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Corticosteroid Therapy in the Neonatal Period
Corticosteroid Therapy in the Neonatal Period HARVEY D. KLEVIT, M.D.*
There are only a few well-defined indications for the use of corticosteroid therapy in the newborn period. However, the clinician confronted with an extremely ill baby, whose condition is rapidly deteriorating, may consider the administration of steroids because they are potentially life-saving in certain situations. Since the exact nature of the infant's illness may not be known at the time when rapid decisions are imperative, corticosteroids are frequently used empirically on such occasions. The physician may later learn that the use of these agents in pharmacologic amounts could have had an untoward effect on the infant's condition and may have contributed to his demise. This commentary will discuss the use of adrenal steroid hormones in newborn infants with endocrine disorders requiring replacement of physiologic quantities of hormone, and with other serious systemic illness where large to massive doses of steroids are sometimes beneficial. The structure, biochemistry, and physiology of the human fetal adrenal cortex have been the subjects of comprehensive reviews. 6 ,14 The adrenal cortex of the newborn infant secretes cortisol at a rate comparable to that of older infants, children, and adults when expressed in terms of total body surface area. l l ACTH ,injected soon after birth produces a rapid rise in blood cortisol and corticosterone,!' 9 although it is now rarely used therapeutically in newborn infants. The administration of ACTH to young infants produces a negative sodium balance owing to the secretion of "salt-losing" steroids 13 or substances antagonistic to the sodium-conserving effect of aldosterone. The administration of synthetic steroid analogues with glucocorticoid activity may avoid certain unwanted physiologic effects while preserving the desired hormonal action. The choice between cortisol or one of the newer compounds will depend upon the condition requiring treatment and the patient's electrolyte metabolism. Compounds such as triamcinolone and dexamethasone may result in negative sodium balance *Associate Clinical Professor of Pediatrics, University of Oregon Medical School; Endocrinologist, Bess Kaiser Hospital, Portland, Oregon
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which, in the very young infant, can escape detection until it is too late for correction. The majority of disorders of the newborn period requiring steroid therapy are congenital and permanent, demanding continuous treatment. In a few transient conditions the administration of corticosteroid is controversial. In these, treatment should be continued only for the duration of the illness.
PERMANENT CONDITIONS REQUIRING STEROID THERAPY Congenital Adrenal Hyperplasia Hereditary deficiency of one of several enzymes necessary for cortisol biosynthesis produces the adrenogenital syndrome. Diminished or absent (cortisol) production stimulates increased ACTH release which brings about the accumulation of relatively inactive steroid precursors, some of which are converted to virilizing androgens. This can result in masculinization of the newborn female in utero with clitoral hypertrophy, labial fusion, and the presence of a urogenital sinus. In contrast, male infants are not born with visible evidence of androgen excess; diagnosis is usually not made early in life except in the salt-losing form of the disease which is caused by the relative inability to synthesize aldosterone as well as cortisol. An infant with the latter variant of adrenal hyperplasia will usually develop hyponatremia, hyperkalemia, and dehydration after the seventh day of life. The earliest clinical signs are vomiting, poor weight gain, and diarrhea. The vomiting is sometimes projectile and leads to an erroneous diagnosis of pyloric stenosis. The failure to recognize the significance of these signs promptly has resulted in death (see Emergency Treatment). In another form of this disease, hypertension results from excessive production of mineralocorticoid, with salt and water retention. In adrenal hyperplasia, as in other hereditary metabolic disorders, accurate biochemical diagnosis is essential before committing the patient to a lifetime of treatment. Borderline values of urinary steroids may be obtained during the first weeks of life, necessitating serial measurements followed by suppression tests. The diagnosis of the most common variety of congenital adrenal hyperplasia, the C-21 hydroxylase enzyme defect, is made in the laboratory as follows: 1. The 24-hour urinary excretion of 17-ketosteroids is elevated and gradually increases. It is important to remember that the normal newborn infant has elevated urinary steroid concentrations as a result of placental transport of these substances from mother to fetus. In the normal infant a value of less than 1 mg. per 24 hours is generally reached by the tenth to fourteenth days of life and this value does not rise significantly for several years. In the infant with congenital adrenal hyperplasia, urinary 17-ketosteroid excretion remains greater than 1 mg. per 24 hours and increases with age. 2. There are measurable quantities of pregnanetriol in the urine. This steroid metabolite is not normally detected in the urine of infants
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and children. With a deficiency of the 21-hydroxylase enzyme there is accumulation of 17-hydroxyprogesterone which is reduced to pregnanetriol in the liver and excreted in the urine. Pregnanetriol excretion in excess of 1 mg. per 24 hours is virtually diagnostic of congenital adrenal hyperplasia. However, this substance may not be detected in urine until the third or fourth week of life. 3. Urinary 17-hydroxycorticosteroid excretion may be normal or diminished. This measurement is of little value in the neonatal period. The healthy infant may have extremely low values as measured by conventional techniques which determine only glucuronide conjugates. The newborn uses catabolic processes other than glucuronidation for removal of cortisol metabolites (e.g., 6,B-hydroxylation) because of "hepatic immaturity." Measurement of 17-ketogenic steroids in the urine may cause confusion, since they can be elevated owing to cortisol metabolites such as pregnanetriol. 4. Suppression tests should be performed to distinguish congenital adrenal hyperplasia from other virilizing disorders associated with elevated 17-ketosteroids and pregnanetriol (e.g., adrenal tumor). A reliable method is to administer 10 mg. cortisone acetate intramuscularly every 12 hours for 5 days and then to remeasure urinary ketosteroids and pregnanetriol. In congenital adrenal hyperplasia both will fall from elevated toward normal levels. Since approximately one third of infants with C-21 hydroxylase defect are salt-losers, it is important to watch for early signs of hyponatremia and dehydration in the virilized female suspected of having adrenal hyperplasia. Prior to institution of steroid therapy, urinary and serum sodium and potassium determinations should be obtained at frequent intervals, and treatment should be started as soon as salt loss becomes evident. The diagnosis of a salt-losing syndrome is suggested by falling serum sodium and chloride concentrations with rising serum potassium and non-protein nitrogen concentrations. A rising ratio of urinary sodium to potassium concentrations also suggests the salt-losing variety of congenital adrenal hyperplasia. The hypertensive variety of congenital adrenal hyperplasia is caused by a deficiency in C-ll,B-hydroxylase. 5 Virilization of the female infant is present, but salt-wasting does not appear in either sex. The 17-ketosteroids are elevated, the pregnanetriol may be elevated, and the urinary 17-hydroxycorticosteroids are increased as a result of the production and excretion of large quantities of Reichstein's Compound S. The rare 3,B-hydroxysteroid dehydrogenase deficiency syndrome 2 is manifested by virilization of the female, partial feminization of the male (hypospadias and cryptorchidism), and salt-loss in both sexes. The biochemical diagnosis can be made only by chromatographic separation and measurement of individual urinary steroids. This disease has been almost universally fatal in spite of early and adequate treatment. The goal of treatment in all forms of the disease is to provide sufficient glucocorticoid to satisfy the physiologic requirement, inhibit excessive ACTH secretion, and prevent further virilization of the infant. Cortisone and hydrocortisone are the drugs of choice because they produce a degree of salt retention beneficial in the sodium-wasting form of
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congenital adrenal hyperplasia, yet are not harmful in the other forms. The newer synthetic steroid analogues do not share this advantage and should not be used in the infant. Depot injections have not been successful. The details of treatment are given below. A number of the features of this regimen also apply to the use of corticosteroids in neonatal infants who do not have congenital adrenal hyperplasia. GLUCOCORTICOID THERAPY. The excessive ACTH release responsible for the adrenal secretion of large amounts of androgenic and other abnormal steroids is suppressed with cortisone acetate. Twenty mg. intramuscularly per 24 hours for one week is generally sufficient. A 24 hour urine specimen should be obtained after the fifth day of treatment for measurement of 17-ketosteroids and pregnanetriol. The infant is then started on replacement therapy. The proper dose of steroid cannot be predicted with any more accuracy than can the initial dose of insulin for a diabetic patient. In the past, many infants were given cortisone acetate intramuscularly every third day. Equally satisfactory replacement is accomplished with oral hydrocortisone; the cypionate ester (Fluid Cortef, Upjohn) is available in a 10 mg. per 5 ml. liquid suspension. The average infant will require approximately 15 mg. each day in three divided doses. Parents should be taught to administer the drug with a calibrated dropper rather than with the highly variable kitchen teaspoon. Some authorities prefer to give half of the daily dose early in the morning followed by one-fourth doses at 8 hour intervals. This corresponds more closely to the diurnal variation in cortisol secretion present in older infants and children. If the infant grows at a normal rate, shows no signs of progressive virilization (phallic enlargement, sexual hair), and his urinary 17-ketosteroids and pregnanetriol are not elevated, the dose need not be altered. Obviously the patient who becomes cushingoid in appearance is receiving too much steroid. It is important to show parents how to give intramuscular injections of cortisone acetate so that therapy need not be interrupted when vomiting prevents an infant from taking oral medication. Emergency Treatment. If the infant is dangerously ill or in shock when first seen and the clinical findings suggest a diagnosis of congenital adrenal hyperplasia, therapy should be started immediately without laboratory confirmation of the disease. Hydrocortisone hemisuccinate (Solu-Cortef) is given intravenously (2 mg. per kg.). Shock and dehydration should be treated with appropriate fluids and electrolytes. An additional 2 mg. per kg. per 8 hrs. of Solu-Cortef should be added to the infant's intravenous fluids. With clinical improvement intramuscular cortisone acetate may be substituted as described above. MINERALOCORTICOID THERAPY. In addition to cortisol replacement, treatment of shock, and repletion of body sodium and water, a saltretaining steroid should be given to the infant with adrenal insufficiency of any cause, including the salt-losing form of adrenal hyperplasia. Deoxycorticosterone acetate (DOCA) is available in sesame oil (5 mg. per mI.); usually 1 to 2 mg. intramuscularly every 12 hours is sufficient to
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maintain renal sodium conservation. After replacement of fluids and electrolytes, the infant with adrenal insufficiency can be given a longacting DOCA preparation; approximately 25 mg. Percorten pivalate (Ciba) administered every 3 to 4 weeks is generally adequate. The infant's blood pressure should be checked frequently, since an overdose of this or other mineralocorticoid preparations may produce severe hypertension which is slow to disappear even when therapy is discontinued. 17• 19 It is important to remember that the hyponatremic infant in whom the diagnosis of congenital adrenal hyperplasia is considered may be placed on DOCA and salt supplementation without interfering with the characteristic steroid pattern in the urine. The mineralocorticoids have little effect upon ACTH secretion; hence, the 17-ketosteroids and pregnanetriol will remain elevated in the urine, allowing a definitive diagnosis to be established without the infant going into shock "while he waits." Hereditary Hypoaldosteronism Due to a C-1S Oxidation Defect An inborn error of metabolism involving only mineralocorticoid synthesis may produce symptoms during the first month of life. 23 • 24 This disorder is associated with an hereditary inability to convert IS-hydroxycorticosterone to aldosterone. Since a normal amount of cortisol is synthesized, there is no increase in ACTH release. Aldosterone precursors accumulate as a result of the activation of the renin/angiotensin system. These infants are hyponatremic and hyperkalemic, but there are no signs of fetal virilization. The urinary 17-hydroxycorticoids and 17ketosteroids are normal, and pregnanetriol is absent. A large amount of IS-hydroxycorticosterone metabolite is in the urine. The aldosterone secretion and excretion rates are virtually zero. Treatment consists of DOCA and supplemental salt as described under Congenital Adrenal Hyperplasia. Cortisol is unnecessary. Congenital Adrenal Insufficiency Severe hyponatremia, hyperkalemia, vomiting, and dehydration may occur during the first weeks of life in infants born with hypoplasia of the adrenal glands. At postmortem examination, there are small adrenal glands occasionally associated with absence of the pituitary gland. The disease has been reported in siblings. Urinary steroid excretion does not increase following ACTH administration. These addisonian infants should be treated with both cortisol and mineralocorticoid as outlined in the section on Congenital Adrenal Hyperplasia. Rarely, adrenal insufficiency may occur in the newborn as a result of hemorrhage into the large involuting fetal adrenal gland. This may be a result of a clotting deficiency, infection, anoxia, or traumatic breech delivery. The majority of infants exhibit no clinical signs of adrenal insufficiency and are recognized from bilateral suprarenal calcifications. If clinical signs of adrenal insufficiency should occur, treatment with cortisol and DOCA should be instituted as outlined under Congenital Adrenal Hyperplasia.
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TRANSIENT CONDITIONS IN WHICH STEROID HORMONES ARE EMPLOYED "Transient" Adrenal Insufficiency of the Newborn In 1946 Jaudon 1o reported a series of male infants who displayed persistent vomiting, sodium loss, dehydration, and subsequent circulatory collapse. Treatment with DOCA, salt, and adrenocortical extract produced rapid improvement, with relapse when therapy was discontinued. After a variable interval, the patients were able to maintain normal sodium balance without steroid therapy. Jaudon reasoned that this course was a reflection of the immaturity of the infant's adrenal cortex, with subsequent maturation allowing normal steroidogenesis. Initially, several of the infants were thought to have hypertrophic pyloric stenosis. We had the opportunity to study one of Jaudon's patients 12 years after the report. He and his younger brother were both explored surgically for pyloric stenosis during early infancy. At ages 10 and 12, respectively, both boys were markedly virilized and had an insatiable craving for salt. Both had very elevated urinary 17-ketosteroids and pregnanetriol; glucocorticoid administration produced normal levels, indicating that they had actually survived congenital adrenal hyperplasia (salt-losing) without treatment. The infant with hyponatremia resulting from urinary salt loss presents a difficult diagnostic and therapeutic problem. If urinary steroid assays fail to detect a defect in cortisol or aldosterone synthesis (see above), empirical therapy with DOCA and salt should be attempted. It is difficult to maintain a normal serum sodium in some patients with "idiopathic salt-loss" in spite of adult doses of mineralocorticoid and massive salt intake. One may speculate that a renal tubular insensitivity to mineralocorticoid is present in those hyponatremic infants with normal or elevated urinary aldosterone excretion. These patients respond poorly to administered mineralocorticoid. Russell et al. 22 reported a reversible salt-wasting syndrome of early infancy in which aldosterone is not released in the face of sodium deprivation. After one year of age the infants could be maintained without mineralocorticoid and salt supplementation in spite of extremely low aldosterone production. None of the patients had evidence of virilization and all had normal urinary steroid metabolites which increased following ACTH administration. It is likely that the majority of patients reported by Jaudon represented cases of either congenital adrenal hyperplasia or the reversible salt-wasting syndrome of Russell. 22 Neonatal Thyrotoxicosis With few exceptions, Graves' disease in the newborn has occurred when the mother has had hyperthyroidism during pregnancy or has displayed residual exophthalmos from a previous episode of hyperthyroidism. Fetal tachycardia is sometimes noted during labor, persisting after birth and frequently precipitating congestive heart failure. The newborn
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displays jerky movements, restlessness, and a startled facial expression. Exophthalmos is generally present and is sometimes associated with conjunctival chemosis. The thyroid gland is enlarged but generally does not cause airway obstruction as in other types of neonatal goiter. Hyperthermia develops slowly over the first hours of life. The symptoms of neonatal thyrotoxicosis gradually subside after the second to third weeks of life. Neonatal thyrotoxicosis is frequently severe and reminiscent of thyroid storm in the adult. The mortality rate is high unless therapy is instituted immediately. The etiology of neonatal hyperthyroidism was initially thought to be on the basis of placental transfer of thyrotropin from mother to fetus. With the discovery of L.A.T.S. (long acting thyroid stimulator) numerous investigators reported high titers of this material in the serum of thyrotoxic newborn infants. L.A.T.S. is a 7S gamma globulin (IgG) which has unexplained thyrotropic properties. It crosses the placenta with ease, stimulates the fetal thyroid, and produces exophthalmos. Since L.A.T.S. may remain in the mother's serum in spite of control of her thyrotoxicosis, her infant may suffer from the disease. As L.A.T.S. disappears from the infant's circulation, his symptoms gradually subside. Hyperthyroidism is associated with a rapid turnover of adrenal corticosteroids and may produce a state of relative adrenal insufficiency in an infant. Therefore, corticosteroids should be administered to seriously ill infants. Cortisone acetate, 15 mg. intramuscularly every 12 hours would be adequate replacement in newborn infants. Iodides are effective in inhibiting release of thyroid hormone. One to two drops of Lugol's solution every 8 hours by gavage is recommended. Reserpine, 0.15 mg. per kg. per day intramuscularly in three divided doses is used to combat the effects of increased epinephrine sensitivity in hyperthyroidism. Antithyroid drugs may be employed if the infant does not respond to these measures within 36 hours. Propylthiouracil is generally employed, 6 mg. per kg. per day in three divided doses. A 50 mg. tablet is easily dissolved in 50 ml. of saline and facilitates administration via gavage tube. In most cases the infant can be weaned from therapy at 6 to 8 weeks of age with impunity. Neonatal Hypoglycemia Symptomatic hypoglycemia in the newborn infant is associated with conditions such as sepsis, central nervous system damage, low birth weight for gestational age, erythroblastosis fetalis, maternal diabetes, and toxemia. The premature infant is particularly susceptible to hypoglycemia. A blood glucose determination should be performed upon any infant who manifests pallor, sweating, lethargy, poor muscle tone, weak suck, "jitteriness," irritability, convulsions, or cyanosis which is not due to an obvious cardiopulmonary abnormality. Hypoglycemia is generally considered to be present in premature infants with blood sugars (true glucose method) less than 20 mg. per 100 mI. and in full-term infants with blood glucose of less than 30 mg. per 100 mI. during the
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first two days of life; thereafter, 40 mg. per 100 ml. or above is considered normal. The administration of 2 mg. per kg. per 24 hours of hydrocortisone hemisuccinate (Solu-Cortef) by continuous intravenous infusion is indicated in infants with symptomatic hypoglycemia in whom 10% intravenous glucose infusions are not adequate to maintain normal blood glucose levels. In an asymptomatic infant, if the blood sugar cannot be maintained at a normal level with the use of an intravenous glucose solution, prednisone may be given orally (1 mg. per kg. per 24 hours in three divided doses). Some authorities prefer ACTH, but its effect on sodium balance and the necessity of frequent injections outweighs any advantages of this agent. Steroid Therapy in Infectious Disease Adrenal function has been measured in infants and children with meningitis of various etiologies. 18 These studies indicate that the addition of exogenous cortisol is unnecessary in most cases of bacterial meningitis, since the cortisol production rate and plasma cortisol level are both elevated. Those patients with low plasma cortisol concentration generally were in shock from meningococcal infection, and adrenal hemorrhage was found at autopsy. Thus, there would appear to be little reason to use steroids in physiologic dosage to treat neonatal infants with sepsis or meningitis if they can maintain normal circulatory dynamics, preferably measured by central venous pressure, and have no laboratory or clinical signs of adrenal insufficiency. However, if an infant with septicemia develops signs of shock, pharmacologic quantities of steroids may be indicated. Septic shock is most likely caused by arteriolar vasodilatation from the action of endotoxin of gram-negative bacteria. Lillehei and associates l6 have recommended intravenous cortisol in dosages ranging from 15 to 25 mg. per kg. for adults with endotoxic shock. Although this treatment has not been evaluated in young infants, the use of high dosages of steroids in the newborn with suspected gram-negative septic shock is justified. Hodes 8 recommends intravenous hydrocortisone, 35 to 50 mg. per kg. administered over a 10 minute period. This may be repeated, depending upon clinical response, at 30 to 60 minute intervals for four doses. The beneficial effect of high dose steroid therapy in endotoxic shock may be related to adrenergic blockade, decreased lactic acid formation, and generation of adenosine triphosphate. In addition, hypovolemia should be treated with blood or plasma and metabolic acidosis corrected. Heparinization should be considered if signs of intravascular coagulation appear (purpura or scattered .petechiae). Yu and Grauaug 27 have advocated the use of corticosteroids in newborn infants with purulent meningitis, regardless of the etiology or the presence of shock. In a retrospective uncontrolled survey, they reported on 44 cases of meningitis divided equally into steroid treatment and non-treated groups collected over an 8 year period. The difference in survival rates in two groups was of questionable statistical significance. The incidence of complications such as subdural effusion or hydrocephalus was identical in the two groups. DeLemos and Haggerty 4 have recently reported on a double-blind
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controlled investigation of the effect of large doses of methylprednisolone on the survival and long-term sequelae of infants and children with bacterial meningitis. There was no statistically significant difference between treatment and control groups for mortality, time required for sterilization of spinal fluid, and incidence of subdural effusion. Psychometric testing performed 1 to 4 years after the attack of meningitis revealed residual damage in 42 per cent of the steroid-treated group and in 20 per cent of the control group.
Sclerema Neonatorum Tallow-like hardening of the subcutaneous tissue may occur in the newborn term infant and more commonly in the premature infant as a sign of a severe underlying infection or an abnormal metabolic process. In the pre-antibiotic era this condition was almost always fatal. In recent years some of these infants have survived when the condition was associated with sepsis that was treated appropriately and vigorously with antibiotics. High doses of corticosteroids have been advocated for sclerematous infants, but there is no clear evidence for or against their use. Levin et al. 15 could find no difference in mortality rates between steroid treated and untreated newborns. Warwick et al. 26 state that steroids are warranted only when adrenal insufficiency is present. However, since acidosis, hyperkalemia, and hyponatremia are frequently present with sclerema, it is not possible to diagnose adrenal insufficiency in such patients without hormone assays, which are difficult to obtain in the best equipped centers and are not available on an emergency basis. Gellis 7 advocates the use of both corticosteroids and antimicrobials in all infants with sclerema. If steroids are utilized, 2 mg. per kg. per 8 hours of a continuous intravenous infusion of hydrocortisone hemisuccinate would be an appropriate dose.
The Infant of the Steroid-Treated Mother The outcome of 34 gestations in women receIvmg prednisolone during pregnancy for a variety of illnesses was evaluated by Warrell and Taylor. 25 Compared to a control group of mothers with similar illnesses not treated with steroids, the study group had a significantly higher incidence of stillbirths and placental insufficiency syndromes. There was no clinical evidence for suppression of the fetal adrenal in these infants. BongiovannP has reviewed 260 pregnancies during which mothers received pharmacologic doses of corticosteroid. He concludes that these infants "rarely, if ever, demonstrate evidence of adrenocortical insufficiency." Kenny et al. 12 measured cortisol production rates in eight infants born to steroid-treated mothers. None of these children demonstrated symptomatic adrenal suppression, and they all had normal cortisol production. However, we have seen one infant of a mother with rheumatoid arthritis treated with prednisone during pregnancy who developed hypoglycemia on the second day of life. This newborn infant required intravenous glucose and glucagon for 3 days before he was able to maintain a normal blood glucose and had no further symptoms suggesting adrenal insufficiency.
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Oppenheimer21 reported cystic lesions of the adrenal glands of infants whose mothers received steroids during pregnancy. More recently, she has described similar lesions in the adrenals of infants with no history of maternal steroid administration. 2o Therefore, on the basis of available information, prophylactic steroid therapy of infants born to steroid-treated mothers is not indicated. Blood glucose determinations should be obtained at frequent intervals and hypoglycemia should be considered as a possible manifestation of adrenal suppression. Intravenous 10 to 15 per cent glucose infusion and the administration of cortisol (20 to 30 mg. per square meter per 24 hours, or 2 mg. per kg. per 8 hours) for several days should be adequate therapy for the rare infant who develops temporary adrenal inactivity.
SUMMARY Adrenal steroid therapy in the newborn is mandatory in only a few rare hereditary or congenital endocrine syndromes and in acquired adrenal hemorrhage. In these diseases cortisol or mineralocorticoids or both are used in physiologic replacement dosage. They should also be used in some cases of neonatal thyrotoxicosis and hypoglycemia. The use of pharmacologic quantities of steroid hormones in the neonatal infant with abnormalities such as septic shock, meningitis and sc1erema remains controversial.
REFERENCES 1. Bertrand, J., Gilly, R, and Loras, B.: Neonatal adrenal function: Free glucuroconjugated plasma 17 hydroxycorticosteroids in 102 infants from birth to 42 days of age: Effect of ACTH or oestrogen administration. International Congress on Hormonal Steroids, Milan, Italy, 1962, p. 279 2. Bongiovanni, A. M.: The adrenogenital syndrome with deficiency of 3,B-hydroxysteroid dehydrogenase. J. Clin. Invest., 41 :2086, 1962. 3. Bongiovanni, A. M., and McPadden, A. J.: Steroids during pregnancy and possible fetal consequences. Fertil. Steril., 11:181, 1960. 4. deLemos, R. A., and Haggerty, R J.: Corticosteroids as an adjunct to treatment in bacterial meningitis. Pediatrics, 44:30, 1969. 5. Eberlein, W. R, and Bongiovanni, A. M.: Plasma and urinary corticosteroids in the hypertensive form of congenital adrenal hyperplasia. J. BioI. Chern., 223:85, 1956. 6. Gardner, L. I.: Development of the normal fetal and neonatal adrenal. In Gardner, L. I., ed.: Endocrine and Genetic Disease of Childhood. Philadelphia, W. B. Saunders Co., 1969, p. 392. 7. Gellis, S. S.: Year Book of Pediatrics, 1964-1965, p. 49-50. 8. Hodes, H. L.: Endotoxin shock. Pediatrics, 44:248, 1969. 9. Hughes, E. R, Seely, J. R, Kelley, V. C., and Ely, R S.: Corticosteroid levels before and after corticotropin. Amer. J. Dis. Child., 104:605, 1962. 10. Jaudon, J. C.: Hypofunction of the adrenals in early life. J. Pediat., 29:696, 1946. 11. Kenny, F. M., Malvaux, P., and Migeon, C. J.: Cortisol Production rate in newborn babies, older infants, and children, Pediatrics, 31 :360, 1963. 12. Kenny, F. M., Preeyasombat, C., Spaulding, J. S., and Migeon, C. J.: Cortisol production rate. IV. Infants born of steroid-treated mothers and of diabetic mothers. Infants with trisomy syndrome and with anencephaly. Pediatrics, 37:960, 1966. 13. Klein, R.: Evidence for and against the existence of a salt-losing hormone. J. Pediat., 57:452, 1960. 14. KIevit, H. D.: Fetal-placental-maternal interrelations involving steroid hormones. PEDIAT. CLIN. N. AMER., 13:59, 1966.
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15. Levin, S. E., Bakst, C. M., and Isserow, L.: Sclerema neonatorum treated with corticosteroids. Brit. Med. J., 2:1533, 1961. 16. Lillehei, R. C., Longerbeam, J. K., Bloch, J. H., and Manax, W. G.: The nature ofirreversible shock. Experimental and clinical observations. Ann. Surg., 160:682, 1964. 17. Marks, J. F., and Fink, C. W.: Prolonged hypertension following cessation of desoxycorticosterone therapy in congenital adrenal hyperplasia. Pediatrics, 40: 184, 1967. 18. Migeon, C. J., Kenny, F. M., Hung, W., and Voorhess, M. L.: Study of adrenal function in children with meningitis. Pediatrics, 40:163,1967. 19. Monteleone, J. A.: Hypertensive encephalopathy with overdosage of deoxycorticosterone. Pediatrics, 43 :294, 1969. 20. Oppenheimer, E. H.: Do adrenocorticosteroids affect fetal risk when given to the mother for general disease during pregnancy? Are the fetal adrenals suppressed? Modern Medicine, March 24, 1969, p. 223. 21. Oppenheimer, E. H.: Lesions of the adrenals of an infant following maternal corticosteroid therapy. Bull. Johns Hopkins Hosp., 114: 146, 1964. 22. Russell, A., Levin, B., Sinclair, L., and Oberholzer, V.: A reversible salt-wasting syndrome of the newborn and infant. Arch. Dis. Childhood, 38:313, 1963. 23. Ulick, S., Gautier, E., Vetter, K. K., Markello, J. R., Yaffe, S., and Lowe, C. U.: An aldosterone biosynthetic defect in a salt-losing disorder. J. Clin Endocrinol., 24:669, 1964. 24. Visser, H. K. A., and Cost, W. S.: A new hereditary defect in the biosynthesis of aldosterone: Urinary C-21 corticosteroid pattern in three related patients with a salt-losing syndrome, suggesting an 18-oxidation defect. Acta Endocrin. (Kbh.), 47:589, 1964. 25. Warrell, D. W., and Taylor, R.: Outcome for the fetus of mothers receiving prednisolone during pregnancy. Lancet, 1: 117, 1968. 26. Warwick, W. J., Ruttenberg, H. D., and Quie, P. G.: Sclerema neonatorum: A sign, not a disease. J.A.M.A., 184:680, 1963. 27. Yu, J. S., and Grauaug, A.: Purulent meningitis in the neonatal period. Arch. Dis. Child., 38:391,1963. 5055 North Greeley Avenue Portland, Oregon 97217
There are only a few well-defined indications for the use of corticosteroid therapy in the newborn period. However, the clinician confronted with an extremely ill baby, whose condition is rapidly deteriorating, may consider the administration of steroids because they are potentially life-saving in certain situations. Since the exact nature of the infant's illness may not be known at the time when rapid decisions are imperative, corticosteroids are frequently used empirically on such occasions. The physician may later learn that the use of these agents in pharmacologic amounts could have had an untoward effect on the infant's condition and may have contributed to his demise. This commentary will discuss the use of adrenal steroid hormones in newborn infants with endocrine disorders requiring replacement of physiologic quantities of hormone, and with other serious systemic illness where large to massive doses of steroids are sometimes beneficial. The structure, biochemistry, and physiology of the human fetal adrenal cortex have been the subjects of comprehensive reviews. 6 ,14 The adrenal cortex of the newborn infant secretes cortisol at a rate comparable to that of older infants, children, and adults when expressed in terms of total body surface area. l l ACTH ,injected soon after birth produces a rapid rise in blood cortisol and corticosterone,!' 9 although it is now rarely used therapeutically in newborn infants. The administration of ACTH to young infants produces a negative sodium balance owing to the secretion of "salt-losing" steroids 13 or substances antagonistic to the sodium-conserving effect of aldosterone. The administration of synthetic steroid analogues with glucocorticoid activity may avoid certain unwanted physiologic effects while preserving the desired hormonal action. The choice between cortisol or one of the newer compounds will depend upon the condition requiring treatment and the patient's electrolyte metabolism. Compounds such as triamcinolone and dexamethasone may result in negative sodium balance *Associate Clinical Professor of Pediatrics, University of Oregon Medical School; Endocrinologist, Bess Kaiser Hospital, Portland, Oregon
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which, in the very young infant, can escape detection until it is too late for correction. The majority of disorders of the newborn period requiring steroid therapy are congenital and permanent, demanding continuous treatment. In a few transient conditions the administration of corticosteroid is controversial. In these, treatment should be continued only for the duration of the illness.
PERMANENT CONDITIONS REQUIRING STEROID THERAPY Congenital Adrenal Hyperplasia Hereditary deficiency of one of several enzymes necessary for cortisol biosynthesis produces the adrenogenital syndrome. Diminished or absent (cortisol) production stimulates increased ACTH release which brings about the accumulation of relatively inactive steroid precursors, some of which are converted to virilizing androgens. This can result in masculinization of the newborn female in utero with clitoral hypertrophy, labial fusion, and the presence of a urogenital sinus. In contrast, male infants are not born with visible evidence of androgen excess; diagnosis is usually not made early in life except in the salt-losing form of the disease which is caused by the relative inability to synthesize aldosterone as well as cortisol. An infant with the latter variant of adrenal hyperplasia will usually develop hyponatremia, hyperkalemia, and dehydration after the seventh day of life. The earliest clinical signs are vomiting, poor weight gain, and diarrhea. The vomiting is sometimes projectile and leads to an erroneous diagnosis of pyloric stenosis. The failure to recognize the significance of these signs promptly has resulted in death (see Emergency Treatment). In another form of this disease, hypertension results from excessive production of mineralocorticoid, with salt and water retention. In adrenal hyperplasia, as in other hereditary metabolic disorders, accurate biochemical diagnosis is essential before committing the patient to a lifetime of treatment. Borderline values of urinary steroids may be obtained during the first weeks of life, necessitating serial measurements followed by suppression tests. The diagnosis of the most common variety of congenital adrenal hyperplasia, the C-21 hydroxylase enzyme defect, is made in the laboratory as follows: 1. The 24-hour urinary excretion of 17-ketosteroids is elevated and gradually increases. It is important to remember that the normal newborn infant has elevated urinary steroid concentrations as a result of placental transport of these substances from mother to fetus. In the normal infant a value of less than 1 mg. per 24 hours is generally reached by the tenth to fourteenth days of life and this value does not rise significantly for several years. In the infant with congenital adrenal hyperplasia, urinary 17-ketosteroid excretion remains greater than 1 mg. per 24 hours and increases with age. 2. There are measurable quantities of pregnanetriol in the urine. This steroid metabolite is not normally detected in the urine of infants
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and children. With a deficiency of the 21-hydroxylase enzyme there is accumulation of 17-hydroxyprogesterone which is reduced to pregnanetriol in the liver and excreted in the urine. Pregnanetriol excretion in excess of 1 mg. per 24 hours is virtually diagnostic of congenital adrenal hyperplasia. However, this substance may not be detected in urine until the third or fourth week of life. 3. Urinary 17-hydroxycorticosteroid excretion may be normal or diminished. This measurement is of little value in the neonatal period. The healthy infant may have extremely low values as measured by conventional techniques which determine only glucuronide conjugates. The newborn uses catabolic processes other than glucuronidation for removal of cortisol metabolites (e.g., 6,B-hydroxylation) because of "hepatic immaturity." Measurement of 17-ketogenic steroids in the urine may cause confusion, since they can be elevated owing to cortisol metabolites such as pregnanetriol. 4. Suppression tests should be performed to distinguish congenital adrenal hyperplasia from other virilizing disorders associated with elevated 17-ketosteroids and pregnanetriol (e.g., adrenal tumor). A reliable method is to administer 10 mg. cortisone acetate intramuscularly every 12 hours for 5 days and then to remeasure urinary ketosteroids and pregnanetriol. In congenital adrenal hyperplasia both will fall from elevated toward normal levels. Since approximately one third of infants with C-21 hydroxylase defect are salt-losers, it is important to watch for early signs of hyponatremia and dehydration in the virilized female suspected of having adrenal hyperplasia. Prior to institution of steroid therapy, urinary and serum sodium and potassium determinations should be obtained at frequent intervals, and treatment should be started as soon as salt loss becomes evident. The diagnosis of a salt-losing syndrome is suggested by falling serum sodium and chloride concentrations with rising serum potassium and non-protein nitrogen concentrations. A rising ratio of urinary sodium to potassium concentrations also suggests the salt-losing variety of congenital adrenal hyperplasia. The hypertensive variety of congenital adrenal hyperplasia is caused by a deficiency in C-ll,B-hydroxylase. 5 Virilization of the female infant is present, but salt-wasting does not appear in either sex. The 17-ketosteroids are elevated, the pregnanetriol may be elevated, and the urinary 17-hydroxycorticosteroids are increased as a result of the production and excretion of large quantities of Reichstein's Compound S. The rare 3,B-hydroxysteroid dehydrogenase deficiency syndrome 2 is manifested by virilization of the female, partial feminization of the male (hypospadias and cryptorchidism), and salt-loss in both sexes. The biochemical diagnosis can be made only by chromatographic separation and measurement of individual urinary steroids. This disease has been almost universally fatal in spite of early and adequate treatment. The goal of treatment in all forms of the disease is to provide sufficient glucocorticoid to satisfy the physiologic requirement, inhibit excessive ACTH secretion, and prevent further virilization of the infant. Cortisone and hydrocortisone are the drugs of choice because they produce a degree of salt retention beneficial in the sodium-wasting form of
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congenital adrenal hyperplasia, yet are not harmful in the other forms. The newer synthetic steroid analogues do not share this advantage and should not be used in the infant. Depot injections have not been successful. The details of treatment are given below. A number of the features of this regimen also apply to the use of corticosteroids in neonatal infants who do not have congenital adrenal hyperplasia. GLUCOCORTICOID THERAPY. The excessive ACTH release responsible for the adrenal secretion of large amounts of androgenic and other abnormal steroids is suppressed with cortisone acetate. Twenty mg. intramuscularly per 24 hours for one week is generally sufficient. A 24 hour urine specimen should be obtained after the fifth day of treatment for measurement of 17-ketosteroids and pregnanetriol. The infant is then started on replacement therapy. The proper dose of steroid cannot be predicted with any more accuracy than can the initial dose of insulin for a diabetic patient. In the past, many infants were given cortisone acetate intramuscularly every third day. Equally satisfactory replacement is accomplished with oral hydrocortisone; the cypionate ester (Fluid Cortef, Upjohn) is available in a 10 mg. per 5 ml. liquid suspension. The average infant will require approximately 15 mg. each day in three divided doses. Parents should be taught to administer the drug with a calibrated dropper rather than with the highly variable kitchen teaspoon. Some authorities prefer to give half of the daily dose early in the morning followed by one-fourth doses at 8 hour intervals. This corresponds more closely to the diurnal variation in cortisol secretion present in older infants and children. If the infant grows at a normal rate, shows no signs of progressive virilization (phallic enlargement, sexual hair), and his urinary 17-ketosteroids and pregnanetriol are not elevated, the dose need not be altered. Obviously the patient who becomes cushingoid in appearance is receiving too much steroid. It is important to show parents how to give intramuscular injections of cortisone acetate so that therapy need not be interrupted when vomiting prevents an infant from taking oral medication. Emergency Treatment. If the infant is dangerously ill or in shock when first seen and the clinical findings suggest a diagnosis of congenital adrenal hyperplasia, therapy should be started immediately without laboratory confirmation of the disease. Hydrocortisone hemisuccinate (Solu-Cortef) is given intravenously (2 mg. per kg.). Shock and dehydration should be treated with appropriate fluids and electrolytes. An additional 2 mg. per kg. per 8 hrs. of Solu-Cortef should be added to the infant's intravenous fluids. With clinical improvement intramuscular cortisone acetate may be substituted as described above. MINERALOCORTICOID THERAPY. In addition to cortisol replacement, treatment of shock, and repletion of body sodium and water, a saltretaining steroid should be given to the infant with adrenal insufficiency of any cause, including the salt-losing form of adrenal hyperplasia. Deoxycorticosterone acetate (DOCA) is available in sesame oil (5 mg. per mI.); usually 1 to 2 mg. intramuscularly every 12 hours is sufficient to
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maintain renal sodium conservation. After replacement of fluids and electrolytes, the infant with adrenal insufficiency can be given a longacting DOCA preparation; approximately 25 mg. Percorten pivalate (Ciba) administered every 3 to 4 weeks is generally adequate. The infant's blood pressure should be checked frequently, since an overdose of this or other mineralocorticoid preparations may produce severe hypertension which is slow to disappear even when therapy is discontinued. 17• 19 It is important to remember that the hyponatremic infant in whom the diagnosis of congenital adrenal hyperplasia is considered may be placed on DOCA and salt supplementation without interfering with the characteristic steroid pattern in the urine. The mineralocorticoids have little effect upon ACTH secretion; hence, the 17-ketosteroids and pregnanetriol will remain elevated in the urine, allowing a definitive diagnosis to be established without the infant going into shock "while he waits." Hereditary Hypoaldosteronism Due to a C-1S Oxidation Defect An inborn error of metabolism involving only mineralocorticoid synthesis may produce symptoms during the first month of life. 23 • 24 This disorder is associated with an hereditary inability to convert IS-hydroxycorticosterone to aldosterone. Since a normal amount of cortisol is synthesized, there is no increase in ACTH release. Aldosterone precursors accumulate as a result of the activation of the renin/angiotensin system. These infants are hyponatremic and hyperkalemic, but there are no signs of fetal virilization. The urinary 17-hydroxycorticoids and 17ketosteroids are normal, and pregnanetriol is absent. A large amount of IS-hydroxycorticosterone metabolite is in the urine. The aldosterone secretion and excretion rates are virtually zero. Treatment consists of DOCA and supplemental salt as described under Congenital Adrenal Hyperplasia. Cortisol is unnecessary. Congenital Adrenal Insufficiency Severe hyponatremia, hyperkalemia, vomiting, and dehydration may occur during the first weeks of life in infants born with hypoplasia of the adrenal glands. At postmortem examination, there are small adrenal glands occasionally associated with absence of the pituitary gland. The disease has been reported in siblings. Urinary steroid excretion does not increase following ACTH administration. These addisonian infants should be treated with both cortisol and mineralocorticoid as outlined in the section on Congenital Adrenal Hyperplasia. Rarely, adrenal insufficiency may occur in the newborn as a result of hemorrhage into the large involuting fetal adrenal gland. This may be a result of a clotting deficiency, infection, anoxia, or traumatic breech delivery. The majority of infants exhibit no clinical signs of adrenal insufficiency and are recognized from bilateral suprarenal calcifications. If clinical signs of adrenal insufficiency should occur, treatment with cortisol and DOCA should be instituted as outlined under Congenital Adrenal Hyperplasia.
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TRANSIENT CONDITIONS IN WHICH STEROID HORMONES ARE EMPLOYED "Transient" Adrenal Insufficiency of the Newborn In 1946 Jaudon 1o reported a series of male infants who displayed persistent vomiting, sodium loss, dehydration, and subsequent circulatory collapse. Treatment with DOCA, salt, and adrenocortical extract produced rapid improvement, with relapse when therapy was discontinued. After a variable interval, the patients were able to maintain normal sodium balance without steroid therapy. Jaudon reasoned that this course was a reflection of the immaturity of the infant's adrenal cortex, with subsequent maturation allowing normal steroidogenesis. Initially, several of the infants were thought to have hypertrophic pyloric stenosis. We had the opportunity to study one of Jaudon's patients 12 years after the report. He and his younger brother were both explored surgically for pyloric stenosis during early infancy. At ages 10 and 12, respectively, both boys were markedly virilized and had an insatiable craving for salt. Both had very elevated urinary 17-ketosteroids and pregnanetriol; glucocorticoid administration produced normal levels, indicating that they had actually survived congenital adrenal hyperplasia (salt-losing) without treatment. The infant with hyponatremia resulting from urinary salt loss presents a difficult diagnostic and therapeutic problem. If urinary steroid assays fail to detect a defect in cortisol or aldosterone synthesis (see above), empirical therapy with DOCA and salt should be attempted. It is difficult to maintain a normal serum sodium in some patients with "idiopathic salt-loss" in spite of adult doses of mineralocorticoid and massive salt intake. One may speculate that a renal tubular insensitivity to mineralocorticoid is present in those hyponatremic infants with normal or elevated urinary aldosterone excretion. These patients respond poorly to administered mineralocorticoid. Russell et al. 22 reported a reversible salt-wasting syndrome of early infancy in which aldosterone is not released in the face of sodium deprivation. After one year of age the infants could be maintained without mineralocorticoid and salt supplementation in spite of extremely low aldosterone production. None of the patients had evidence of virilization and all had normal urinary steroid metabolites which increased following ACTH administration. It is likely that the majority of patients reported by Jaudon represented cases of either congenital adrenal hyperplasia or the reversible salt-wasting syndrome of Russell. 22 Neonatal Thyrotoxicosis With few exceptions, Graves' disease in the newborn has occurred when the mother has had hyperthyroidism during pregnancy or has displayed residual exophthalmos from a previous episode of hyperthyroidism. Fetal tachycardia is sometimes noted during labor, persisting after birth and frequently precipitating congestive heart failure. The newborn
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displays jerky movements, restlessness, and a startled facial expression. Exophthalmos is generally present and is sometimes associated with conjunctival chemosis. The thyroid gland is enlarged but generally does not cause airway obstruction as in other types of neonatal goiter. Hyperthermia develops slowly over the first hours of life. The symptoms of neonatal thyrotoxicosis gradually subside after the second to third weeks of life. Neonatal thyrotoxicosis is frequently severe and reminiscent of thyroid storm in the adult. The mortality rate is high unless therapy is instituted immediately. The etiology of neonatal hyperthyroidism was initially thought to be on the basis of placental transfer of thyrotropin from mother to fetus. With the discovery of L.A.T.S. (long acting thyroid stimulator) numerous investigators reported high titers of this material in the serum of thyrotoxic newborn infants. L.A.T.S. is a 7S gamma globulin (IgG) which has unexplained thyrotropic properties. It crosses the placenta with ease, stimulates the fetal thyroid, and produces exophthalmos. Since L.A.T.S. may remain in the mother's serum in spite of control of her thyrotoxicosis, her infant may suffer from the disease. As L.A.T.S. disappears from the infant's circulation, his symptoms gradually subside. Hyperthyroidism is associated with a rapid turnover of adrenal corticosteroids and may produce a state of relative adrenal insufficiency in an infant. Therefore, corticosteroids should be administered to seriously ill infants. Cortisone acetate, 15 mg. intramuscularly every 12 hours would be adequate replacement in newborn infants. Iodides are effective in inhibiting release of thyroid hormone. One to two drops of Lugol's solution every 8 hours by gavage is recommended. Reserpine, 0.15 mg. per kg. per day intramuscularly in three divided doses is used to combat the effects of increased epinephrine sensitivity in hyperthyroidism. Antithyroid drugs may be employed if the infant does not respond to these measures within 36 hours. Propylthiouracil is generally employed, 6 mg. per kg. per day in three divided doses. A 50 mg. tablet is easily dissolved in 50 ml. of saline and facilitates administration via gavage tube. In most cases the infant can be weaned from therapy at 6 to 8 weeks of age with impunity. Neonatal Hypoglycemia Symptomatic hypoglycemia in the newborn infant is associated with conditions such as sepsis, central nervous system damage, low birth weight for gestational age, erythroblastosis fetalis, maternal diabetes, and toxemia. The premature infant is particularly susceptible to hypoglycemia. A blood glucose determination should be performed upon any infant who manifests pallor, sweating, lethargy, poor muscle tone, weak suck, "jitteriness," irritability, convulsions, or cyanosis which is not due to an obvious cardiopulmonary abnormality. Hypoglycemia is generally considered to be present in premature infants with blood sugars (true glucose method) less than 20 mg. per 100 mI. and in full-term infants with blood glucose of less than 30 mg. per 100 mI. during the
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first two days of life; thereafter, 40 mg. per 100 ml. or above is considered normal. The administration of 2 mg. per kg. per 24 hours of hydrocortisone hemisuccinate (Solu-Cortef) by continuous intravenous infusion is indicated in infants with symptomatic hypoglycemia in whom 10% intravenous glucose infusions are not adequate to maintain normal blood glucose levels. In an asymptomatic infant, if the blood sugar cannot be maintained at a normal level with the use of an intravenous glucose solution, prednisone may be given orally (1 mg. per kg. per 24 hours in three divided doses). Some authorities prefer ACTH, but its effect on sodium balance and the necessity of frequent injections outweighs any advantages of this agent. Steroid Therapy in Infectious Disease Adrenal function has been measured in infants and children with meningitis of various etiologies. 18 These studies indicate that the addition of exogenous cortisol is unnecessary in most cases of bacterial meningitis, since the cortisol production rate and plasma cortisol level are both elevated. Those patients with low plasma cortisol concentration generally were in shock from meningococcal infection, and adrenal hemorrhage was found at autopsy. Thus, there would appear to be little reason to use steroids in physiologic dosage to treat neonatal infants with sepsis or meningitis if they can maintain normal circulatory dynamics, preferably measured by central venous pressure, and have no laboratory or clinical signs of adrenal insufficiency. However, if an infant with septicemia develops signs of shock, pharmacologic quantities of steroids may be indicated. Septic shock is most likely caused by arteriolar vasodilatation from the action of endotoxin of gram-negative bacteria. Lillehei and associates l6 have recommended intravenous cortisol in dosages ranging from 15 to 25 mg. per kg. for adults with endotoxic shock. Although this treatment has not been evaluated in young infants, the use of high dosages of steroids in the newborn with suspected gram-negative septic shock is justified. Hodes 8 recommends intravenous hydrocortisone, 35 to 50 mg. per kg. administered over a 10 minute period. This may be repeated, depending upon clinical response, at 30 to 60 minute intervals for four doses. The beneficial effect of high dose steroid therapy in endotoxic shock may be related to adrenergic blockade, decreased lactic acid formation, and generation of adenosine triphosphate. In addition, hypovolemia should be treated with blood or plasma and metabolic acidosis corrected. Heparinization should be considered if signs of intravascular coagulation appear (purpura or scattered .petechiae). Yu and Grauaug 27 have advocated the use of corticosteroids in newborn infants with purulent meningitis, regardless of the etiology or the presence of shock. In a retrospective uncontrolled survey, they reported on 44 cases of meningitis divided equally into steroid treatment and non-treated groups collected over an 8 year period. The difference in survival rates in two groups was of questionable statistical significance. The incidence of complications such as subdural effusion or hydrocephalus was identical in the two groups. DeLemos and Haggerty 4 have recently reported on a double-blind
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controlled investigation of the effect of large doses of methylprednisolone on the survival and long-term sequelae of infants and children with bacterial meningitis. There was no statistically significant difference between treatment and control groups for mortality, time required for sterilization of spinal fluid, and incidence of subdural effusion. Psychometric testing performed 1 to 4 years after the attack of meningitis revealed residual damage in 42 per cent of the steroid-treated group and in 20 per cent of the control group.
Sclerema Neonatorum Tallow-like hardening of the subcutaneous tissue may occur in the newborn term infant and more commonly in the premature infant as a sign of a severe underlying infection or an abnormal metabolic process. In the pre-antibiotic era this condition was almost always fatal. In recent years some of these infants have survived when the condition was associated with sepsis that was treated appropriately and vigorously with antibiotics. High doses of corticosteroids have been advocated for sclerematous infants, but there is no clear evidence for or against their use. Levin et al. 15 could find no difference in mortality rates between steroid treated and untreated newborns. Warwick et al. 26 state that steroids are warranted only when adrenal insufficiency is present. However, since acidosis, hyperkalemia, and hyponatremia are frequently present with sclerema, it is not possible to diagnose adrenal insufficiency in such patients without hormone assays, which are difficult to obtain in the best equipped centers and are not available on an emergency basis. Gellis 7 advocates the use of both corticosteroids and antimicrobials in all infants with sclerema. If steroids are utilized, 2 mg. per kg. per 8 hours of a continuous intravenous infusion of hydrocortisone hemisuccinate would be an appropriate dose.
The Infant of the Steroid-Treated Mother The outcome of 34 gestations in women receIvmg prednisolone during pregnancy for a variety of illnesses was evaluated by Warrell and Taylor. 25 Compared to a control group of mothers with similar illnesses not treated with steroids, the study group had a significantly higher incidence of stillbirths and placental insufficiency syndromes. There was no clinical evidence for suppression of the fetal adrenal in these infants. BongiovannP has reviewed 260 pregnancies during which mothers received pharmacologic doses of corticosteroid. He concludes that these infants "rarely, if ever, demonstrate evidence of adrenocortical insufficiency." Kenny et al. 12 measured cortisol production rates in eight infants born to steroid-treated mothers. None of these children demonstrated symptomatic adrenal suppression, and they all had normal cortisol production. However, we have seen one infant of a mother with rheumatoid arthritis treated with prednisone during pregnancy who developed hypoglycemia on the second day of life. This newborn infant required intravenous glucose and glucagon for 3 days before he was able to maintain a normal blood glucose and had no further symptoms suggesting adrenal insufficiency.
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Oppenheimer21 reported cystic lesions of the adrenal glands of infants whose mothers received steroids during pregnancy. More recently, she has described similar lesions in the adrenals of infants with no history of maternal steroid administration. 2o Therefore, on the basis of available information, prophylactic steroid therapy of infants born to steroid-treated mothers is not indicated. Blood glucose determinations should be obtained at frequent intervals and hypoglycemia should be considered as a possible manifestation of adrenal suppression. Intravenous 10 to 15 per cent glucose infusion and the administration of cortisol (20 to 30 mg. per square meter per 24 hours, or 2 mg. per kg. per 8 hours) for several days should be adequate therapy for the rare infant who develops temporary adrenal inactivity.
SUMMARY Adrenal steroid therapy in the newborn is mandatory in only a few rare hereditary or congenital endocrine syndromes and in acquired adrenal hemorrhage. In these diseases cortisol or mineralocorticoids or both are used in physiologic replacement dosage. They should also be used in some cases of neonatal thyrotoxicosis and hypoglycemia. The use of pharmacologic quantities of steroid hormones in the neonatal infant with abnormalities such as septic shock, meningitis and sc1erema remains controversial.
REFERENCES 1. Bertrand, J., Gilly, R, and Loras, B.: Neonatal adrenal function: Free glucuroconjugated plasma 17 hydroxycorticosteroids in 102 infants from birth to 42 days of age: Effect of ACTH or oestrogen administration. International Congress on Hormonal Steroids, Milan, Italy, 1962, p. 279 2. Bongiovanni, A. M.: The adrenogenital syndrome with deficiency of 3,B-hydroxysteroid dehydrogenase. J. Clin. Invest., 41 :2086, 1962. 3. Bongiovanni, A. M., and McPadden, A. J.: Steroids during pregnancy and possible fetal consequences. Fertil. Steril., 11:181, 1960. 4. deLemos, R. A., and Haggerty, R J.: Corticosteroids as an adjunct to treatment in bacterial meningitis. Pediatrics, 44:30, 1969. 5. Eberlein, W. R, and Bongiovanni, A. M.: Plasma and urinary corticosteroids in the hypertensive form of congenital adrenal hyperplasia. J. BioI. Chern., 223:85, 1956. 6. Gardner, L. I.: Development of the normal fetal and neonatal adrenal. In Gardner, L. I., ed.: Endocrine and Genetic Disease of Childhood. Philadelphia, W. B. Saunders Co., 1969, p. 392. 7. Gellis, S. S.: Year Book of Pediatrics, 1964-1965, p. 49-50. 8. Hodes, H. L.: Endotoxin shock. Pediatrics, 44:248, 1969. 9. Hughes, E. R, Seely, J. R, Kelley, V. C., and Ely, R S.: Corticosteroid levels before and after corticotropin. Amer. J. Dis. Child., 104:605, 1962. 10. Jaudon, J. C.: Hypofunction of the adrenals in early life. J. Pediat., 29:696, 1946. 11. Kenny, F. M., Malvaux, P., and Migeon, C. J.: Cortisol Production rate in newborn babies, older infants, and children, Pediatrics, 31 :360, 1963. 12. Kenny, F. M., Preeyasombat, C., Spaulding, J. S., and Migeon, C. J.: Cortisol production rate. IV. Infants born of steroid-treated mothers and of diabetic mothers. Infants with trisomy syndrome and with anencephaly. Pediatrics, 37:960, 1966. 13. Klein, R.: Evidence for and against the existence of a salt-losing hormone. J. Pediat., 57:452, 1960. 14. KIevit, H. D.: Fetal-placental-maternal interrelations involving steroid hormones. PEDIAT. CLIN. N. AMER., 13:59, 1966.
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15. Levin, S. E., Bakst, C. M., and Isserow, L.: Sclerema neonatorum treated with corticosteroids. Brit. Med. J., 2:1533, 1961. 16. Lillehei, R. C., Longerbeam, J. K., Bloch, J. H., and Manax, W. G.: The nature ofirreversible shock. Experimental and clinical observations. Ann. Surg., 160:682, 1964. 17. Marks, J. F., and Fink, C. W.: Prolonged hypertension following cessation of desoxycorticosterone therapy in congenital adrenal hyperplasia. Pediatrics, 40: 184, 1967. 18. Migeon, C. J., Kenny, F. M., Hung, W., and Voorhess, M. L.: Study of adrenal function in children with meningitis. Pediatrics, 40:163,1967. 19. Monteleone, J. A.: Hypertensive encephalopathy with overdosage of deoxycorticosterone. Pediatrics, 43 :294, 1969. 20. Oppenheimer, E. H.: Do adrenocorticosteroids affect fetal risk when given to the mother for general disease during pregnancy? Are the fetal adrenals suppressed? Modern Medicine, March 24, 1969, p. 223. 21. Oppenheimer, E. H.: Lesions of the adrenals of an infant following maternal corticosteroid therapy. Bull. Johns Hopkins Hosp., 114: 146, 1964. 22. Russell, A., Levin, B., Sinclair, L., and Oberholzer, V.: A reversible salt-wasting syndrome of the newborn and infant. Arch. Dis. Childhood, 38:313, 1963. 23. Ulick, S., Gautier, E., Vetter, K. K., Markello, J. R., Yaffe, S., and Lowe, C. U.: An aldosterone biosynthetic defect in a salt-losing disorder. J. Clin Endocrinol., 24:669, 1964. 24. Visser, H. K. A., and Cost, W. S.: A new hereditary defect in the biosynthesis of aldosterone: Urinary C-21 corticosteroid pattern in three related patients with a salt-losing syndrome, suggesting an 18-oxidation defect. Acta Endocrin. (Kbh.), 47:589, 1964. 25. Warrell, D. W., and Taylor, R.: Outcome for the fetus of mothers receiving prednisolone during pregnancy. Lancet, 1: 117, 1968. 26. Warwick, W. J., Ruttenberg, H. D., and Quie, P. G.: Sclerema neonatorum: A sign, not a disease. J.A.M.A., 184:680, 1963. 27. Yu, J. S., and Grauaug, A.: Purulent meningitis in the neonatal period. Arch. Dis. Child., 38:391,1963. 5055 North Greeley Avenue Portland, Oregon 97217