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The effect of triiodothyronine on neonatal hyperbilirubinemia
T h e Journal o[ P E D I A T R I C S
413
The effect of triiodotbyronine on neonatal byper bi li ru bi nem ia Newborn in[ants with hyperbilirubinemia who required exchange trans[usions were given triidothyronine /or 4 days [ollowing the initial trans[usion. No differences were noted between treated and control in[ants in respect to number of subsequent trans[usions required.
Grant Morrow, III, M.D., r Alfred M. Bongiovanni, M.D.,
John H. A. Bomberger, M.D., and Thomas R. Boggs, Jr., M.D. PHILADELPHIA,
PA.
I N 1 9 5 6 Christensen I reported his observation that thyroid deficient infants suffered prolonged jaundice. Since that time several investigators have used triiodothyronine in an attempt to lower neonatal serum bilirubin levels. Lees 2 found significantly lower bilirubin levels in premature infants given 5 mcg. of triiodothyronine daily for 5 days. Shrand and Ruthven a were unable to confirm this finding although they employed a dose of 10 meg. WestphaP achieved a small but statistically significant reduction of the serum bilirubin level by administering 25 mcg. of triiodothyronine to full-term and premature infants for 4 days. Our objective was to deFrom the Department o[ Pediatrics, School of Medicine, University o[ Pennsylvania, and [rom the Section on Newborn Pediatrics o[ the Pennsylvania Hospital and the Children's Hospital of Philadelphia. This work was supported in part by United States Public Health Service National Institute o[ Neurological Diseases and Blindness Grant Nos. HD-00371-11, NB-04828-02, NB-05138-02, and NB-02367-08 [rom the United States Public Health Service. *Address, 700 Spruce Street, Ph~ladelpMa 7, Pa,
termine whether the administration of triiodothyronine would reduce the number of exchange transfusions required by infants sufficiently jaundiced to need an initial procedure.
METHODS From October, 1963, through March, 1964, all infants requiring exchange transfusions at Children's Hospital of Philadelphia or at Pennsylvania Hospital were placed in the study group. Within 3 to 5 hours after the initial exchange transfusion each infant was given orally 25 mcg. of triiodothyroniner once a day for 4 days. Protein-bound iodine determinations were performed on 25 patients prior to the first exchange transfusion and again after a period of 4 days. Babies were observed from birth at Pennsylvania Hospital, whereas the infants at Children's Hospital had been referred at varying ages from other institutions. Determinations of bilirubin were done spectro~Cytomel: Smith, I{line, & French Laboratory.
4 14
March 1966
M o r r o w et aI.
photometrically by White's 5 method. Blood samples were obtained by puncture of the femoral vein or from the umbilical vein at birth. The exchange transfusions were performed via the umbilical vein using citrated whole blood in a 2:1 ratio by volume of donor blood to infant's blood. The procedures were usually completed in less than 30 minutes. The exchange transfusions were performed by identical techniques as described by Boggs and Westphal 6 at the two institutions. Bilirubin levels were frequently determined in both laboratories and were found to agree within a range of one milligram. The diagnosis of Rh hemolytic disease was based upon an incompatibility between the mother's and the infant's Rh genotype and a positive direct Coombs test in the infant. In the majority of patients, the expected antibody was demonstrated in the mother's serum. The diagnosis of idiopathic hyperbilirubinemia Was made when the infant's direct Coombs test was negative, and exchange transfusion was not performed before 48 hours of age. Exchange transfusions were done as necessary to maintain the total serum bilirubin level below 20 mg. per 100 ml. in the full-term infant and 18 rag. per 100 ml. in the premature infant. The control group consisted of 126 infants with Rh hemolytic disease and 108 infants with idiopathic hyperbilirubinemia who had been cared for at the same institutions during 1962 and 1963. Each infant in the control group had at least one exchange transfusion. Infants with ABO hemolytic disease were not included in either study or control groups. ABO hemolytic disease is defined as that condition in which there is an incompatibility between the infant's and mother's ABO groups, and, in addition, the direct Coombs test is weakly positive and/or the infant requires an exchange transfusion within the first 48 hours of life. RESULTS
The study ~group consisted of 48 infants who received triiodothyronine. Twenty-three of these patients had Rh hemolytic disease
and 25 had no evidence suggestive of hemolytic disease and were therefore diagnosed as having idiopathic hyperbilirubinemia. Table I presents the findings in infants with Rh hemolytic disease and Table II depicts the findings in infants with idiopathic hyperbilirubinemia. The case material is subdivided according to the institution where the infant was cared for because of the differences in ages of the infants at the time of admission. There is no significant difference in the number of exchange transfusions per patient between the control and the study groups, whether the infants had Rh hemolytic disease or idiopathic hyperbilirubinemia. Table III analyzes the control material as contributed from the two hospitals. Among infants with hemolytic disease the number of exchange transfusions per patient and the average age in hours at the time of the first exchange do not differ significantly. The mean pre-exchange bilirubin level in the infants at Children's Hospital was significantly higher than in those at Pennsylvania Hospital (p < 0.001). In contrast, infants with idiopathic hyperbilirubinemia at Children's Hospital had more exchange transfusions per patient, higher pre-exchange bilirubin levels, and were older at the time of the first exchange transfusion than those at Pennsylvania Hospital. Table IV lists the serum protein-bound iodine levels of 25 patients before and 4 days after the administration of triiodothyronine; the PBI levels are significantly depressed in the group as a whole. DISCUSSION
As previously mentioned, Westphal found a small but statistically significant depression of the total serum bilirubin concentration in infants given 25 meg. of triiodothyronine orally for 4 days. This depression averaged 1.1 rag. per 100 ml. over approximately a 48 hour period. His patients had no identifiable hemolytic process or known pathologic process adversely affecting the clearance of bilirubin. Westphal did not feel that triiodothyronine was clinically useful in
Volume 68
Number 3
Triiodothyronine re neonatal hyperbilirubinemia
4 15
T a b l e I. I n f a n t s w i t h R h h e m o l y t i c d i s e a s e ~
Pennsylvania Hospital Control group
Children's Hospital Control group Study group
1963
1962
1962
.
Study group
1963
No. of patients
53
36
17
24
13
6
No. of exchange transfusions per patient
2.5 -+ 0.2t
2.1 + 0.2
2.1 .+ 0.3
2.2 .+ 0.3
2.1 .+ 0.4
2.5 -+ 0.7
Age at first exchange (hours)
23.0 _+ 3.8
18.6 .+ 3.4
28.0 -+ 7.7
16.7 -+ 7.1
13.9 -+ 6.7
15.7 -+ 12.5
S e r u m bilirubin (mg. per 13.6-+1.1 12.2-+0.9 14.8_+1.3 7.7_+1.0 7.9-+1.3 8.9-+2.0 100 ml.) before first exchange eTable I compares untreated infants (control group) with RH hemolytic disease by year and institutimt with infants given triiodothyronine (study group). In any one category at the same institution there is no statistically significant difference between either control vs. control or control vs. study groups. tExpressed in standard errors.
Table II, Infants with idiopathic hyperbilirubinemia ~
Pennsylvania Hospital Control group Study group 1962 1963
Children's Hospital Control group 1963
1962
Study group
No. of patients
42
25
14
No. of exchange transfusions p e r patient
1.6 -+ 0.2]
1.5 .+ 0.2
1.6 .+ 0.2
15
Age at first exchange (hours)
104.3_+6.8
104.2-+5.8
106.9-+7.4
1.1 + .05 94.6.+4.8
26
I1
1.2 -+ 0.1
1.1 -+ .06
87.5.+3.3
79.0-+4.8
S e r u m bilirubin (mg. per 22.3 +- 0.8 21.3 + 0.6 21.4 .+ 0.9 19.9 .+ 0.4 19.4 .+ 0.3 19.1 -+ 0.2 100 ml.) before first exchange ~Table II compares untreated infants (control group) with idiopathic hyperbilirubinemia by year and institution with babies given triiodothyronlne (study group), In any one category at the same institution there is no statistically significant difference between either control vs. control or control vs. study groups. "~Expressed in standard errors.
Table III. Control infants 1962-1963 r
Rh hemolytic disease Children's Pennsylvania Hospital Hospital No. of patients
I_diopathic hype_rbilirubinemia P
89
37
-
No. of exchange transfusions per p a t i e n t
2.3 + 0.14t
2.1 .+ 0.25
> 0.05
Age at first exchange transfusion ( h o u r s )
21.3 + 2.6
15.7 -+ 5.2
> 0.05
I
Children's Hospital 67
I
Pennsylvania Hospital 41
-
1.5 + 0.11
1.1 + 0.07
,~ .005
104.3 -+ 4.8
90.1 + 2.8
< .02
S e r u m bilirubin level 13.1 + 1.0 7.7 .+ 0.8 < 0.001 22.0 .+0.5 19.6 .+ 0.2 < .001 (mg. p e r 100 ml.) before first exchange 9~Table ItI compares the data of infants in the control grour~s of each institution. The only.slgnificance difference among the infants with Rh hemolytic disease is the pre-exchange bilirubin level, All three categoraes are significantly different in the group with idiopathic hyperbilirubinemia. tExpressed in standard errors.
4 16
March 1966
M o r r o w et al.
Table IV. Serum protein-bound iodine levels before and 4 days after the initial exchange transfusion N
Pre-exchange level #g per 100 ml.
After 4 days of triiodothyronine
p
Rh hemolytic disease
13
10.9 -+0.5 ~
7.9 +-0.5
~ 0.01
Idiopathic hyperbilirubinemia
12
9.1 +-0.5
6.2 + 0.4
~ 0.001
Total
25
9.7 +-0.4
7.1 -+0.4
< 0.001
Diagnosis
~Expressed in standard errors.
the treatment of hyperbilirubinemia. Our failure to reduce the need for repeated exchange transfusions by the administration of triiodothyronine tends to substantiate Westphal's opinion. An unavoidable difficulty was the fact that of the 20 infants needing more than one exchange transfusion, 19 had the second one performed less than 24 hours after the initial procedure. The mechanism for the action of triiodothyronine in normal newborn infants is unknown. Westphal felt it might decrease the bilirubin level by accelerating maturation of the glucuronic acid conjugating system. However, Werder and Yaffe ~ found that thyroid deficiency does not impair this system. He rendered pregnant mice hypothyroid with 6-propylthiouracil and found that the offspring of the hypothyroid mothers, although hypothyroid themselves, had glucuronyl transferase activity identical with that of normal controls. This fact does not rule out the possibility that thyroid could accelerate the conjugating mechanism, but it tends to militate against this as the primary mechanism. Williams and Billing s have investigated the decrease in serum bilirubin levels following administration of prednisolone to adults with infectious hepatitis and obstructive jaundice. They found no evidence that this change could be accounted for by increased biliary excretion of bile, a change in renal clearance of bile pigments, or a decrease in the rate of red cell breakdown. T o account for the depression of serum bilirubin concentration, Williams and Billing suggested that cortical steroid therapy might enhance bilirubin excretion by activation of an "additional meta-
bolic pathway." Triiodothyronine may have a similar effect. Several interesting points were noted in the infants of the control group (Table I I I ) . Because all patients at Children's Hospital were referred from other institutions at later ages and with higher bilirubin levels, we anticipated that the number of exchange transfusions per patient would be higher than at Pennsylvania Hospital. I n the group with idiopathic hyperbilirubinemia, this was true. However, in the group with Rh hemolytic disease, no significant difference in the number of exchange transfusions per patient was noted. Although the babies with Rh hemolytic disease were referred to Children's Hospital at an older age (21.3 vs. 15.7 hours), the difference is not statistically significant: both groups received therapy relatively early. Several investigators have noted a depression of levels of protein-bound iodine following administration of triiodothyronine? ~ 11, 1~ Danowski and associates 12 found that the level of PBI in the normal neonate rose from 8.3 _+ 0.5 ~ /~g per 100 ml. in the first 12 hours to 12.0 _+ 0.6 r /xg per 100 ml. in the age period of one to 3.5 days. After the first week of life the levels returned to approximately their initial values, i.e., 7.4 _+ 0.5 /zg per cent. Westphal and Man~a found that although levels of butanol-extractable iodine were depressed by exchange transfusions, they returned to and became stable at preexchange levels within 2 to 3 hours after the procedure. The values listed in Table I V show a significant drop in the level of protein-bound iodine over a similar 4 day span. *Standard errors.
Volume 68 Number 3
Triiodothyronine re neonatal hyperbiIirubinemia
We believe that the drop in PBI levels indicates that the triiodothyronine was absorbed. SUMMARY
T w e n t y - t h r e e infants with hemolytic disease of the n e w b o r n a n d 25 infants with idiopathic hyperbilirubinemia at two institutions were given 25 mcg. of triiodothyronine daily for 4 days after a n initial exchange transfusion. T h e r e was no significant difference in the n u m b e r of exchange transfusions per p a t i e n t a m o n g those who received triiodothyronine a n d those who did not. It is concluded that triiodothyronine as administered in this study is not effective in controlling hyperbilirubinemia, regardless of its cause. We wish to express our appreciation to Dr. Lois Johnson fo~ her many helpful suggestions in the preparation of this paper. REFERENCES
I. Christensen, J. F.: Prolonged icterus neonatorum and congenital myxedema, Acta. paediat. 45: 367, 1956. 2. Lees, Martin H., and Ruthven, C. R. J.: The effect of triiodothyronine in neonatal hyperbilirubinemia, Lancet 2: 371, 1959. 3. Shrand, H., and Ruthven, C. R. J.: Effect of triiodothyronine on serum bilirubin level and neonatal development of the premature infant, Lancet 2: 1274, 1960.
4 17
4. Westphal, M., Boggs, T. R., Jr., Eberlein, Walter R., and Bongiovanni, Alfred M.: Neonatal billrubin levels following administration of 1-triiodothyronine, Proc. Soc. Exper. Biol. & Med. 101: 363, 1959. 5. White, D., Haidar, G. A., and Reinhold, J. G.: Spectrophotometric measurement of bilirubin concentrations in the serum of newborns by the use of a microcapillary method, Clin. Chem. 4: 211, 1958. 6. Boggs, T. R., Jr., and Westphal, Milton C., Jr.: Mortality of exchange transfusion, Pediatrics 26: 745, 1960. 7. Werder, Edmond A., and Yaffe, Sumner J.: Glucuronyl transferase activity in experimental neonatal hypothyroidism, Biol. Neonat. 6: 8, 1964. 8. Williams, Roger, and Billing, Barbara H.: Action of steroid therapy in jaundice, Lancet 2: 392, 1961. 9. Starr, Paul, Snipes, G., and Liebhold-Schueck, Ruth: Biologic effects of triiodothyronine in human subjects, J. Clin. Endocrinol. 15: 98, 1955. 10. Starr, Paul, and Liebhold-Schueck, Ruth: Effect of oral thyroxine and tri-iodo-thyronine on radioactive iodine uptake and serum protein bound iodine in normal human subjects, Proc. Soc. Exper. Biol. & Med. 83: 52, 1953. I1. Lavietes, Paul H., and Epstein, R. H.: Thyroid therapy of myxedema, Ann. Int. Med. 60: 79, 1964. 12. Danowski, T. S., Johnston, S. Y., Price, W. C. McKelvy, IV[., Stevenson, S. S., and McCluskey, E. R.: Protein-bound iodine in infants from birth to one year of age, Pediatrics 7: 240, 1951. 13. Westphal, Milton, and Man, Evelyn B.: Serum butanol-extractable iodine following exchange transfusion, J. Clin. Endocrinol. 22: 452, 1962.
413
The effect of triiodotbyronine on neonatal byper bi li ru bi nem ia Newborn in[ants with hyperbilirubinemia who required exchange trans[usions were given triidothyronine /or 4 days [ollowing the initial trans[usion. No differences were noted between treated and control in[ants in respect to number of subsequent trans[usions required.
Grant Morrow, III, M.D., r Alfred M. Bongiovanni, M.D.,
John H. A. Bomberger, M.D., and Thomas R. Boggs, Jr., M.D. PHILADELPHIA,
PA.
I N 1 9 5 6 Christensen I reported his observation that thyroid deficient infants suffered prolonged jaundice. Since that time several investigators have used triiodothyronine in an attempt to lower neonatal serum bilirubin levels. Lees 2 found significantly lower bilirubin levels in premature infants given 5 mcg. of triiodothyronine daily for 5 days. Shrand and Ruthven a were unable to confirm this finding although they employed a dose of 10 meg. WestphaP achieved a small but statistically significant reduction of the serum bilirubin level by administering 25 mcg. of triiodothyronine to full-term and premature infants for 4 days. Our objective was to deFrom the Department o[ Pediatrics, School of Medicine, University o[ Pennsylvania, and [rom the Section on Newborn Pediatrics o[ the Pennsylvania Hospital and the Children's Hospital of Philadelphia. This work was supported in part by United States Public Health Service National Institute o[ Neurological Diseases and Blindness Grant Nos. HD-00371-11, NB-04828-02, NB-05138-02, and NB-02367-08 [rom the United States Public Health Service. *Address, 700 Spruce Street, Ph~ladelpMa 7, Pa,
termine whether the administration of triiodothyronine would reduce the number of exchange transfusions required by infants sufficiently jaundiced to need an initial procedure.
METHODS From October, 1963, through March, 1964, all infants requiring exchange transfusions at Children's Hospital of Philadelphia or at Pennsylvania Hospital were placed in the study group. Within 3 to 5 hours after the initial exchange transfusion each infant was given orally 25 mcg. of triiodothyroniner once a day for 4 days. Protein-bound iodine determinations were performed on 25 patients prior to the first exchange transfusion and again after a period of 4 days. Babies were observed from birth at Pennsylvania Hospital, whereas the infants at Children's Hospital had been referred at varying ages from other institutions. Determinations of bilirubin were done spectro~Cytomel: Smith, I{line, & French Laboratory.
4 14
March 1966
M o r r o w et aI.
photometrically by White's 5 method. Blood samples were obtained by puncture of the femoral vein or from the umbilical vein at birth. The exchange transfusions were performed via the umbilical vein using citrated whole blood in a 2:1 ratio by volume of donor blood to infant's blood. The procedures were usually completed in less than 30 minutes. The exchange transfusions were performed by identical techniques as described by Boggs and Westphal 6 at the two institutions. Bilirubin levels were frequently determined in both laboratories and were found to agree within a range of one milligram. The diagnosis of Rh hemolytic disease was based upon an incompatibility between the mother's and the infant's Rh genotype and a positive direct Coombs test in the infant. In the majority of patients, the expected antibody was demonstrated in the mother's serum. The diagnosis of idiopathic hyperbilirubinemia Was made when the infant's direct Coombs test was negative, and exchange transfusion was not performed before 48 hours of age. Exchange transfusions were done as necessary to maintain the total serum bilirubin level below 20 mg. per 100 ml. in the full-term infant and 18 rag. per 100 ml. in the premature infant. The control group consisted of 126 infants with Rh hemolytic disease and 108 infants with idiopathic hyperbilirubinemia who had been cared for at the same institutions during 1962 and 1963. Each infant in the control group had at least one exchange transfusion. Infants with ABO hemolytic disease were not included in either study or control groups. ABO hemolytic disease is defined as that condition in which there is an incompatibility between the infant's and mother's ABO groups, and, in addition, the direct Coombs test is weakly positive and/or the infant requires an exchange transfusion within the first 48 hours of life. RESULTS
The study ~group consisted of 48 infants who received triiodothyronine. Twenty-three of these patients had Rh hemolytic disease
and 25 had no evidence suggestive of hemolytic disease and were therefore diagnosed as having idiopathic hyperbilirubinemia. Table I presents the findings in infants with Rh hemolytic disease and Table II depicts the findings in infants with idiopathic hyperbilirubinemia. The case material is subdivided according to the institution where the infant was cared for because of the differences in ages of the infants at the time of admission. There is no significant difference in the number of exchange transfusions per patient between the control and the study groups, whether the infants had Rh hemolytic disease or idiopathic hyperbilirubinemia. Table III analyzes the control material as contributed from the two hospitals. Among infants with hemolytic disease the number of exchange transfusions per patient and the average age in hours at the time of the first exchange do not differ significantly. The mean pre-exchange bilirubin level in the infants at Children's Hospital was significantly higher than in those at Pennsylvania Hospital (p < 0.001). In contrast, infants with idiopathic hyperbilirubinemia at Children's Hospital had more exchange transfusions per patient, higher pre-exchange bilirubin levels, and were older at the time of the first exchange transfusion than those at Pennsylvania Hospital. Table IV lists the serum protein-bound iodine levels of 25 patients before and 4 days after the administration of triiodothyronine; the PBI levels are significantly depressed in the group as a whole. DISCUSSION
As previously mentioned, Westphal found a small but statistically significant depression of the total serum bilirubin concentration in infants given 25 meg. of triiodothyronine orally for 4 days. This depression averaged 1.1 rag. per 100 ml. over approximately a 48 hour period. His patients had no identifiable hemolytic process or known pathologic process adversely affecting the clearance of bilirubin. Westphal did not feel that triiodothyronine was clinically useful in
Volume 68
Number 3
Triiodothyronine re neonatal hyperbilirubinemia
4 15
T a b l e I. I n f a n t s w i t h R h h e m o l y t i c d i s e a s e ~
Pennsylvania Hospital Control group
Children's Hospital Control group Study group
1963
1962
1962
.
Study group
1963
No. of patients
53
36
17
24
13
6
No. of exchange transfusions per patient
2.5 -+ 0.2t
2.1 + 0.2
2.1 .+ 0.3
2.2 .+ 0.3
2.1 .+ 0.4
2.5 -+ 0.7
Age at first exchange (hours)
23.0 _+ 3.8
18.6 .+ 3.4
28.0 -+ 7.7
16.7 -+ 7.1
13.9 -+ 6.7
15.7 -+ 12.5
S e r u m bilirubin (mg. per 13.6-+1.1 12.2-+0.9 14.8_+1.3 7.7_+1.0 7.9-+1.3 8.9-+2.0 100 ml.) before first exchange eTable I compares untreated infants (control group) with RH hemolytic disease by year and institutimt with infants given triiodothyronine (study group). In any one category at the same institution there is no statistically significant difference between either control vs. control or control vs. study groups. tExpressed in standard errors.
Table II, Infants with idiopathic hyperbilirubinemia ~
Pennsylvania Hospital Control group Study group 1962 1963
Children's Hospital Control group 1963
1962
Study group
No. of patients
42
25
14
No. of exchange transfusions p e r patient
1.6 -+ 0.2]
1.5 .+ 0.2
1.6 .+ 0.2
15
Age at first exchange (hours)
104.3_+6.8
104.2-+5.8
106.9-+7.4
1.1 + .05 94.6.+4.8
26
I1
1.2 -+ 0.1
1.1 -+ .06
87.5.+3.3
79.0-+4.8
S e r u m bilirubin (mg. per 22.3 +- 0.8 21.3 + 0.6 21.4 .+ 0.9 19.9 .+ 0.4 19.4 .+ 0.3 19.1 -+ 0.2 100 ml.) before first exchange ~Table II compares untreated infants (control group) with idiopathic hyperbilirubinemia by year and institution with babies given triiodothyronlne (study group), In any one category at the same institution there is no statistically significant difference between either control vs. control or control vs. study groups. "~Expressed in standard errors.
Table III. Control infants 1962-1963 r
Rh hemolytic disease Children's Pennsylvania Hospital Hospital No. of patients
I_diopathic hype_rbilirubinemia P
89
37
-
No. of exchange transfusions per p a t i e n t
2.3 + 0.14t
2.1 .+ 0.25
> 0.05
Age at first exchange transfusion ( h o u r s )
21.3 + 2.6
15.7 -+ 5.2
> 0.05
I
Children's Hospital 67
I
Pennsylvania Hospital 41
-
1.5 + 0.11
1.1 + 0.07
,~ .005
104.3 -+ 4.8
90.1 + 2.8
< .02
S e r u m bilirubin level 13.1 + 1.0 7.7 .+ 0.8 < 0.001 22.0 .+0.5 19.6 .+ 0.2 < .001 (mg. p e r 100 ml.) before first exchange 9~Table ItI compares the data of infants in the control grour~s of each institution. The only.slgnificance difference among the infants with Rh hemolytic disease is the pre-exchange bilirubin level, All three categoraes are significantly different in the group with idiopathic hyperbilirubinemia. tExpressed in standard errors.
4 16
March 1966
M o r r o w et al.
Table IV. Serum protein-bound iodine levels before and 4 days after the initial exchange transfusion N
Pre-exchange level #g per 100 ml.
After 4 days of triiodothyronine
p
Rh hemolytic disease
13
10.9 -+0.5 ~
7.9 +-0.5
~ 0.01
Idiopathic hyperbilirubinemia
12
9.1 +-0.5
6.2 + 0.4
~ 0.001
Total
25
9.7 +-0.4
7.1 -+0.4
< 0.001
Diagnosis
~Expressed in standard errors.
the treatment of hyperbilirubinemia. Our failure to reduce the need for repeated exchange transfusions by the administration of triiodothyronine tends to substantiate Westphal's opinion. An unavoidable difficulty was the fact that of the 20 infants needing more than one exchange transfusion, 19 had the second one performed less than 24 hours after the initial procedure. The mechanism for the action of triiodothyronine in normal newborn infants is unknown. Westphal felt it might decrease the bilirubin level by accelerating maturation of the glucuronic acid conjugating system. However, Werder and Yaffe ~ found that thyroid deficiency does not impair this system. He rendered pregnant mice hypothyroid with 6-propylthiouracil and found that the offspring of the hypothyroid mothers, although hypothyroid themselves, had glucuronyl transferase activity identical with that of normal controls. This fact does not rule out the possibility that thyroid could accelerate the conjugating mechanism, but it tends to militate against this as the primary mechanism. Williams and Billing s have investigated the decrease in serum bilirubin levels following administration of prednisolone to adults with infectious hepatitis and obstructive jaundice. They found no evidence that this change could be accounted for by increased biliary excretion of bile, a change in renal clearance of bile pigments, or a decrease in the rate of red cell breakdown. T o account for the depression of serum bilirubin concentration, Williams and Billing suggested that cortical steroid therapy might enhance bilirubin excretion by activation of an "additional meta-
bolic pathway." Triiodothyronine may have a similar effect. Several interesting points were noted in the infants of the control group (Table I I I ) . Because all patients at Children's Hospital were referred from other institutions at later ages and with higher bilirubin levels, we anticipated that the number of exchange transfusions per patient would be higher than at Pennsylvania Hospital. I n the group with idiopathic hyperbilirubinemia, this was true. However, in the group with Rh hemolytic disease, no significant difference in the number of exchange transfusions per patient was noted. Although the babies with Rh hemolytic disease were referred to Children's Hospital at an older age (21.3 vs. 15.7 hours), the difference is not statistically significant: both groups received therapy relatively early. Several investigators have noted a depression of levels of protein-bound iodine following administration of triiodothyronine? ~ 11, 1~ Danowski and associates 12 found that the level of PBI in the normal neonate rose from 8.3 _+ 0.5 ~ /~g per 100 ml. in the first 12 hours to 12.0 _+ 0.6 r /xg per 100 ml. in the age period of one to 3.5 days. After the first week of life the levels returned to approximately their initial values, i.e., 7.4 _+ 0.5 /zg per cent. Westphal and Man~a found that although levels of butanol-extractable iodine were depressed by exchange transfusions, they returned to and became stable at preexchange levels within 2 to 3 hours after the procedure. The values listed in Table I V show a significant drop in the level of protein-bound iodine over a similar 4 day span. *Standard errors.
Volume 68 Number 3
Triiodothyronine re neonatal hyperbiIirubinemia
We believe that the drop in PBI levels indicates that the triiodothyronine was absorbed. SUMMARY
T w e n t y - t h r e e infants with hemolytic disease of the n e w b o r n a n d 25 infants with idiopathic hyperbilirubinemia at two institutions were given 25 mcg. of triiodothyronine daily for 4 days after a n initial exchange transfusion. T h e r e was no significant difference in the n u m b e r of exchange transfusions per p a t i e n t a m o n g those who received triiodothyronine a n d those who did not. It is concluded that triiodothyronine as administered in this study is not effective in controlling hyperbilirubinemia, regardless of its cause. We wish to express our appreciation to Dr. Lois Johnson fo~ her many helpful suggestions in the preparation of this paper. REFERENCES
I. Christensen, J. F.: Prolonged icterus neonatorum and congenital myxedema, Acta. paediat. 45: 367, 1956. 2. Lees, Martin H., and Ruthven, C. R. J.: The effect of triiodothyronine in neonatal hyperbilirubinemia, Lancet 2: 371, 1959. 3. Shrand, H., and Ruthven, C. R. J.: Effect of triiodothyronine on serum bilirubin level and neonatal development of the premature infant, Lancet 2: 1274, 1960.
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