of hospital stay and whether the patient survived were extracted from the patients' files. Ethical approval for the study was obtained from Harran University Clinical Research Ethics Committee (date: 09.01.2023, No.: 23/01/04). The study was completed in accordance with the Declaration of Helsinki as revised in 2013.

Statistical analysis

The Statistical Package for Social Sciences version 21.0 (SPSS, Inc., Chicago, IL) was used for statistical analyses. The data were assessed for normality using visual and analytic methods. The data were tested for normality with the Kolmogorov–Smirnov test. The qualitative variables are expressed as percentages and frequencies and continuous variables are expressed as medians (interquartile range [IQR], p25–p75) as they were distributed non-normally. The chi-square test was performed for categorical variables. Differences between two groups were tested using the Mann–Whitney U-test and differences between three groups were tested using the Kruskal–Wallis test. A value of p < 0.05 was considered statistically significant.

Results

A total of 429 neonates were included in the study. The study group consisted of 202 (47.1%) newborns with HIE/TH, and the control group consisted of 227 (52.9%) newborns with TTN. Of the 202 infants included in the study group, 144 (71.3%) had stage 2 HIE and 58 (28.7%) had stage 3 HIE. Six neonates with the diagnosis of severe HIE died before the 120th hour of life and were excluded from the study. Thyroid hormone levels were rechecked after a median of 18 (15–21) days in all neonates with a 5th day TSH level of >6 μIU/mL. None of the neonates had an fT4 concentration below the reference range and a TSH concentration clearly above the reference range, and none of them needed to be evaluated for accompanying adrenal insufficiency. None of the neonates included in the study had a diagnosis of congenital hypothyroidism in the follow-up, and all of them were discharged from the hospital.

Serum TSH and fT4 levels were found to be higher in the newborns with stage 2 HIE compared with those with stage 3 HIE (p = 0.015, 0.002, respectively). Stage 2 HIE/TH was associated with higher rates of TSH elevation compared with stage 3 HIE/TH, and stage 3 HIE/TH was associated with higher rates of low fT4 levels compared with stage 2 HIE/TH (p = 0.048, 0.038, respectively). Although serum TSH level was higher in the newborns with HIE/TH compared with the newborns with TTN, serum fT4 levels did not change between the newborns with HIE/TH and the newborns with TTN (p < 0.001, 0.14, respectively). HIE/TH was associated with higher rates of TSH elevation and higher rates of low fT4 levels compared with TTN (p < 0.001, 0.023, respectively) (Table 1).

Table 1.

Comparison of Thyroid Hormones by Groups

	Stage 2 HIE (n = 144)	Stage 3 HIE (n = 58)	p-value
TSH, μIU/mL^b	9.9 (6.1–17.6)	8.05 (4.1–12.4)	0.015
Normal TSH^a	21 (14.6)	15 (25.9)	0.048
High TSH^a	123 (85.4)	43 (74.1)	0.048
Free T4, pmol/L^b	21.25 (17.62–26)	18.9 (15–22.13)	0.002
Normal fT4^a	73 (50.7)	38 (65.5)	0.038
High fT4^a	62 (43.1)	14 (24.1)
Low fT4^a	9 (6.3)	6 (10.3)
	HIE/TH (n = 202)	TTN (n = 227)	p value
TSH, μIU/mL^b	9.4 (5–16.25)	3.5 (1.9–6.2)	<0.001
Normal TSH^a	36 (17.8)	130 (57.3)	<0.001
High TSH^a	166 (82.2)	97 (42.7)	<0.001
Free T4, pmol/L^b	20.9 (16.7–24.8)	21.7 (18.1–25.3)	0.141
Normal fT4^a	111 (55)	121 (53.3)	0.023
High fT4^a	76 (37.6)	101 (44.5)
Low fT4^a	15 (7.4)	5 (2.2)

Bold value indicates p-value < 0.05.

Chi-square test (number and percentage).

Mann–Whitney U-test (median and interquartile range).

T4, thyroxine; HIE, hypoxic–ischemic encephalopathy; TSH, thyroid-stimulating hormone.

There was no difference in gender, gestational age, and birth weight between the neonates with HIE/TH and the neonates with TTN. Stage 2 and stage 3 HIE/TH were associated with lower rates of cesarean delivery, lower Apgar scores at the 1st and 5th minutes, lower pH and BE values, and higher rates of inotrope need and longer length of hospital stay compared with the ones with TTN (all p-values <0.001). Both stage 2 and stage 3 HIE/TH were associated with higher rates of TSH elevation compared with TTN, and the difference was more pronounced in stage 2 HIE (p < 0.001). Fifty seven (25.1%) of the neonates with TTN, 109 (75.7%) of the neonates with stage 2 HIE/TH, and 36 (62.1%) of the neonates with stage 3 HIE/TH had TSH levels >6 μIU/mL on day 5.

When evaluated according to reference intervals, the rate of low fT4 was higher in stage 3 HIE compared with TTN (p = 0.006). Whereas stage 3 HIE/TH was significantly associated with higher rates of low fT4 compared with TTN, this relationship was not significant between stage 2 HIE/TH and TTN (Table 2).

Table 2.

Comparison of Demographic, Clinical and Laboratory Characteristics of the Neonates by Groups

	Stage 2 HIE (n = 144)	Stage 3 HIE (n = 58)	TTN (n = 227)	p-value
Female^a	62 (43.1)	24 (41.4)	79 (34.8)	0.249
Cesarean section^a	40 (27.8)	21 (36.2)	152 (67)	<0.001
GA, weeks^b	38 (36.25–39)	38 (36–38)	38 (36–38)	0.05
BW, g^b	3150 (2800–3515)	3040 (2620–3385)	3050 (2650–3480)	0.06
Apgar, 1 min^b	4 (3–5)	3 (2.75–5)	8 (7–8)	<0.001
Apgar, 5 min^b	7 (6–7)	6 (4–6.25)	9 (8–9)	<0.001
pH, mmHg^b	6.94 (6.85–7.02)	6.89 (6.8–7.04)	7.3 (7.24–7.34)	<0.001
Base excess, mM^b	−17 (−19.6 to −14)	−18.45 (−21.65 to −14.37)	−5.2 (−7 to −3.7)	<0.001
TSH, μIU/mL^b	9.9 (6.1–17.6)	8.05 (4.1–12.4)	3.5 (1.9–6.2)	<0.001
TSH >6 μIU/mL^a	109 (75.7)	36 (62.1)	57 (25.1)	<0.001
TSH 6–20 μIU/mL^a	82 (56.9)	31 (53.4)	47 (20.7)	<0.001
TSH >20 μIU/mL^a	27 (18.8)	5 (8.6)	10 (4.4)	<0.001
Normal TSH^a	21 (14.6)	15 (25.9)	130 (57.3)	<0.001
High TSH^a	123 (85.4)	43 (74.1)	97 (42.7)	<0.001
Free T4, pmol/L^b	21.25 (17.62–26)	18.9 (15–22.13)	21.7 (18.1–25.3)	0.002
Normal fT4^a	73 (50.7)	38 (65.5)	121 (53.3)	0.006
High fT4^a	62 (43.1)	14 (24.1)	101 (44.5)
Low fT4^a	9 (6.3)	6 (10.3)	5 (2.2)
Inotrope usage^a	32 (22.2)	26 (44.8)	14 (6.2)	<0.001
Length of hospital stay^b	10 (8–13)	14 (9–20.5)	7 (5–10)	<0.001

Bold value indicates p-value < 0.05.

Chi-square test (number and percentage).

Kruskal–Wallis test (median and interquartile range).

BW, birth weight; T4, thyroxine; GA, gestational age; HIE, hypoxic–ischemic encephalopathy; TSH, thyroid-stimulating hormone.

Discussion

In our study, we found that TSH levels were significantly higher on the postnatal day 5 in the newborns with HIE/TH compared with those with TTN, and in the newborns with stage 2 HIE/TH compared with those with stage 3 HIE/TH. Although fT4 levels of the neonates with stage 3 HIE/TH were significantly lower compared with the ones with stage 2 HIE/TH, fT4 levels did not differ between the HIE/TH group and TTN group. When we made an analysis according to the reference intervals, however, we found that the rate of low fT4 was higher in the HIE/TH group compared with the TTN group, which was statistically significant in stage 3 HIE/TH and statistically insignificant in stage 2 HIE/TH.

We speculated that fT4 production decreased with the negative effects of hypoxia and ischemia on the thyroid gland in the newborns with both stage 2 HIE and stage 3 HIE. However, newborns with stage 2 HIE can partially compensate for hypothyroxinemia by increasing TSH levels, because central involvement owing to hypoxia and ischemia is less than those with stage 3 HIE. On the contrary, neonates with stage 3 HIE may not be able to compensate for low fT4 by increasing TSH because of the severe negative effects of hypoxia and ischemia on the central nervous system.

Before the TH era, it was shown that birth asphyxia did not affect thyroid hormones after the 5th day of life, and the cause might be the timing of blood sampling as it was later after the acute insult, during clinical improvement (Franklin and O'Grady, 1985). Cord blood fT4 levels were found to be lower in hypoxic neonates compared with healthy ones, but cord blood TSH levels were similar between the groups. Low cord blood fT4 levels without an increase in TSH levels were speculated to be the result of central nervous system damage owing to perinatal asphyxia causing transient hypopituitary hypothyroidism (Tahirović, 1994). In another study, an Apgar score <4 was found to be associated with transient hypothyroidism and changes in peripheral thyroid hormone metabolism (Sak et al., 2000). Serum TSH and fT4 levels were found to be lower in neonates with birth asphyxia between the 18th and 24th hours compared with healthy neonates, suggesting central hypothyroidism secondary to asphyxia (Pereira and Procianoy, 2003).

After introduction of TH into the clinical practice, Kobayashi et al. (2018) investigated the relationship between thyroid function tests and brain magnetic resonance imaging (MRI) findings in neonates with HIE/TH, and they found that HIE/TH resulted in low thyroid hormone levels at 24–96 hours after birth, and lower fT3 and fT4 levels between 72 and 96 hours were related with abnormal brain MRI findings. They concluded that abnormal fT3 and fT4 levels between 72 and 96 hours could predict brain damage in neonates with HIE/TH and speculated that this might be owing to suppression of the hypothalamic–pituitary axis in the abnormal brain MRI group associated with poor cerebral circulation.

Yazici et al. (2023) compared serum TSH levels of stage 2/3 HIE/TH newborns with stage 1 HIE newborns who did not receive TH, and found that abnormal serum TSH rate was significantly higher in the TH group (44.4% vs. 19%). TH was shown to be associated with a 4.3-fold increase in TSH after adjusting for gestational age, birth weight, and postnatal day of acquisition of TSH. However, capillary TSH levels after postnatal day 4 were not found to be different between neonates with HIE who received TH and those with HIE who did not receive TH in this study (Yazici et al., 2023). Considered together with our findings, high TSH levels should be interpreted with caution in newborns with HIE/TH, because both HIE and TH are associated with elevated TSH levels, although some studies have shown that thyroid hormones return to normal levels by day 5 (Franklin and O'Grady, 1985; Sak et al., 2000; Tahirović, 1994; Yazici et al., 2023).

To our knowledge, this is the first study in the literature evaluating the relationship of thyroid function tests with HIE stages in a large group of neonates with HIE who underwent TH. We investigated the relationship between thyroid hormones and HIE stage in newborns with HIE/TH, and compared the thyroid hormones of the HIE/TH group with a group of newborns with a similar gestational age and birth weight who were admitted to the NICU for a non-HIE reason. Considering the literature, we did not expect to find such a difference in TSH and fT4 levels on the 5th day, later after the acute insult, between the HIE/TH group and the TTN group, and to detect such a high rate of TSH elevation in the HIE/TH group. We thought that preventing unnecessary repeated blood tests is as important as diagnosing hypothyroidism in newborns with HIE/TH, and it is obvious that there is a need for prospective studies with a larger patient group on this subject.

Our study has some limitations. The main limitation was that the cross-sectional retrospective design of the study did not allow us to evaluate the long-term effect of HIE/TH on thyroid functions. The second limitation was that we did not have a healthy control group, as respiratory difficulty of the neonates with TTN might also have affected the thyroid functions. Fortunately, thyroid functions were evaluated at the 120th hour of life, after acute events, in both the study and the control groups. The third limitation was that we did not include neonates with stage 1 HIE who did not receive TH, as not only HIE but also TH could affect thyroid functions independent of the hypoxic ischemic insult. The fourth limitation was that we did not know the detailed maternal history, including maternal diseases and drug use during pregnancy that might have affected thyroid functions.

Conclusions

Although the existing literature demonstrates transient abnormalities in thyroid hormones returning to normal levels on the fifth day at the latest in neonates with birth asphyxia and HIE/TH (Franklin and O'Grady, 1985; Sak et al., 2000; Tahirović, 1994; Yazici et al., 2023), we found that the rate of TSH elevation was still higher on the 5th day in the neonates with HIE/TH compared with the TTN group. The rate of TSH elevation was high even in the neonates with TTN according to reference intervals. The rate of low fT4 was also higher in the neonates with HIE/TH compared with the ones with TTN on day 5. In the light of our findings, it may be reasonable to interpret fifth day thyroid function tests with caution in newborns with HIE/TH and to measure the thyroid hormone levels of the NICU babies after the postnatal fifth day to avoid unnecessary repetition of tests especially in the ones with HIE/TH.

Authors' Contribution

A.O.G.: Conceptualization, methodology, formal analysis, writing, original draft, review and editing (lead). A.B: Methodology, original draft.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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