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April 2, 1997, Vol 277, No. 13 >
ARTICLE | April 2, 1997

How Safe Is Long-term Prenatal Glucocorticoid Treatment? FREE

Jonathan R. Seckl, PhD, FRCPE; Walter L. Miller, MD
[+] Author Affiliations

Reprints: Walter L. Miller, MD, Bldg MR-IV, Room 209, University of California, San Francisco, San Francisco, CA 94143-0978.


JAMA. 1997;277(13):1077-1079. doi:10.1001/jama.1997.03540370067039
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Article
References

GLUCOCORTICOIDS are commonly used in obstetric practice, both for maternal immunosuppression and for shortterm treatment of the fetus, usually to accelerate lung maturation when there is threatened preterm delivery. The immediate benefits of short-term prepartum glucocorticoid therapy in maturing the fetal lung and reducing neonatal mortality are clearly supported by controlled studies.1,2 Recently, long-term prenatal therapy of fetuses potentially affected with congenital adrenal hyperplasia (CAH) has been advocated,3,4 but the safety of this experimental therapy has not been established in rigorously controlled trials.

See also p 1073.

Congenital adrenal hyperplasia is a recessively inherited disease in which a disordered steroidogenic enzyme, usually P450c21 (21-hydroxylase), diverts adrenal steroid synthesis away from cortisol toward androgens.5 In utero, low fetal plasma cortisol levels stimulate increased corticotropin (ACTH) secretion, which in turn stimulates further adrenal steroidogenesis, resulting in even more androgen synthesis. In an XY male fetus, these adrenal androgens have

REFERENCES

1 +
Crowley P, Chalmers I, Keirse M.  The effects of corticosteroid administration before preterm delivery: an overview of the evidence from clinical trials . Br J Obstet Gynaecol . 1990;;97:11-25.
2 +
Ward RM.  Pharmacologic enhancement of fetal lung maturation . Clin Perinatol . 1994;;21:523-542.
3 +
Forest MG, David M, Morel Y.  Prental diagnosis and treatment of 21-hydroxylase deficiency . J Steriod Biochem Mol Biol . 1993;;45:75-82.
4 +
Speiser PW, New MI.  Prenatal diagnosis and management of congenital adrenal hyperplasia . Clin Perinatol . 1994;;21:631-645.
5 +
Morel Y, Miller WL.  Clinical and molecular genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency . Adv Hum Genet . 1991;;20:1-68.
6 +
Mercado AB, Wilson RC, Cheng KC, Wei JQ, New MI.  Prenatal treatment and diagnosis of congenital adrenal hyperlasia owing to 21-hydroxylase deficiency . J Clin Endocrinol Metab . 1995;;80:2014-2020.
7 +
Dittmann RW, Kappes ME, Kappes MH.  Sexual behavior in adolsecent and adult females with congenital adrenal hyperplasia . Psychoneuroendocrinology . 1992;;17:153-170.
8 +
Kuhnle U, Bollinger M, Schwarz HP, Knorr D.  Partnership and sexuality in adult female patients with congenital adrenal hyperplasia: first results of a cross-sectional quality-of-life evaluation . J Steroid Biochem Mol Biol . 1993;;45:123-126.
9 +
Van Wyk JJ, Gunther DF, Ritzén EM, et al.  The use of adrenalectomy as a treatment for congenital adrenal hyperplasia . J Clin Endocrinol Metab . 1996;;81:3180-3189.
10 +
Miller WL, Tyrrell JB.  The adrenal cortex . In: Felig P, Baxter JD, Frohman L, eds. Endocrinology and Metabolism . 3rd ed. New York, NY: McGraw Hill; 1995;:555-711.
11 +
Brown RW, Kotolevtsev Y, Leckie C,et al.  Isolation and cloning of human placental 11β-hydroxysteroid dehydrogenase-2 cDNA . Biochem J . 1996;;313:1007-1017.
12 +
Beitens IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ.  The metabolic clearance rate, blood production, interconversion and transplacental passage of cortisol and cortisone in pregnancy near term . Pediatr Res . 1973;;7:509-519.
13 +
Stewart PM, Murry BA, Mason JI.  Type 2 11β-hydroxysteroid dehydrogenase in human fetal tissues . J Clin Endocrinol Metab . 1994;;78:1529-1532.
14 +
Brown RW, Diaz R, Robson AC, et al.  The ontogeny of 11β-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development . Endocrinology . 1996;;137:794-797.
15 +
Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS.  Cloning and tissue distribution of the human 11β-hydroxysteroid dehydrogenase type 2 enzyme . Mol Cell Endocrinol . 1994;;105:R11-R17.
16 +
Buescher MA, McClamrock HD, Adashi EY.  Cushing's syndrome in pregnancy . Obstet Gynecol . 1992;;79:130-137.
17 +
Pang S, Clark AT, Freeman LC,et al.  Maternal side-effects of prenatal dexamethasone therapy for fetal congenital adrenal hyperplasia . J Clin Endocrinol Metab . 1992;;75:249-253.
18 +
Forest MG, Betuel H, David M.  Prenatal treatment in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update 88 of the French multicentric study . Endocr Res . 1989;;15:277-301.
19 +
Haan EA, Sergeantson SW, Norman R, et al.  Prenatal diagnosis and successful intrauterine treatment of a female fetus with 21-hydroxylase deficiency . Med J Aust . 1992;;156:132-135.
20 +
Miller WL.  Genetics, diagnosis, and management of 21-hydroxylase deficiency . J Clin Endocrinol Metab . 1994;;78:241-246.
21 +
Reinisch JM, Simon NG, Karwo WG, Gandelman R.  Prenatal exposure to prednisone in humans and animals retards intra-uterine growth . Science . 1978;;202:436-438.
22 +
Novy MJ, Walsh SW.  Dexamethasone and estradiol treatment in pregnant rhesus macaques: effects on gestation length, maternal plasma hormones and fetal growth . Am J Obstet Gynecol . 1983;;145:920-930.
23 +
Seckl JR.  Glucocorticoids and small babies . QJM . 1994;;87:259-262.
24 +
Styne DM, Grumbach MM, Kaplan SL, Wilson CB, Conte FA.  Treatment of Cushing's disease in childhood and adolescence by transsphenoidal microadenomectomy . N Engl J Med . 1984;;310:889-893.
25 +
Magiakou MA, Mastorakos G, Chrousos GP.  Final stature in patients with endogenous Cushing's syndrome . J Clin Endocrinol Metab . 1994;;79:1082-1085.
26 +
Holson RR, Gough B, Sullivan P, Badger T, Sheehan DM.  Prenatal dexamethasone or stress but not ACTH or corticosterone alter sexual behavior in male rats . Neurotoxicol Teratol . 1995;;17:393-401.
27 +
Benediktsson R, Lindsay R, Noble J, Seckl JR, Edwards CRW.  Glucocorticoid exposure in utero: a new model for adult hypertension . Lancet . 1993;;341:339-341.
28 +
Barker DJP, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS.  Fetal nutrition and cardiovascular disease in adult life . Lancet . 1993;;341:938-941.
29 +
Levine RS, Hennekens CH, Jesse MJ.  Blood pressure in prospective population based cohort of newborn and infant twins . BMJ . 1994;;308:298-302.
30 +
Whincup PH, Cook D, Papacosta O, Walker M.  Birth weight and blood pressure: cross-sectional and longitudinal relations in childhood . BMJ . 1995;;311:773-776.
31 +
Edwards CRW, Benediktsson R, Lindsay R, Seckl JR.  Dysfunction of the placental glucocorticoid barrier: a link between the foetal environment and adult hypertension? Lancet . 1993;;341:355-357.
32 +
Meaney MJ, Aitken DH, van Berkel C, Bhatnagar S, Sapolsky RM.  Effect of neonatal handling on age-related impairments associated with the hippocampus . Science . 1988;;239:766-768.
33 +
Weinstock M, Matlina E, Maor GI, Rosen H, McEwen BS.  Prenatal stress selectively alters the reactivity of the hypothalamic-pituitary adrenal system in the female rat . Brain Res . 1992;;595:195-200.
34 +
Diaz R, Ögren SO, Blum M, Fuxe K.  Prenatal corticosterone increases spontaneous and D-amphetamine induced locomotor activity and brain dopamine metabolism in prepubertal male and female rats . Neuroscience . 1995;;66:467-473.
35 +
Stewart PM, Rogerson FM, Mason JI.  Type 2 11β-hydroxysteroid dehydrogenase messenger RNA and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal steroidogenesis . J Clin Endocrinol Metab . 1995;;80:885-890.
36 +
Lindsay RS, Lindsay RM, Edwards CRW, Seckl JR.  Inhibition of 11βhydroxysteroid dehydrogenase in pregnant rats and the programming of blood pressure in the offspring . Hypertension . 1996;;27:1200-1204.
37 +
Lindsay RS, Lindsay RM, Waddell B, Seckl JR.  Programming of glucose tolerance in the rat: role of placental 11β-hydroxysteroid dehydrogenase . Diabetologia . 1996;;39:1299-1305.
38 +
Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC.  Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase . Nat Genet . 1995;;10:394-399.
39 +
Benediktsson R, Brennarnd J, Tibi L, Calder AA, Seckl JR, Edwards CRW.  Fetal osteocalcin levels are related to placental 11β-hydroxysteroid dehydrogenase activity . Clin Endocrinol . 1995;;42:551-555.
40 +
Trautman PD, Meyer-Bahlburg HFL, Postelnek J, New MI.  Effects of early prenatal dexamethasone on the congnitive and behavioral development of young children: results of a pilot study . Psychoneuroendocrinology . 1995;;20:439-449.

Figures

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Crowley P, Chalmers I, Keirse M.  The effects of corticosteroid administration before preterm delivery: an overview of the evidence from clinical trials . Br J Obstet Gynaecol . 1990;;97:11-25.
2 +
Ward RM.  Pharmacologic enhancement of fetal lung maturation . Clin Perinatol . 1994;;21:523-542.
3 +
Forest MG, David M, Morel Y.  Prental diagnosis and treatment of 21-hydroxylase deficiency . J Steriod Biochem Mol Biol . 1993;;45:75-82.
4 +
Speiser PW, New MI.  Prenatal diagnosis and management of congenital adrenal hyperplasia . Clin Perinatol . 1994;;21:631-645.
5 +
Morel Y, Miller WL.  Clinical and molecular genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency . Adv Hum Genet . 1991;;20:1-68.
6 +
Mercado AB, Wilson RC, Cheng KC, Wei JQ, New MI.  Prenatal treatment and diagnosis of congenital adrenal hyperlasia owing to 21-hydroxylase deficiency . J Clin Endocrinol Metab . 1995;;80:2014-2020.
7 +
Dittmann RW, Kappes ME, Kappes MH.  Sexual behavior in adolsecent and adult females with congenital adrenal hyperplasia . Psychoneuroendocrinology . 1992;;17:153-170.
8 +
Kuhnle U, Bollinger M, Schwarz HP, Knorr D.  Partnership and sexuality in adult female patients with congenital adrenal hyperplasia: first results of a cross-sectional quality-of-life evaluation . J Steroid Biochem Mol Biol . 1993;;45:123-126.
9 +
Van Wyk JJ, Gunther DF, Ritzén EM, et al.  The use of adrenalectomy as a treatment for congenital adrenal hyperplasia . J Clin Endocrinol Metab . 1996;;81:3180-3189.
10 +
Miller WL, Tyrrell JB.  The adrenal cortex . In: Felig P, Baxter JD, Frohman L, eds. Endocrinology and Metabolism . 3rd ed. New York, NY: McGraw Hill; 1995;:555-711.
11 +
Brown RW, Kotolevtsev Y, Leckie C,et al.  Isolation and cloning of human placental 11β-hydroxysteroid dehydrogenase-2 cDNA . Biochem J . 1996;;313:1007-1017.
12 +
Beitens IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ.  The metabolic clearance rate, blood production, interconversion and transplacental passage of cortisol and cortisone in pregnancy near term . Pediatr Res . 1973;;7:509-519.
13 +
Stewart PM, Murry BA, Mason JI.  Type 2 11β-hydroxysteroid dehydrogenase in human fetal tissues . J Clin Endocrinol Metab . 1994;;78:1529-1532.
14 +
Brown RW, Diaz R, Robson AC, et al.  The ontogeny of 11β-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development . Endocrinology . 1996;;137:794-797.
15 +
Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS.  Cloning and tissue distribution of the human 11β-hydroxysteroid dehydrogenase type 2 enzyme . Mol Cell Endocrinol . 1994;;105:R11-R17.
16 +
Buescher MA, McClamrock HD, Adashi EY.  Cushing's syndrome in pregnancy . Obstet Gynecol . 1992;;79:130-137.
17 +
Pang S, Clark AT, Freeman LC,et al.  Maternal side-effects of prenatal dexamethasone therapy for fetal congenital adrenal hyperplasia . J Clin Endocrinol Metab . 1992;;75:249-253.
18 +
Forest MG, Betuel H, David M.  Prenatal treatment in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update 88 of the French multicentric study . Endocr Res . 1989;;15:277-301.
19 +
Haan EA, Sergeantson SW, Norman R, et al.  Prenatal diagnosis and successful intrauterine treatment of a female fetus with 21-hydroxylase deficiency . Med J Aust . 1992;;156:132-135.
20 +
Miller WL.  Genetics, diagnosis, and management of 21-hydroxylase deficiency . J Clin Endocrinol Metab . 1994;;78:241-246.
21 +
Reinisch JM, Simon NG, Karwo WG, Gandelman R.  Prenatal exposure to prednisone in humans and animals retards intra-uterine growth . Science . 1978;;202:436-438.
22 +
Novy MJ, Walsh SW.  Dexamethasone and estradiol treatment in pregnant rhesus macaques: effects on gestation length, maternal plasma hormones and fetal growth . Am J Obstet Gynecol . 1983;;145:920-930.
23 +
Seckl JR.  Glucocorticoids and small babies . QJM . 1994;;87:259-262.
24 +
Styne DM, Grumbach MM, Kaplan SL, Wilson CB, Conte FA.  Treatment of Cushing's disease in childhood and adolescence by transsphenoidal microadenomectomy . N Engl J Med . 1984;;310:889-893.
25 +
Magiakou MA, Mastorakos G, Chrousos GP.  Final stature in patients with endogenous Cushing's syndrome . J Clin Endocrinol Metab . 1994;;79:1082-1085.
26 +
Holson RR, Gough B, Sullivan P, Badger T, Sheehan DM.  Prenatal dexamethasone or stress but not ACTH or corticosterone alter sexual behavior in male rats . Neurotoxicol Teratol . 1995;;17:393-401.
27 +
Benediktsson R, Lindsay R, Noble J, Seckl JR, Edwards CRW.  Glucocorticoid exposure in utero: a new model for adult hypertension . Lancet . 1993;;341:339-341.
28 +
Barker DJP, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS.  Fetal nutrition and cardiovascular disease in adult life . Lancet . 1993;;341:938-941.
29 +
Levine RS, Hennekens CH, Jesse MJ.  Blood pressure in prospective population based cohort of newborn and infant twins . BMJ . 1994;;308:298-302.
30 +
Whincup PH, Cook D, Papacosta O, Walker M.  Birth weight and blood pressure: cross-sectional and longitudinal relations in childhood . BMJ . 1995;;311:773-776.
31 +
Edwards CRW, Benediktsson R, Lindsay R, Seckl JR.  Dysfunction of the placental glucocorticoid barrier: a link between the foetal environment and adult hypertension? Lancet . 1993;;341:355-357.
32 +
Meaney MJ, Aitken DH, van Berkel C, Bhatnagar S, Sapolsky RM.  Effect of neonatal handling on age-related impairments associated with the hippocampus . Science . 1988;;239:766-768.
33 +
Weinstock M, Matlina E, Maor GI, Rosen H, McEwen BS.  Prenatal stress selectively alters the reactivity of the hypothalamic-pituitary adrenal system in the female rat . Brain Res . 1992;;595:195-200.
34 +
Diaz R, Ögren SO, Blum M, Fuxe K.  Prenatal corticosterone increases spontaneous and D-amphetamine induced locomotor activity and brain dopamine metabolism in prepubertal male and female rats . Neuroscience . 1995;;66:467-473.
35 +
Stewart PM, Rogerson FM, Mason JI.  Type 2 11β-hydroxysteroid dehydrogenase messenger RNA and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal steroidogenesis . J Clin Endocrinol Metab . 1995;;80:885-890.
36 +
Lindsay RS, Lindsay RM, Edwards CRW, Seckl JR.  Inhibition of 11βhydroxysteroid dehydrogenase in pregnant rats and the programming of blood pressure in the offspring . Hypertension . 1996;;27:1200-1204.
37 +
Lindsay RS, Lindsay RM, Waddell B, Seckl JR.  Programming of glucose tolerance in the rat: role of placental 11β-hydroxysteroid dehydrogenase . Diabetologia . 1996;;39:1299-1305.
38 +
Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC.  Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase . Nat Genet . 1995;;10:394-399.
39 +
Benediktsson R, Brennarnd J, Tibi L, Calder AA, Seckl JR, Edwards CRW.  Fetal osteocalcin levels are related to placental 11β-hydroxysteroid dehydrogenase activity . Clin Endocrinol . 1995;;42:551-555.
40 +
Trautman PD, Meyer-Bahlburg HFL, Postelnek J, New MI.  Effects of early prenatal dexamethasone on the congnitive and behavioral development of young children: results of a pilot study . Psychoneuroendocrinology . 1995;;20:439-449.

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