Download Effect of perinatal asphyxia on thyroid hormones

Jornal de Pediatria - Vol. 77, Nº3 , 2001 175
0021-7557/01/77-03/175
Jornal de Pediatria
Copyright © 2001 by Sociedade Brasileira de Pediatria
ARTIGO ORIGINAL
Effect of perinatal asphyxia on thyroid hormones
Denise N. Pereira,1 Renato S. Procianoy2
Abstract
Objective: to verify the effect of perinatal asphyxia on thyroid hormone levels in term newborn infants.
Methods: we carried out a case-control study with 17 term and asphyxiated (A) and 17 term and control
(N) newborn infants at the Hospital de Clínicas de Porto Alegre. Patients were paired according to color
of skin, sex, type of delivery, gestational age, and weight at birth. We collected umbilical cord plasma T4,
T3, free T4, reverse T3, and TSH after 18 to 24 hours of life and from asphyxiated and control newborn
infants.
Results: there were no differences in thyroid hormones of cord blood, with the exception of reverse T3,
which was higher in A than in controls [median (25th-75th percentile): A= 2(1.4-2); N= 1.41 (1.13-1.92);
P=0.037)]. Thyroid hormone levels were lower in A than in controls on samples collected within 18-24
hours after birth, except for reverse T3, which was similar in both groups [average ± SD: T4 A= 9.79 ± 2.59;
N=14.68 ± 3.05; P<0.001; median T3 A= 40.83 (37.4-80.4); N= 164 (56.96-222.5); P=0.003; average ±
SD: free T4 A=1.85 ± 0.92; N= 2.8 ± 0.74; P=0.004; median: reverse T3 A=1.54 (1.16-1.91); N=1.31(0.872); P=0.507; TSH A=9.1 (6.34-12.95); N=14.5(12.9-17.85); P=0.008].
Conclusions: our data suggest that lower T4, free T4, and T3 levels are secondary to lower TSH levels
in asphyxiated newborns; also, peripheral metabolism of T4 in asphyxiated infants can be altered due to low
T3 and normal reverse T3 levels.
J Pediatr (Rio J) 2001; 77 (3): 175-178: perinatal asphyxia, thyroid hormones, euthyroid syndrome.
Perinatal asphyxia provokes multiple alterations in the
body due to failures in the gas exchange system. Among
these alterations we find hypoxia, hypercapnia, and decrease
of blood pH, thus causing redistribution of the blood flow
from less vital organs to vital organs such as the brain, heart,
and adrenal glands.1
Asphyxia also triggers a rapid increase in the secretion
of some hormones, such as catecholamines, 2
glucocorticoids,2-4 ACTH,4 beta-endorphins,4 antidiuretic
hormone,5-8 aldosterone,1,2,9,10 renin11 and atrial natriuretic
peptide,9,12 as well as a reduction in insulin.1
There are few studies evaluating the effect of perinatal
asphyxia on thyroid hormones,13-16 with conflicting results.
The action of these hormones on the synthesis of
mitochondrial enzymes and structural elements is extremely
important, in addition to participating in thermogenesis,
water and electrolyte transportation, and in the growth and
development of the central nervous system and skeleton.
Low levels of thyroid hormones in nonthyroidal illnesses
are associated to poor prognosis.17 This study aims at
comparing T4, T3, free T4 (FT4), T3 reverse (rT3), and
TSH plasmatic concentrations in the cord blood of term
newborns, asphyxiated or not, and in newborns with 18-24
hours of life.
1. Neonatologist, Hospital de Clínicas de Porto Alegre (HCPA), and associate
professor of Pediatrics, Universidade Luterana do Brazil (ULBRA) School
of Medicine.
2. Professor of Pediatrics, School of Medicine, Universidade Federal do Rio
Grande do Sul; Chief of the Neonatology Service, Hospital de Clínicas de
Porto Alegre.
Patients and methods
The study population consisted of full-term newborns,
with 1- and 5-minute Apgar scores < 7 and umbilical vein
175
Effect of perinatal asphyxia... - Pereira DN et alii
176 Jornal de Pediatria - Vol. 77, Nº3, 2001
blood pH <7.2, sequentially born until a total of 17
asphyxiated newborns. We included as control the first
normal full-term newborn with 1- and 5-minute Apgar
scores grater than or equal to 8 and umbilical vein blood pH
greater than or equal to 7.2, born after the asphyxiated
newborn who had similar birth weight, gestational age, type
of delivery, color and sex.
Those newborns with any sort of malformation or
congenital disease, or those whose mothers had any disease
or were treated with antihypertensive, diuretic,
corticosteroid, or antithyroid drugs were excluded from the
study. Gestational age was evaluated according to obstetric
gestational age and confirmed by physical examination.18
When the difference between obstetric gestational age and
clinical evaluation was higher than 2 weeks, clinical
evaluation was considered. Newborns were classified as
small, big, or appropriate for gestational age, based on
intrauterine growth curves.19
Immediately after birth, umbilical cord was clamped in
two different points, and a blood sample was collected for
venous blood gas analysis and determination of T4, T3,
FT4, rT3, and TSH. Eighteen to 24 hours after birth,
following the example of Borges et al.,13 a blood sample
was collected for arterial blood gas analysis and dosage of
thyroid hormones of each newborn in both groups.
All the asphyxiated newborns were admitted to an
intensive care unit, had control of diuresis during 24 hours
and received parenteral hydration. None of the asphyxiated
newborns was fed during the study period. The controls
were healthy newborns, who received assistance in the
same lodging and who were fed on demand.
T4, T3, FT4, and TSH were measured by
radioimmunoassay with a Coat a Count kit. rT3 was dosed
with reverse T3 kit, also by the radioimmunoassay method.
The values of FT4 and T3 were expressed in ng/dl, TSH
in mU/ml, those of total T4 in mg/dl, and those of rT3, in
ng/ml.
The sample size was calculated considering a significance
of 0.05 and a statistical power of 90% to detect a difference
of 1.33 in the FT4 level between the two groups, based on
the data presented by Borges et al.13 The calculated sample
size was 14 newborns in each group. Continuous variables
were described through means, medians, and standard
deviations, and the categorical variables were described
through the proportion of the data obtained from the sample.
In the analysis, we used the chi-square or Fisher’s exact tests
for categorical variables. In order to assess continuous
variables, we used Student’s t test or Wilcoxon test for pairmatched samples.
This study was approved by the Committee on Ethics of
the Hospital de Clínicas de Porto Alegre. A verbal and
written term of consent was obtained from the newborns’
parents or guardians.
Results
There were no differences between the groups concerning
gestational age (39.2±0.9; 39.3±1.2 weeks: asphyxiated
and non-asphyxiated, respectively), birth weight (3,178.5 ±
653.4; 3,238.5± 362.7 grams: asphyxiated and nonasphyxiated, respectively), sex (12/5: F/M in each group),
ratio AGA/BGA (15/2 in each group), type of delivery (14/
3: vaginal/cesarean in each group) and color (14/3: white/
non-white in each group). The group of asphyxiated
newborns presented significantly lower 1- and 5-minute
Apgar scores. In cord blood, pH and base excess were
significantly lower and pCO2 was significantly higher. We
found that pO2 was lower in this group, but this difference
was not statistically significant (Table 1). Means for T4, T3,
FT4, and TSH were similar in both groups; the mean for rT3
was significantly higher in the asphyxiated group (Table 2).
Table 1 -
Apgar score and biochemical indices in umbilical
cord blood
1-minute Apgar
5-minute Apgar
pH
PCO2
PO2
Base excess
Asphyxiated
n=17
Non-asphyxiated
n=17
P
1 (0-1)
3 (1-5)
6.98± 0.17
68.3± 28.2
22.1± 11.3
-15.3± 6.9
9 (8-10)
10 (9-10)
7.32± 0.07
38.9± 7.4
30.2± 8.5
-4.43± 3.2
< 0.001§
< 0.001§
<0.001*
<0.01*
0.065*
0.001§
Values expressed in mean± standard deviation or median ( 25th-75th
percentiles)
* Student t test for pair-matched samples
§ Wilcoxon test for pair-matched samples
We were not able to verify differences among the means
for pH, pCO2, and base excess in the blood collected from
the newborn with 18-24 hours. However, pO 2 was
significantly higher in the group of asphyxiated babies
(Table 3). There was significant difference among T4, T3,
FT4, and TSH means between the two groups, with lower
means for the asphyxiated group. The mean for rT3 was
similar in both groups (Table 4).
Table 2 -
Plasma concentration of thyroid hormones in
umbilical cord blood
T4(m g/dl)
T3(ng/dl)
FT4(ng/dl)
rT3(ng/ml)
TSH(m U/ml)
Asphyxiated
n=17
Non-asphyxiated
n=17
11.2± 4.19
68 (44.2-173.7)
1.37± 0.59
2 (1.4-2)
14.1(7.2- 31.1)
10.4± 3.22
62.5(41.8-90.3)
1.36± 0.24
1.4 (1.1-1.92)
10.2(7.7- 12.1)
P
0.453*
0.619§
0.951*
0.037§
0.07 §
Values expressed in mean± standard deviation or median ( 25th-75th
percentiles)
* Student t test for pair-matched samples
§ Wilcoxon test for pair-matched samples
Effect of perinatal asphyxia... - Pereira DN et alii
Table 3 -
Jornal de Pediatria - Vol. 77, Nº3 , 2001 177
pH and blood gases in the blood of newborns with
18-24 hours of life
pH
PCO2
PO2
Base excess
Asphyxiated
n=17
Non-asphyxiated
n=17
P
7.39± 0.08
28.3± 4.98
109.4± 51.5
-5.43± 5.37
7.45± 0.06
27.5± 5.6
72.6± 16.6
-3.6± 2.4
0.082*
0.669*
<0.05*
0.36§
Values expressed in mean± standard deviation or median ( 25th-75th
percentiles)
* Student t test for pair-matched samples
§ Wilcoxon test for pair-matched samples
Discussion
Several agents intervene with the thyroid function, acting
on several stages of its metabolism. The effect of hypoxia
on thyroid hormones has been long recognized. In animals,
hypoxia reduces thyroid function and extrathyroidal
metabolism of T4.20 Similarly, Moshang et al.21 found an
increase in the levels of rT3 in patients with acute hypoxemia,
suggesting a reduction in its degradation. In the same study,
patients with chronic hypoxemia showed decreased levels
of T3, and increased rT3 levels, revealing alterations in
extrathyroidal metabolism.
There are few studies on the effect of perinatal asphyxia
on thyroid hormones and the available studies present
conflicting results, probably related to methodological
differences.13-16
In our study, the matching of cases and controls provided
us with two similar series, in which the greatest difference
among newborns was related to asphyxiation and nonasphyxiation. Moreover, the pair-matched case-control study
reduced the probability of confounding biases by neutralizing
the influence of several factors, such as sex, gestational age,
weight, color, and type of delivery, on hormone levels. The
groups showed differences to whether or not they received
enteral nutrition. However, the nutrition variable does not
Table 4 -
Plasma concentration of thryoid hormones in
asphyxiated and non-asphyxiated newborns with
18-24 hours of life
T4(m g/dl)
T3(ng/dl)
FT4(ng/dl)
rT3(ng/ml)
TSH(m U/ml)
Asphyxiated
n=17
Non-asphyxiated
n=17
P
9.79± 2.6
40.8(37.4-80.4)
1.85± 0.92
1.54 (1.2-1.9)
9.1 (6.34-12.9)
14.7± 3.1
164 (57-222.5)
2.8± 0.74
1.3 (0.87-2)
14.5(12.9-17.8)
<0.001*
0.003§
0.004*
0.507§
0.008§
Values expressed in mean± standard deviation or median ( 25th-75th
percentiles)
* Student t test for pair-matched samples
§ Wilcoxon test for pair-matched samples
cause impact on hormonal levels provided malnutrition is
not present.22
In cord blood, the values for pH, base excess, and pO2
means were lower and the values for pCO2 were higher in
the group of asphyxiated newborns, as expected. All the
differences were statistically significant, except for pO 2.
Within the 18-24 hours of life, there were not differences
between the two groups in terms of the values obtained
through gas analysis, except for pO2, which was higher in
the group of asphyxiated newborns. This increased value
was certainly due to the use of supplementary oxygen and/
or mechanical ventilation in this group, with the highest
oxygen supply.
The means for thyroid hormones, in cord blood, were
similar in both groups, except for rT3, which was higher in
the group of asphyxiated newborns. This result resembles
those obtained by Borges et al.,13 who did not find differences
in the concentration of FT4 and FT3 in cord blood, and
those presented by Franklin et al.,15 which did not find
statistical differences in the concentration of T4, T3, rT3,
FT4, TBG, and TSH between normal and asphyxiated
newborns.
The increase of rT3 observed in cord blood may indicate
an alteration in the peripheral metabolism of thyroid
hormones through the inhibition of 5'-deiodinase activity,
which is similar to what occurs in acute hypoxia. 21
On the other hand, in newborns with 18-24 hours of life,
lower levels of T4, T3, FT4, and TSH were observed in
asphyxiated newborns, in which the basal levels (in cord
blood), with exception of FT4, failed to increase. Borges et
al.13 found that FT4 and FT3 levels failed to increase within
the first 48 hours of life in the group of asphyxiated
newborns, even though their TSH levels were normal.
Alterations in thyroid hormone metabolism due to
nonthyroidal illnesses are known as euthyroid sick
syndrome.23-25
The typical pattern of the euthyroid sick syndrome
includes a reduction in T3 concentration and an increase in
rT3 concentration, with a suppressed response of TSH to
TRH and only a minimum tendency towards a reduction in
serum T4 and TBG levels.22 The level of involvement of the
thyroid function is correlated with the severity of the disease,
and the prognosis gets worse with the reduction of hormone
levels.15,22,24
The characteristics of this syndrome have been described
in several situations, such as protein-energy malnutrition,26
postoperative period of large surgeries, 24 sepsis, 15
meconium aspiration,15 and asphyxia.13 This syndrome is
also associated with the use of certain drugs, such as
corticosteroids, 25,27-29 dopamine, 27-29 iodized
contrasts,25,27-29 among others.
The difference in the behavior of FT4 and TSH found in
our study and in that conducted by Borges et al. 13 may be the
consequence of multiple alterations that result from this
syndrome.23-25
178 Jornal de Pediatria - Vol. 77, Nº3, 2001
We conclude that there are differences in the plasma
concentration of T4, T3, TSH, and FT4 of asphyxiated
newborns; however, these differences are less pronounced
in this group. Alterations in hormone production and in the
peripheral metabolism of T4 may be responsible for these
differences, since we found low levels of T3 in contrast to
normal levels of reverse T3.
Central hypothyroidism is the most common alteration
found within the first 24 hours, where low levels of thyroid
hormones are secondary to low TSH concentration. We
were not able to determine the duration and extension of
these alterations in the metabolism of asphyxiated newborns,
since this would lead to an ethical restriction, requiring
several collections during several days, both in asphyxiated
and control newborns.
The importance of thyroid hormones to the normal
development of the brain and intellectual function, and their
relation with patients’ prognosis requires follow-up studies
that correlate hormonal alterations with the occurrence of
neurological sequelae. Studies that evaluate the role of T4
and/or T3 restoration in patients with subnormal hormonal
levels should also be considered.
References
1. Phibbs RH. Delivery room management. In: Avery GB, Fletcher
MA, MacDonald MG. Neonatology, Pathophysiology and
Management of the Newborn. 5th ed. Philadelphia: Lippincott
Williams & Wilkins; 1999. p. 279-99.
2. Kaneoka T, Ozono H, Goto U, Aso M, Shirakawa K. Plasma-noradrenalin and adrenalin concentrations in feto-maternal blood:
Their relations to feto-maternal endocrine levels, cardiotocographic
and mechanocardiographic values, and umbilical arterial blood
biochemical profilings. J Perinatal Med 1979;7:302-10.
3. Procianoy RS, Giacomini CB, Oliveira MLB. Fetal and neonatal
cortical adrenal function in birth asphyxia. Acta Paediatr Scand
1988;77:671-4.
4. Bacigalupo G, Langner K, Schimidt S, Saling E. Plasma
immunoreactive beta-endorphin, ACTH and cortisol concentrations
in mothers and their neonates immediately after delivery - their
relationship to the duration of labour. J Perinat Med 1987;15: 45-52.
5. De Vane GW, Porter JC. An apparent stress-induced release of
arginine vasopressin by human neonates. J Clin Endocrinol Metab
1980;51:1412-6.
6. Rudolph AM, Itskovitz J, Iwamoto H, Reuss ML, Heymann MA.
Fetal cardiovascular responses to stress. Semin Perinatol 1981;5:
109-21.
7. Ruth V, Fyhrquist F, Clemons G, Raivio KO. Cord plasma
vasopressin, erythropoeitin, and hypoxanthine as indices of asphyxia
at birth. Pediatr Res 1988;24:490-4.
8. Speer ME, Gorman WA, Kaplan SL, Rudolph AJ. Elevation of
plasma concentrations of arginine vasopressin following perinatal
asphyxia. Acta Paediatr Scand 1984;73:610-4.
9. Lopez EN, Lozano JM, Garcia MN, del Rio CG, Abril ML.
Concentraciones plasmáticas de péptido natriurético atrial,
vasopresina y aldosterona en sangre de cordón umbilical: sus
relaciones com la asfixia perinatal. An Esp Pediatr 1990;3:49-52.
Effect of perinatal asphyxia... - Pereira DN et alii
10. Pereira DN, Procianoy RS. Transient elevation of aldosterone levels
in perinatal asphyxia. Acta Paediatr 1997;86:851-3.
11. Jones CT, Roebuck MM, Walker DW, Johnston BM. The role of the
adrenal medulla and peripheral sympathetic nerves in the
physiological responses of the fetal sheep to hypoxia. J Dev Physiol
1988;10: 17-36.
12. Cheung CY, Brace RA. Fetal hypoxia elevates plasma atrial
natriuretic factor concentration. Am J Obstet Gynecol 1988;
159:1263-8.
13. Borges M, Lanes R, Moret LA, Balochi D, Gonzalez S. Effect of
asphyxia on free thyroid hormone levels in full term newborns.
Pediatr Res 1985;19:1305-7.
14. Tahirovíc HF. Transient hypothyroxinemia in neonates with birth
asphyxia delivered by emergency cesarean section. J Pediatric
Endocrinol and Metabol 1994;7:39-41.
15. Franklin R, O’Grady C. Neonatal thyroid function: Effects of
nonthyroidal illness. J Pediatr 1985;107:599-602.
16. Wilson DM, Hopper AO, McDougall JR, Bayer MF, Hintz RL,
Stevenson DK, et al. Serum free thyroxine values in term, premature
and sick infants. J Pediatr 1982;101:113-7.
17. Nicoloff JT, LoPresti JS. Nonthyroidal illnesses. In: Braverman LE,
Utiger RD, eds. The Thyroid - a Fundamental and Clinical Text. 7th
ed. Philadelphia-NY: Lippincott-Raven; 1996. p. 286-96.
18. Capurro H, Korichezky S, Fonseca D, Caldeyro-Barcia R. Simplified
method for diagnosis of gestational age in the newborn infant. J
Pediatr 1978;93:120-2.
19. Battaglia FC, Lubchenco LO. A practical classification of newborn
infants by weight and gestational age. J Pediatr 1967;71: 159-63.
20. Galton VA. Some effects of altitude on thyroid function.
Endocrinology 1972;91:1393-7.
21. Moshang Jr T, Chance KH, Kaplan MM, Utiger RD, Takahashi O.
Effects of hypoxia on thyroid function tests. J Pediatr 1980;97:602-4.
22. Trotta EA. Síndrome do Doente Eutireóideo em Crianças com
Sepse ou Síndrome Séptica [dissertação]. Porto Alegre: Universidade
Federal do Rio Grande do Sul; 1991.
23. Allen DB, Dietrich KA, Zimmerman JR. Thyroid hormones
metabolism and level of ilness severity in pediatric cardiac surgery
patients. J Pediatr 1989;114:59-62.
24. Chopra IJ, Hershman JM, Pardridge WM, Nicoloff JT. Thyroid
function in nonthyroidal illness. Ann Intern Med 1983;98:946-67.
25. DeGroot LJ, Larsen PR, Hennemann G. The Thyroid and its
Diseases. 6th ed. Churchill Livingstone Inc.; 1996
26. Bacci V, Schussler GC, Kaplan TB. The relationship between serum
triiodothyronine and thyrotropin during systemic illness. J Clin
Endocrinol Metabol 1982;54:1229-35.
27. Wartofsky L, Burman KD. Alterations in thyroid function in patients
with systemic illness: the “euthyroid sick sindrome”. Endocr Rev
1982;3:164-217.
28. Stockigt JR. Guidelines for diagnosis and monitoring of thyroid
disease: nonthyroidal illness. Clin Chem 1996;42:188-92.
29. Singer PA. Clinical approach to thyroid function testing. In: Stephen
AF, ed. Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine
and Radiotherapy. 2 nd ed. Philadelphia: Lippincott-Raven
Publishers; 1997. p. 41-52.
Correspondence:
Renato S. Procianoy
Rua Tobias da Silva, 99/302
CEP 90570-020 - Porto Alegre, RS, Brazil
Phone/fax: ++ 55 51 3222.7889