0021-972X/78/47061236I02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society
Vol. 47, No. 6 Printed in U.S.A.
Effects of Dexamethasone on Fetal and Maternal Thyroxine, Triiodothyronine, Reverse Triiodothyronine, and Thyrotropin Levels* RAPIN OSATHANONDH, INDER J. CHOPRA, AND DAN TULCHINSKY Department of Obstetrics and Gynecology, Harvard Medical School, and Boston Hospital for Women, Boston, Massachusetts 02115; and the Department of Medicine, UCLA Center for the Health Sciences (I.J.C.), Los Angeles, California 90024 ABSTRACT. The concentrations of T4, T3, rT3, and TSH were measured at term pregnancy in maternal and umbilical plasma and in amniotic fluid of 11 normal patients who received 8-16 mg dexamethasone 3-48 h before elective cesarean section and of 10 control patients who received no dexamethasone. The mean (±SE) concentrations of T4 (micrograms per dl) in maternal and umbilical plasma of dexamethasone-treated patients (12.5 ± 0.9 and 13.0 ± 0.9) were not significantly different (P > 0.05) from those of the control patients (13.9 ± 1.5 and 10.4 ± 0.6, respectively). The mean (±SE) maternal plasma concentrations of T3 and rT 3 (nanograms per dl) of dexamethasone-treated patients (204 ± 6 and 82 ± 11) were not significantly different (P > 0.05) from those of the control patients (201 ± 26 and 72 ± 6, respectively). However, the mean (±SE) concentra-
G
LUCOCORTICOIDS are currently administered to pregnant patients in order to enhance fetal lung maturation and prevent the respiratory distress syndrome of the premature newborn (1). Dexamethasone, a synthetic glucocorticoid, when given at a dose of 8 mg before delivery, will readily cross the placenta and increase the total glucocorticoid activity in maternal and umbilical plasma to above physiological levels (2, 3). The effects of glucocorticoids on thyroid function have been studied only in nonpregnant subjects (4-15). Administration of dexamethasone to normal, nonpregnant adults will cause a reduction in plasma TSH levels and in the pituitary responsiveness to TRH infusion (4-10) as well as a decrease of serum T4 and T3 and an
Received April 10, 1978. Address requests for reprints to: Rapin Osathanondh, M. D., Boston Hospital for Women, 221 Longwood Avenue, Boston, Massachusetts 02115. * This work was supported in part by Grants AM16155 and KO4 AM-70225 from the USPHS (I.J.C.).
tions of T 3 and rT 3 (nanograms per dl) in umbilical plasma of dexamethasone-treated patients (106 ± 13 and 360 ± 35) were 3- and 2-fold and significantly higher (P < 0.05) than those of the control group (39 ± 6 and 195 ± 19, respectively). No significant differences (P > 0.05) were observed between the mean concentrations of TSH (microunits per ml) in maternal and umbilical plasma of dexamethasone-treated patients (2.5 ± 0.5 and 3.0 ± 1.0) and those of the control group (2.8 ± 0.5 and 6.9 ± 2.7, respectively). Under the conditions studied, no differences in the mean concentrations of amniotic fluid T4, T3, rT3) or TSH were observed between the two groups of patients (P > 0.05). The increase of T 3 and rT 3 levels in umbilical plasma after dexamethasone administration indicates alteration in fetal thyroid economy. (J Clin Endocrinol Metab 47: 1236, 1978)
elevation of serum rT3 concentrations (13-15). In pregnant women, the effect of maternal dexamethasone administration on fetal thyroid function is not known. Therefore, the present study was undertaken to determine the effect of maternal dexamethasone administration on fetal and maternal thyroid function at term pregnancy. The study reports the concentrations of T4, T3, rT3, and TSH in maternal and umbilical plasma and in amniotic fluid of patients undergoing elective cesarean section 3-48 h after having received 8-16 mg dexamethasone. Materials and Methods Twenty-one pregnant women at term who were scheduled to undergo elective repeat cesarean section participated in this study. All patients fully understood and signed a consent form approved by the research advisory committee of the Boston Hospital for Women. Eleven patients received 8-16 mg dexamethasone USP (Hexadrol; Organon Inc., West Orange, NJ) by mouth 3-48 h before elective repeat cesarean section, and 10 patients received no
1236
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CORD BLOOD T4, T3) rT3, AND TSH AFTER DEXAMETHASONE
1237
TABLE 1. Concentrations of T4, T3, rT3, and TSH in maternal and umbilical vein plasma of 11 normal pregnant patients at term who received 8-16 mg dexamethasone 3-48 h before undergoing elective repeat cesarean section compared to those of 10 normal patients who received no dexamethasone (control) Maternal plasma T4
T3 (ng/dl)
rT3 (ng/dl)
Umbilical plasma TSH ml)
T4(Mg/dl)
T 3 (ng/dl)
rT3 (ng/dl)
Control
13.9 ± 1.5 (8-26)
201 ± 26 (75-330)
72 ± 6 (50-105)
2.8 ± 0.5 (2-5)
10.4 ± 0.6 (7-14)
39 ± 6 (15-85)
195 ± 19 (130-300)
6.9 ± 2.7 (2-17)
Dexamethasone
12.5 ± 0.9 (8-18)
204 ± 6 (185-235)
82 ± 11 (50-150)
2.5 ± 0.5 (2-4)
13.0 ± 0.9 (9-17)
106 ± 13 (44-202)"
360 ± 35 (210-600)°
3.0 ± 1.0 (2-7)*
Values are mean ± SE; range is in parentheses. 0 P < 0.05.
medications and served as a control group. Of patients who received dexamethasone, 5 received a single dose of 8 mg 8 h before the delivery; 2 received 8 mg in two divided doses at 12 and 3 h before the delivery; 3 received 12 mg in three divided doses at 24, 16, and 8 h before the delivery; and 1 received 16 mg in four divided doses at 48, 36, 24, and 12 h before the delivery. At the time of elective cesarean section, 10 ml amniotic fluid and 10 ml maternal peripheral and umbilical vein plasma were obtained and immediately frozen. All patients were delivered, under spinal anesthesia, of normal infants with birthweight of 2800-3500 g and good Apgar scores. Concentrations of T4, T3, rT3, and TSH were determined by RIA (4, 16-18). In 3 dexamethasone-treated patients, the percentages of free T4 and free T 3 were estimated in maternal and umbilical sera by equilibrium dialysis (19). Dexamethasone did not interfere in the various RIAs in concentrations up to 1 /xg/tube; this amount would correspond to a plasma concentration of dexamethasone of 4 mg/dl in the T4 RIA, 500 jug/dl in the T 3 RIA, 1 mg/dl in the rT 3 RIA, and 250 /xg/dl in the TSH RIA. Analysis of the results for the significant differences was conducted by the t test.
Results Table 1 presents the concentrations of T4, T3, rT3, and TSH in maternal and umbilical plasma of 11 pregnant patients at term who recieved 8-16 mg dexamethasone 3-48 h before elective cesarean section and in 10 patients who received no dexamethasone and served as a control group. The mean concentrations of T4, T3, rT3) TSH, and the percentages of free T4 and free T3 in maternal plasma of patients who received dexamethasone were not significantly different from those of the nontreated group {P > 0.05). In umbilical vein,
TABLE 2. Concentrations of T4, T3, rT3, and TSH in
amniotic fluid of 11 normal pregnant patients at term who received 8-16 mg dexamethasone 3-48 h before undergoing elective repeat cesarean section compared to those of 10 normal patients who received no dexamethasone (control) T4 (Mg/dl)
T3 (ng/dl)
rT 3 (ng/dl)
TSH
(jaU/ml)
Control
0.76 ± 0.1 (0.3-1.3)
0.05).
Discussion Dexamethasone administration to the mother seems to have a significant effect on the fetal thyroid economy but apparently not on the fetal pituitary-thyroid axis. In our study, the administration of 8-16 mg dexa-
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1238
OSATHANONDH, CHOPRA, AND TULCHINSKY
methasone 3-48 h before delivery caused a significant increase in the concentrations of T 3 and rT 3 in umbilical plasma without affecting the concentrations of T4 or TSH. Unlike the lowering effect of glucocorticoids on TSH secretion in the nonpregnant adult (4-10), dexamethasone treatment seemed to have had no significant effect on the mean concentrations of TSH in maternal or umbilical plasma. The increased concentration of umbilical plasma T3 after dexamethasone administration may play a role in enhancing fetal lung maturation. The frequency and severity of the respiratory distress syndrome have been reported to be higher in newborns with low umbilical serum T 3 levels (20). Studies in several species of animals have suggested that exogenous T4 administration will stimulate surfactant production and fetal lung maturation (21-23). Our finding of increased T 3 levels in umbilical plasma after dexamethasone treatment is opposite to the reported lowering effect of dexamethasone on serum T 3 levels in nonpregnant adult subjects (13-15). It is in accord, however, with the findings in catheterized fetal lambs of increased plasma T3 levels during the physiological cortisol surge before normal labor and with increased T4 to T 3 conversion in fetal tissues observed after in vivo cortisol treatment (24-28). It should be pointed out that a wide range of pharmacological doses were employed in our study and that the route and timing of glucocorticoid administration were not identical to those in animal studies. In the fetal lamb, the rise of plasma T 3 level after cortisol treatment was associated with increased tissue T4 to T 3 conversion and the fall of plasma T4 and rT 3 levels (24-27). Our findings differed from these data in that the T4 levels did not decrease and the rT 3 levels increased. This difference may relate to interspecies variations. It is possible that in the human fetus, the simultaneous rise of umbilical plasma T 3 and rT 3 concentrations after dexamethasone treatment is due to increased peripheral conversions of T4 to both T 3 and rT3. In this regard, the lack of a fall of T4 levels in the umbilical plasma after such treatment would suggest that dexamethasone also exerts a direct influ-
JCE & M • 1978 Vol47 • N o 6
ence on the secretion of T4 from the human fetal thyroid gland. Alternatively, the simultaneous rise of umbilical plasma T 3 and rT 3 levels without any change in T4 levels after dexamethasone treatment may be due to increased conversion of the T4 to T 3 in extrathyroidal tissues and/or decreased clearance of T 3 and rT 3 from the fetal circulation. To date, no other data concerning effect(s) of dexamethasone on the human fetal thyroid are available in favor or denial of these possibilities. The lack of change in amniotic fluid T 3 and rT 3 levels after dexamethasone administration is of interest. It may imply that T 3 and rT 3 in amniotic fluid originate from the maternal rather than the fetal circulation. However, since previous studies suggest limited transfer of T 3 and rT 3 from the maternal circulation into the amniotic fluid (29, 30), a fetal origin for these iodothyronines should be considered. It may well be that transfer of iodothyronines of fetal origin into the amniotic fluid is rather slow and that more than 48 h are required before any change would be detected in amniotic fluid. Alternatively, dexamethasone, which is readily transferred into the amniotic fluid (2), could have influenced the degradation of these iodothyronines. In the mother, in contrast to the nonpregnant woman in whom dexamethasone is known to affect serum T 3 and rT 3 levels (13-15, 31-33), no significant change in blood levels of T 3 or rT 3 has been observed after dexamethasone treatment. Thus, it seems that during pregnancy, dexamethasone may not alter the maternal peripheral metabolism or clearance rate of these iodothyronines. A further study of this situation should be interesting. References 1. LIGGINS, G. C, AND R. N. HOWIE, A controlled trial of
antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants, Pediatrics 50: 515, 1972. 2. OSATHANONDH, R., D . TULCHINSKY, H. KAMALI, M. DEM.
FENCL, AND H. W. TAEUSCH, JR., Dexamethasone levels in
treated pregnant women and newborn infants, J Pediatr 90: 617, 1977. 3. BALLARD, P. L, P. GRANBERG, AND R. A. BALLARD, Gluco-
corticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome, J Clin Invest 56: 1548, 1975.
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CORD BLOOD T4, T3, rT3( AND TSH AFTER DEXAMETHASONE 4. WILBUR, J. F., AND R. D. UTIGER, The effect of glucocorticoids on thyrotropin secretion, J Clin Invest 48: 2096,1969. 5. NICOLOFF, J. T., D. A. FISHER, AND M. D. APPLEMAN, JR.,
The role of glucocorticoids in the regulati jn of thyroid function in man, J Clin Invest 49: 1922, 1970. 6. HAIGLER, E. D., JR., J. A. PITTMAN, JR., J. M. HERSHMAN,
AND C. M. BAUGH, Direct evaluation of pituitary thyrotropin reserve utilizing synthetic thyrotropin releasing hormone, J Clin Endocrinol Metab 33: 573, 1971. 7. WOOLF, P. D., D. GONZALEZ-BARCENA, D. S. SCHALCH, L. A. LEE, J. P. ARZAC, A. V. SCHALLY, AND A. J. KASTIN, Lack of
effect of steroids on thyrotropin-releasing hormone (TRH) mediated thyrotropin (TSH) release in man, Neuroendocrinology 13: 56, 1973. 8. OTSUKI, M., M. DAKODA, AND S. BABA, Influence of glucocor-
ticoids on TRF-induced TSH response in man, J Clin Endocrinol Metab 36: 95, 1973.
1239
5'-triiodothyronine (reverse T3), J Clin Invest 54: 583, 1974. 19. STERLING, K., AND M. A. BRENNER, Free thyroxine in human serum: simplified measurement with the aid of magnesium precipitation, J Clin Invest 44: 153,1966. 20. CUESTAS, R. A., A. LINDALL, AND R. R. ENGEL, LOW thyroid
hormones and respiratory-distress syndrome of the newborn, studies on cord blood, N EnglJ Med 295: 297, 1976. 21. REDDING, R. A., W. H. J. DOUGLAS, AND M. STEIN, Thyroid
hormone influence upon lung surfactant metabolism, Science 175: 994, 1972. 22. Wu, B., Y. KIKKAWA, 0. M. ORZALESI, E. K. MOTOYAMA, M. KAIBARA, C. J. ZIGAS, AND C. D. COOK, The effect of thyroxine
on the maturation of fetal rabbit lungs, Biol Neonate 22: 161, 1973. 23. SMITH, B. T., AND J. S. TORDAY, Factors affecting lecithin synthesis by fetal lung cells in culture, Pediatr Res 8: 848, 1974.
9. FAGLIA, G., C. FERRARI, P. BECK-PECCOZ, A. SPADA, P. TRA-
24. Wu, S. Y., A. H. KLEIN, I. J. CHOPRA, AND D. A. FISHER,
VAGLINI, AND B. AMBROSI, Reduced plasma thyrotropin response to thyrotropin releasing hormone after dexamethasone administration in normal subjects, Horm Metab Res 5: 289, 1973.
Alterations in tissue T4-5'-monodeiodinating activity in perinatal period, Endocrinology 103: 235, 1978. 25. KLEIN, A. H., AND D. A. FISHER, The prenatal T 3 surge in the fetal sheep, Clin Res 26: 199A, 1978.
10. R E , R. N., I. A. KOURIDES, E. C. RIDGWAY, B. D. WEINTRAUB,
26. KLEIN, A. H., T. H. ODDIE, AND D. A. FISHER, The prenatal
AND F. MALOOF, Glucocorticoid effect on TSH and prolactin secretion, Clin Res 22: 347A, 1974. 11. INGBAR, S. H., AND N. FREINKEL, The influence of ACTH, cortisone and hydrocortisone on the distribution and peripheral metabolism of thyroxine, J Clin Invest 34: 1375, 1955. 12. INGBAR, S. H., AND N. FREINKEL, ACTH, cortisone and the metabolism of iodine, Metabolism 5: 652, 1956.
T 3 surge in the fetal sheep, Pediatr Res 12: 395,1978. 27. NATHANIELSZ, P. W., Ontogenesis of hypothalamic-pituitarythyroid function and metabolism in man, sheep, and rat, Recent Prog Horm Res 33: 110,1976. 28. NATHANIELSZ, P. W., Experimental observations on fetal thyroid function in different species, In Nathanielsz, P. W. (ed.), Fetal Endocrinology, Amsterdam, North-Holland Inc., 1976, p. 69.
13. DUICK, D. S., D. W. WARREN, J. T. NICOLOFF, C. L. OTIS,
AND M. S. CROXSON, Effect of single dose dexamethasone on the concentration of serum triiodothyronine in man, J Clin Endocrinol Metab 39: 1151, 1974. 14. WILLIAMS, D. E., I. J. CHOPRA, J. ORGIAZZI, AND D. H.
SOLOMON, Acute effects of corticosteroids on thyroid activity in Graves' disease, J Clin Endocrinol Metab 41: 354, 1975. 15. BURR, W. A., D. B. RAMSDEN, R. S. GRIFFITHS, E. G. BLACK, R. HOFFENBERG, H. MEINHOLD, AND K. W. WENZEL, Effect
of a single dose of dexamethasone on serum concentrations of thyroid hormones, Lancet 2: 58, 1976. 16. CHOPRA, I. J., A radioimmunoassay for measurement of thyroxine in unextracted serum, J Clin Endocrinol Metab 34: 938, 1972. 17. CHOPRA, I. J., R. S. Ho, AND R. LAM, An improved radioimmunoassay for measurement of triiodothyronine in human serum: its application to clinical and physiological studies, J Lab Clin Med 80: 729, 1972. 18. CHOPRA, I. J., A radioimmunoassay for measurement of 3, 3',
29. FISHER, D. A., J. H. DUSSAULT, J. SACK, AND I. J. CHOPRA,
Ontogenesis of hypothalamic-pituitary-thyroid function and metabolism in man, sheep, and rat, Recent Prog Horm Res 33: 59,1976. 30. CHOPRA, I. J., AND B. F. CRANDALL, Thyroid hormones and thyrotropin in amniotic fluid, N EnglJ Med 293: 740, 1975. 31. CHOPRA, I. J., D. E. WILLIAMS, J. ORGIAZZI, AND D. H.
SOLOMON, Opposite effects of dexamethasone on serum concentrations of 3, 3', 5'-triiodothyronine (reverse T3) and 3,3',5triiodothyronine (T3), J Clin Endocrinol Metab 41: 911,1975. 32. CHOPRA, I. J., U. CHOPRA, S. R. SMITH, M. REZA, AND D. H.
SOLOMON, Reciprocal changes in serum concentrations of 3,3',5'-triiodothyronine (reverse T3) and 3,3',5-triiodothyronine (T3) in systemic illnesses, J Clin Endocrinol Metab 41: 1043, 1975. 33. CHOPRA, I. J., AND S. R. SMITH, Circulating thyroid hormones and thyrotropin in adult patients with protein-calorie malnutrition, J Clin Endocrinol Metab 40: 221, 1975.
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Vol. 47, No. 6 Printed in U.S.A.
Effects of Dexamethasone on Fetal and Maternal Thyroxine, Triiodothyronine, Reverse Triiodothyronine, and Thyrotropin Levels* RAPIN OSATHANONDH, INDER J. CHOPRA, AND DAN TULCHINSKY Department of Obstetrics and Gynecology, Harvard Medical School, and Boston Hospital for Women, Boston, Massachusetts 02115; and the Department of Medicine, UCLA Center for the Health Sciences (I.J.C.), Los Angeles, California 90024 ABSTRACT. The concentrations of T4, T3, rT3, and TSH were measured at term pregnancy in maternal and umbilical plasma and in amniotic fluid of 11 normal patients who received 8-16 mg dexamethasone 3-48 h before elective cesarean section and of 10 control patients who received no dexamethasone. The mean (±SE) concentrations of T4 (micrograms per dl) in maternal and umbilical plasma of dexamethasone-treated patients (12.5 ± 0.9 and 13.0 ± 0.9) were not significantly different (P > 0.05) from those of the control patients (13.9 ± 1.5 and 10.4 ± 0.6, respectively). The mean (±SE) maternal plasma concentrations of T3 and rT 3 (nanograms per dl) of dexamethasone-treated patients (204 ± 6 and 82 ± 11) were not significantly different (P > 0.05) from those of the control patients (201 ± 26 and 72 ± 6, respectively). However, the mean (±SE) concentra-
G
LUCOCORTICOIDS are currently administered to pregnant patients in order to enhance fetal lung maturation and prevent the respiratory distress syndrome of the premature newborn (1). Dexamethasone, a synthetic glucocorticoid, when given at a dose of 8 mg before delivery, will readily cross the placenta and increase the total glucocorticoid activity in maternal and umbilical plasma to above physiological levels (2, 3). The effects of glucocorticoids on thyroid function have been studied only in nonpregnant subjects (4-15). Administration of dexamethasone to normal, nonpregnant adults will cause a reduction in plasma TSH levels and in the pituitary responsiveness to TRH infusion (4-10) as well as a decrease of serum T4 and T3 and an
Received April 10, 1978. Address requests for reprints to: Rapin Osathanondh, M. D., Boston Hospital for Women, 221 Longwood Avenue, Boston, Massachusetts 02115. * This work was supported in part by Grants AM16155 and KO4 AM-70225 from the USPHS (I.J.C.).
tions of T 3 and rT 3 (nanograms per dl) in umbilical plasma of dexamethasone-treated patients (106 ± 13 and 360 ± 35) were 3- and 2-fold and significantly higher (P < 0.05) than those of the control group (39 ± 6 and 195 ± 19, respectively). No significant differences (P > 0.05) were observed between the mean concentrations of TSH (microunits per ml) in maternal and umbilical plasma of dexamethasone-treated patients (2.5 ± 0.5 and 3.0 ± 1.0) and those of the control group (2.8 ± 0.5 and 6.9 ± 2.7, respectively). Under the conditions studied, no differences in the mean concentrations of amniotic fluid T4, T3, rT3) or TSH were observed between the two groups of patients (P > 0.05). The increase of T 3 and rT 3 levels in umbilical plasma after dexamethasone administration indicates alteration in fetal thyroid economy. (J Clin Endocrinol Metab 47: 1236, 1978)
elevation of serum rT3 concentrations (13-15). In pregnant women, the effect of maternal dexamethasone administration on fetal thyroid function is not known. Therefore, the present study was undertaken to determine the effect of maternal dexamethasone administration on fetal and maternal thyroid function at term pregnancy. The study reports the concentrations of T4, T3, rT3, and TSH in maternal and umbilical plasma and in amniotic fluid of patients undergoing elective cesarean section 3-48 h after having received 8-16 mg dexamethasone. Materials and Methods Twenty-one pregnant women at term who were scheduled to undergo elective repeat cesarean section participated in this study. All patients fully understood and signed a consent form approved by the research advisory committee of the Boston Hospital for Women. Eleven patients received 8-16 mg dexamethasone USP (Hexadrol; Organon Inc., West Orange, NJ) by mouth 3-48 h before elective repeat cesarean section, and 10 patients received no
1236
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CORD BLOOD T4, T3) rT3, AND TSH AFTER DEXAMETHASONE
1237
TABLE 1. Concentrations of T4, T3, rT3, and TSH in maternal and umbilical vein plasma of 11 normal pregnant patients at term who received 8-16 mg dexamethasone 3-48 h before undergoing elective repeat cesarean section compared to those of 10 normal patients who received no dexamethasone (control) Maternal plasma T4
T3 (ng/dl)
rT3 (ng/dl)
Umbilical plasma TSH ml)
T4(Mg/dl)
T 3 (ng/dl)
rT3 (ng/dl)
Control
13.9 ± 1.5 (8-26)
201 ± 26 (75-330)
72 ± 6 (50-105)
2.8 ± 0.5 (2-5)
10.4 ± 0.6 (7-14)
39 ± 6 (15-85)
195 ± 19 (130-300)
6.9 ± 2.7 (2-17)
Dexamethasone
12.5 ± 0.9 (8-18)
204 ± 6 (185-235)
82 ± 11 (50-150)
2.5 ± 0.5 (2-4)
13.0 ± 0.9 (9-17)
106 ± 13 (44-202)"
360 ± 35 (210-600)°
3.0 ± 1.0 (2-7)*
Values are mean ± SE; range is in parentheses. 0 P < 0.05.
medications and served as a control group. Of patients who received dexamethasone, 5 received a single dose of 8 mg 8 h before the delivery; 2 received 8 mg in two divided doses at 12 and 3 h before the delivery; 3 received 12 mg in three divided doses at 24, 16, and 8 h before the delivery; and 1 received 16 mg in four divided doses at 48, 36, 24, and 12 h before the delivery. At the time of elective cesarean section, 10 ml amniotic fluid and 10 ml maternal peripheral and umbilical vein plasma were obtained and immediately frozen. All patients were delivered, under spinal anesthesia, of normal infants with birthweight of 2800-3500 g and good Apgar scores. Concentrations of T4, T3, rT3, and TSH were determined by RIA (4, 16-18). In 3 dexamethasone-treated patients, the percentages of free T4 and free T 3 were estimated in maternal and umbilical sera by equilibrium dialysis (19). Dexamethasone did not interfere in the various RIAs in concentrations up to 1 /xg/tube; this amount would correspond to a plasma concentration of dexamethasone of 4 mg/dl in the T4 RIA, 500 jug/dl in the T 3 RIA, 1 mg/dl in the rT 3 RIA, and 250 /xg/dl in the TSH RIA. Analysis of the results for the significant differences was conducted by the t test.
Results Table 1 presents the concentrations of T4, T3, rT3, and TSH in maternal and umbilical plasma of 11 pregnant patients at term who recieved 8-16 mg dexamethasone 3-48 h before elective cesarean section and in 10 patients who received no dexamethasone and served as a control group. The mean concentrations of T4, T3, rT3) TSH, and the percentages of free T4 and free T3 in maternal plasma of patients who received dexamethasone were not significantly different from those of the nontreated group {P > 0.05). In umbilical vein,
TABLE 2. Concentrations of T4, T3, rT3, and TSH in
amniotic fluid of 11 normal pregnant patients at term who received 8-16 mg dexamethasone 3-48 h before undergoing elective repeat cesarean section compared to those of 10 normal patients who received no dexamethasone (control) T4 (Mg/dl)
T3 (ng/dl)
rT 3 (ng/dl)
TSH
(jaU/ml)
Control
0.76 ± 0.1 (0.3-1.3)
0.05).
Discussion Dexamethasone administration to the mother seems to have a significant effect on the fetal thyroid economy but apparently not on the fetal pituitary-thyroid axis. In our study, the administration of 8-16 mg dexa-
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1238
OSATHANONDH, CHOPRA, AND TULCHINSKY
methasone 3-48 h before delivery caused a significant increase in the concentrations of T 3 and rT 3 in umbilical plasma without affecting the concentrations of T4 or TSH. Unlike the lowering effect of glucocorticoids on TSH secretion in the nonpregnant adult (4-10), dexamethasone treatment seemed to have had no significant effect on the mean concentrations of TSH in maternal or umbilical plasma. The increased concentration of umbilical plasma T3 after dexamethasone administration may play a role in enhancing fetal lung maturation. The frequency and severity of the respiratory distress syndrome have been reported to be higher in newborns with low umbilical serum T 3 levels (20). Studies in several species of animals have suggested that exogenous T4 administration will stimulate surfactant production and fetal lung maturation (21-23). Our finding of increased T 3 levels in umbilical plasma after dexamethasone treatment is opposite to the reported lowering effect of dexamethasone on serum T 3 levels in nonpregnant adult subjects (13-15). It is in accord, however, with the findings in catheterized fetal lambs of increased plasma T3 levels during the physiological cortisol surge before normal labor and with increased T4 to T 3 conversion in fetal tissues observed after in vivo cortisol treatment (24-28). It should be pointed out that a wide range of pharmacological doses were employed in our study and that the route and timing of glucocorticoid administration were not identical to those in animal studies. In the fetal lamb, the rise of plasma T 3 level after cortisol treatment was associated with increased tissue T4 to T 3 conversion and the fall of plasma T4 and rT 3 levels (24-27). Our findings differed from these data in that the T4 levels did not decrease and the rT 3 levels increased. This difference may relate to interspecies variations. It is possible that in the human fetus, the simultaneous rise of umbilical plasma T 3 and rT 3 concentrations after dexamethasone treatment is due to increased peripheral conversions of T4 to both T 3 and rT3. In this regard, the lack of a fall of T4 levels in the umbilical plasma after such treatment would suggest that dexamethasone also exerts a direct influ-
JCE & M • 1978 Vol47 • N o 6
ence on the secretion of T4 from the human fetal thyroid gland. Alternatively, the simultaneous rise of umbilical plasma T 3 and rT 3 levels without any change in T4 levels after dexamethasone treatment may be due to increased conversion of the T4 to T 3 in extrathyroidal tissues and/or decreased clearance of T 3 and rT 3 from the fetal circulation. To date, no other data concerning effect(s) of dexamethasone on the human fetal thyroid are available in favor or denial of these possibilities. The lack of change in amniotic fluid T 3 and rT 3 levels after dexamethasone administration is of interest. It may imply that T 3 and rT 3 in amniotic fluid originate from the maternal rather than the fetal circulation. However, since previous studies suggest limited transfer of T 3 and rT 3 from the maternal circulation into the amniotic fluid (29, 30), a fetal origin for these iodothyronines should be considered. It may well be that transfer of iodothyronines of fetal origin into the amniotic fluid is rather slow and that more than 48 h are required before any change would be detected in amniotic fluid. Alternatively, dexamethasone, which is readily transferred into the amniotic fluid (2), could have influenced the degradation of these iodothyronines. In the mother, in contrast to the nonpregnant woman in whom dexamethasone is known to affect serum T 3 and rT 3 levels (13-15, 31-33), no significant change in blood levels of T 3 or rT 3 has been observed after dexamethasone treatment. Thus, it seems that during pregnancy, dexamethasone may not alter the maternal peripheral metabolism or clearance rate of these iodothyronines. A further study of this situation should be interesting. References 1. LIGGINS, G. C, AND R. N. HOWIE, A controlled trial of
antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants, Pediatrics 50: 515, 1972. 2. OSATHANONDH, R., D . TULCHINSKY, H. KAMALI, M. DEM.
FENCL, AND H. W. TAEUSCH, JR., Dexamethasone levels in
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