Complications Mary Ellen Rimsza,

Therapy

MD

\s=b\ The

complications of corticosteroid in children are protean. Perhaps the most important of these are adrenal insufficiency after withdrawal of steroids, immunosuppression, and growth failure. The physician who is caring for a child receiving corticosteroids must be aware of these common complications as well as the many less frequent side effects, therapy

as cataracts, pseudotumor cerebri, pancreatitis, and steroid myopathy, to

such

few. In all children, the risk of using corticosteroids should be weighed carefully before therapy with these agents is begun. (Am J Dis Child 132:806-810, 1978) name a

Since

of Corticosteroid

their introduction

more

than

two decades ago, corticosteroids

have been used in the management of a wide variety of diseases. They have considerably reduced the morbidity and mortality in children suffering from nephrosis, leukemia, asthma, rheumatoid arthritis, and many other diseases. However, the complications of steroid therapy are protean and they may do more harm than the underlying disease for which they are prescribed. It is the purpose of this article to review the more important complications of steroid therapy in the

pediatrie patient (Table).

From the Department of Pediatrics, Maricopa County General Hospital, Phoenix, Ariz. Reprint requests to Department of Pediatrics, Maricopa County General Hospital, 2601 E Roosevelt St, Phoenix, AZ 85008 (Dr Rimsza).

OPHTHALMOLOGIC COMPLICATIONS

Serious and often irreversible oph¬ thalmic complications have occurred after both systemic and topical ad¬ ministrations of corticosteroids. These complications include glaucoma, pos¬ terior subcapsular cataracts, bacterial and fungal infections of the eye, and exacerbations of herpes keratitis. Steroids applied to the eye or given systemically may produce increased intraocular pressure within a few days of starting therapy. Patients with a positive family history for glaucoma may be at increased risk for this complication. The ocular hypertensive effect seems to be due to decreased aqueous outflow. This complication is dose-related and intraocular pressure usually returns to pretreatment levels with cessation of therapy.' In 1960, Black et al2 first reported

posterior subcapsular cataracts in association with long-term steroid therapy. Kobayashi et al3 observed posterior subcapsular cataracts in 28% of the nephrotic children receiving steroids. More recently, Fine et al4 reported 41 cases of posterior subcap¬ sular cataracts among 69 children

during the first two years of steroid therapy after renal transplantation.

The incidence of cataracts in the first posttransplant year increased with increasing corticosteroid dosage, and four patients had sufficient visual

to require cataract ex¬ traction.' Posterior subcapsular cata¬ racts secondary to steroid therapy are

impairment

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much more frequent in children than in adults.' Although cataract growth usually ceases when steroids are stopped, the damage is irreversible.' Corticosteroids may activate dor¬ mant herpes keratitis and increase the risk of fungal and bacterial infections of the eye.' CNS COMPLICATIONS

The best known CNS complication of corticosteroid therapy is pseudotumor cerebri. This occurs more com¬ monly in children, although isolated cases in adults have been reported." In a review of 28 cases of pseudotumor cerebri associated with steroid thera¬ py in children, 15 of the patients had been receiving triamcinolone. The average duration of therapy prior to onset of symptoms was 2% years, although it has occurred within five months of starting steroids and as late as seven years thereafter.7 Pseudotumor cerebri associated with steroid therapy may be second¬ ary to a "relative" adrenal insuffi¬ ciency. In practically all cases re¬ ported, the syndrome develops when the steroid therapy is being modified by either a decrease in dosage or a change to another compound. Pseudo¬ tumor cerebri has been reported in association with Addison's disease.'-8 In addition, 16 children with pseudo¬ tumor cerebri in whom no underlying condition was detected have shown resolution of their clinical manifesta¬ tions and a decrease in CSF pressure to the normal range with corticoste-

roid therapy. Four of these children had failed to respond to repeated lumbar puncture prior to the initiation of corticosteroid therapy." These findings then create a dilem¬

ma for the pediatrician treating a child with steroid-associated pseudo¬ tumor cerebri. Should the steroids be increased, decreased, or kept at the same dosage? If the patient is receiv¬ ing triamcinolone diacetate, it has been recommended that another corti¬ costeroid be substituted. Reassuring¬ ly, Gordon and Kelsey8 found that no patient in whom steroid therapy was continued had evidence of increasing severity of symptoms or failed to have This is a spontaneous remission. when the particularly important phy¬ sician is dealing with a child in whom steroid therapy cannot be stopped, such as the child with congenital adre¬ nal hyperplasia.

HEMATOLOGIC COMPLICATIONS Corticosteroids will increase the total WBC count, with an increase in the percent neutrophils and a decrease in the percent monocytes, lympho¬ cytes, and eosinophils.'" John" studied ten children who received steroids for a variety of nonhematologic diseases. He found total WBC counts of greater than 20,000/cu mm in eight of the ten children. The WBC counts remained increased throughout therapy, but returned to normal within one week of stopping therapy. Total neutrophil counts were greater than 14,000/cu mm in nine of ten patients as well." Studies in nephrotic patients have also shown that the higher the prednisone dosage, the greater the increase in the total WBC count.12 The neutrophils in the peripheral blood are divided into two pools: the circulating granulocytic pool and the marginating granulocytic pool. Steroids are thought to increase the neutrophil count by shifting the neutrophils from the marginating pool to the circulating pool.13 Dale et al13 have demonstrated that patients given prednisone on alter¬ nate days have a normal neutrophil and monocyte count on the day· off prednisone, but show transient neutrophilia and monocytopenia within four hours after an oral dose of pred¬ nisone. Using a cutaneous skin-

window as a model, they have also shown that the neutrophil response at the site of tissue injury is normal in the patient on alternate day therapy, but the monocytic response is sup¬

pressed.'3

The decrease in eosinophil count in the steroid-treated patient is believed to be due to a reversible sequestration in the reticuloendothelial system, and to decreased marrow release. The

foreign body-induced eosinophilic re¬ sponse is also suppressed, perhaps due to stabilization of the lysosomal mem¬

branes and decreased histamine re¬ lease. Other hématologie effects of steroids include increased erythropoiesis and thrombocytosis.10 Corticosteroid-induced purpura re¬ sembles "senile" purpura. This purpu¬ ra

usually occurs on extensor surfaces,

dorsum of the hand, and radial aspect of the forearm. It is thought to result from a loss of dermal collagen and elastin with subsequent shearing of small dermal vessels. The purpuric lesions are usually large and may persist for weeks.1" GASTROINTESTINAL COMPLICATIONS

Gastrointestinal complications that have been associated with corticoste¬ roid therapy include peptic ulcer, pancreatitis, and hepatomegaly. Al¬ though it has generally been thought that the administration of steroids increases the risk of peptic ulcers, proof of this in controlled human stud¬ ies is lacking. Patients with rheuma¬ toid arthritis who are receiving corti¬ costeroids have a high incidence of peptic ulcer disease, but these patients are often taking other ulcerogenic drugs, such as salicylates, phenylbutazone, and indomethacin. It is of inter¬ est that patients with ulcerative coli¬ tis and chronic skin diseases who receive corticosteroids do not have an increased incidence of peptic ulcers, and peptic ulcers are not a common complication of Cushing's disease." Recently, Conn and Blitzer1' re¬ viewed a large number of controlled investigations of steroid therapy in adults to see if, indeed, steroids increase the risk of ulcer disease. They found no statistically significant dif¬ ference in the incidence of peptic

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ulcers between controls and steroid treated groups in 32 investigations representing more than 5,000 pa¬ tients. In addition, they found that the patients with "steroid-induced" ulcers were no more likely than controls to have hemorrhage or perfo¬ ration from their ulcers.15 Pancreatitis is a rare disease in children and when in 1957, Baar and Wolff'" reported two cases of acute hemorrhagic pancreatitis in steroidtreated children, steroids were strong¬ ly implicated as the cause. Stumpf et al17 found pancreatic lesions in 44 of 53 rabbits at autopsy after hydrocortisone therapy, which further suggested a causal relationship. Oppenheimer and Boitnott1- reviewed the autopsy incidence of pancreatitis in 100 chil¬ dren with leukemia or nephrosis and found a 40% incidence of pancreatic lesions in nephrotic patients who received corticosteroids compared with a 14% incidence in controls. Three patients had acute hemorrhagic pancreatitis. There was a 16% inci¬ dence of pancreatic lesions in the chil¬ dren with leukemia, aplastic anemia, or tumors who had received corticoste¬ roid or adrenocorticotropic hormone and no pancreatic lesions in the control group. The steroid dosage in these patients varied, but in some cases was as low as 15 mg/day of prednisone.1" There is no correlation between the type of steroid, dosage, or duration of therapy and the incidence of pancreatitis.1" Fatty infiltration of the liver has been reported in adults. The fatty liver has been implicated as a source of fat emboli, which may be responsi¬ ble for intestinal infarction or aseptic necrosis of bone in patients on steroid therapy.2" Fatal fat embolism, thought to be secondary to corticoste¬ roid therapy, has been reported in a 9-year-old child.21 MUSCULOSKELETAL COMPLICATIONS The major musculoskeletal side ef¬ fects of corticosteroid therapy include

myopathy, osteoporosis, fractures,

and avascular necrosis of bone. Steroid myopathy usually develops insidiously. The weakness involves both upper and lower extremities, and

is more severe in the proximal muscu¬ lature. Muscle wasting is also noted. There is a higher incidence of myopa¬ thy when using corticosteroids with a 9 -fluoro configuration, such as triamcinolone or dexamethasone. However, steroid myopathy has also been reported in association with prednisone, prednisolone, and corti¬ sone therapy. There is no relation between dosage or duration of thera¬ py and the incidence of myopathy.22 In a series of 250 patients with rheumat¬ ic fever who received corticosteroids, muscle weakness developed in five, which disappeared within two months when corticosteroids were discontin¬ ued. In two cases, weakness decreased when prednisone was substituted for

dexamethasone.23

Osteoporosis occurs commonly in patients with endogenous Cushing's

disease and is thought to be a common complication of steroid therapy. The catabolic effects of steroids, as well as the increased urinary excretion of calcium and decreased gastrointesti¬ nal absorption of calcium may all play roles in the development of osteoporo¬ sis. It is difficult to evaluate the role of steroids in osteoporosis because of inadequate quantitative criteria for the diagnosis of osteoporosis and insufficient knowledge of the sponta¬ neous incidence of osteoporosis in association with various diseases." Studies on the incidence of osteoporo¬ sis in children given steroids are lack¬ ing, but one of the complications of osteoporosis, vertebral collapse, has been reported in children.24 Osteoporosis has also been postu¬ lated as the cause of steroid associated avascular necrosis of the femoral head.25 Fisher and Bickel,20 however, have hypothesized that fat emboli in subchondral arterioles are responsible for this necrosis. Steroid associated aseptic necrosis has been reported in children suffering from asthma, rheu¬ matoid disease, idiopathic thrombocytopenic purpura, and after renal transplantation.25-2" In a series of ten transplant patients receiving cortico¬ steroids, symptoms of aseptic necrosis appeared from two to ten months posttransplantation. Although the aseptic necrosis occurs most common¬ ly in the femoral head, involvement of

the knee and humeral head has also been reported.25 Recently, there have been case reports of acute arthralgia in adults secondary to large pulse doses of methylprednisolone. Some authors be¬ lieve these arthralgias may be second¬ ary to subtle avascular necrosis.27 RENAL COMPLICATIONS

The

major renal complications of

corticosteroids include nephrocalcino-

sis, nephrolithiasis, and uricosuria. Kobayashi et al2S in 1967, reported five cases of urinary lithiasis in steroid-treated children. They found increased urinary calcium excretion in these patients despite normal serum calcium levels. In a review of urinary tract calculi and nephrocalcinosis in pediatrie patients by Daeschner et al,29 both Cushing's syndrome and

administration of corticosteroid were listed as predisposing factors for nephrocalcinosis and lithiasis. ENDOCRINE AND METABOLIC COMPLICATIONS

Perhaps the most important compli¬ cations of steroid therapy in children are

the

endocrine and metabolic

disturbances, including growth fail¬ ure, "steroid diabetes," hyperlipidemia, adrenal atrophy, hypocalcemia, hypokalemic alkalosis, and sodium retention with subsequent hyperten¬ sion.24 Growth failure is

perhaps the most important complication, but many

studies on growth delay in steroidtreated children are difficult to inter¬ pret because the underlying disease for which the steroids are prescribed is usually associated with growth delay. It is particularly difficult to interpret studies on growth delay in which there is underlying endocrine disease: for example, hypopituitarism and congenital adrenal hyperplasia. In children receiving steroid therapy for nonendocrine disorders, questions re¬ garding growth delay include: (1) What dose is necessary to suppress growth? (2) What is the potential for "catch-up growth" once steroids are discontinued? (3) What is the effect of alternate day therapy on growth? (4) What is the mechanism of this growth

delay?

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Kerrebijn and Kroon'" studied the growth suppressive effects of steroids on

asthmatic children ages 6 to 10

no external signs of sexual maturity. They found that chil¬ dren receiving less than 3 mg/sq m/ day of prednisone grew normally; those receiving more than 4 mg/sq m/day of prednisone had an increase in height of only 2 cm/yr, less than half of that expected for their age.3" In a study by Lam and Arneil31 of nephrotic children, it was found that no child treated for less than three months had a change in the growth velocity, and although three of 14 chil¬ dren treated for less than six months had a decrease in their growth veloci¬ ty during therapy, all had returned to their normal growth channel at follow-up five to ten years later. Among 16 children treated for longer than six months, 12 had a decrease in their growth velocity, and four of these had failed to return to their normal growth channel five to ten years after corticosteroids were

years who had

stopped.

Studies by Morris32 of asthmatic children suggested that the time needed for recovery from growth suppression may equal the time required for the development of the growth retardation. Thus, it seems that children treated for less than six months and with doses of less than 3 mg/sq m/day of prednisone do not suffer from substantial growth sup¬ pression. However, children treated for longer than six months may show a permanent decrease in growth chan¬ nel and final adult height. Asthmatic patients receiving alter¬ nate day prednisone may have sub¬ stantially less growth delay than those on daily doses. Nephrotic patients receiving alternate day therapy also suffer less growth delay. In addition, Soyka33 showed that children who had received daily steroid therapy often resumed normal growth when they were switched to alternate day thera¬ py. Whether this increase in growth was related to the alternate day regi¬ men or the decrease in total weekly dosage of corticosteroids is un¬ known. Some of the mechanisms proposed to explain this steroid-induced growth

suppression include decreased growth hormone releasing hormone, de¬ creased growth hormone, suppression of somatomedin synthesis or release,

alteration in the somatomedinactive site in the cartilage cell. These first two theories have been disproved by Root et al34 and Sadeghi-Nejad and Senior35 who have shown that basal and insulin-stimulated growth hor¬ mone levels are normal in children on both daily and alternate day steroid regimens. Somatomedin suppression, however, may play an important role in growth retardation. Elders et al36 have shown that plasma somatomedin activity decreases rapidly after an intravenous dose of methylprednisolone, and remains low during contin¬ uous therapy, but increases to normal when medication is omitted during the course of alternate day therapy. Studies on the somatomedin-active site in the cartilage have not yet been done. Steroid diabetes is a well-known complication. It is characterized by or an

insulin-resistance, hyperinsulinemia, rarity of ketosis, and near-normal fasting serum glucose levels despite a noticeably abnormal glucose tolerance test curves. The oral glucose tolerance test becomes

more

abnormal with

increasing corticosteroid dosage. On low prednisone dosages, only the fast¬ ing and three-hour serum glucose levels are increased. As the predni¬ sone dosage is increased, the mean fasting, one-hour, and three-hour se¬ rum glucose levels are all increased and the glucose tolerance test is simi¬ lar to that of an insulin-dependent diabetic.37 Although ketoacidosis is rare in steroid-induced diabetes, it has been reported in both children and adults.38 In children with a positive family history for diabetes, a diabetic glucose tolerance test is more likely to develop while receiving steroids. Ruiz et al3" found 15

of steroidinduced diabetes among 53 patients who had had renal transplants. Pa¬ tients with a positive family history of diabetes had a higher incidence of this cases

complication.

This steroid-induced diabetes may be an important factor in another metabolic side effect of steroid thera¬ py, hyperlipidemia. Pennisi et al4"

Steroid

Complications

Ophthalmologlc Posterior subcapsular

cataracts

Glaucoma Reactivation of herpes keratitis CNS Pseudotumor cerebri Psychiatric disturbances and

dependency Hematopoietic system Leukocytosis, neutrophilia Monocytopenia, lymphopenia, eosinopenia Purpura Gastrointestinal system Pancreatitis Peptic ulcer Fatty Infiltration of the liver Renal system

Nephrocalcinosis Nephrolithiasis Uricosuria Musculoskeletal system

Myopathy Osteoporosis and fractures Aseptic necrosis of bone

Endocrine and metabolic Diabetes Adrenal insufficiency Growth failure

Hyperlipldemia Lipomatosis Hypocalcemia Hypokalemic alkalosis Sodium retention and

metyrapone. However, steroid-treated asthmatic

hypertension

recently reported hyperlipidemia in 18 of 27 children receiving steroids after renal transplantation. In this series, the serum cholesterol level increased with increasing steroid dosage, but was not related to the degree of obesi¬ ty. Two patients were found to have decreased postheparin lipolytic activi¬ ty and an abnormal accumulation of chylomicrons. The hyperlipidemia in these cases was reversed when steroid dosage was reduced.4" Abnormal fat accumulations are responsible for much of the classical "cushingoid" appearance of the child receiving steroids: the "buffalo" hump, truncal obesity, and the cheru¬ bic facies. Another less common com¬ plication of steroids is mediastinal lipomatosis.

Roentgenographically,

there is smooth symmetrical widening of the superior mediastinum. Price and Rigler11 found eight cases of mediastinal lipomatosis among 97 renal transplant patients (ages 14 to 50 years) who had received corticoste¬ roids. This complication developed in those patients who were receiving a

higher

mean

tion of steroid therapy is adrenal insufficiency after withdrawal of the drug, Adrenal atrophy probably does not occur in children receiving ster¬ oids for less than seven days.24 The duration of adrenal insufficiency af¬ ter cessation of steroid therapy is controversial. Graber et al42 found that serum adrenocorticotropic hor¬ mone and cortisol levels did not return to normal after withdrawal of steroids or adrenocorticotropic hormone until nine months later. Aceto et al43 stud¬ ied the responses to metyrapone administration among 23 asthmatic children who had received glucocorticoids for long periods. They found a normal response to metyrapone in 70% of the children during the first month after glucocorticoid therapy had been discontinued. Two to six months after discontinuing glucocorticoids, 86% of the children had a normal response to

daily prednisone dosage

than in those patients who did not. Perhaps, the most serious complica-

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children respond to hypoglycémie stress with a normal increase in plas¬ ma cortisol within two weeks of steroid withdrawal." Responsiveness of the pituitary-adrenal axis is proba¬

bly preserved to a greater degree in patients on alternate day therapy.

Ackerman and Nolan45 evaluated the adrenal response to hypoglycemia in ten adult nephrotic patients. They found that the plasma 17-hydroxycorticosteroid levels after hypoglycemia were normal in patients on alternate day therapy, but depressed in those receiving daily therapy. In any case, a child who has received steroids within the previous year should receive addi¬ tional corticosteroids at times of severe stress, such as surgery. IMMUNOLOGIC COMPLICATIONS

The

anti-inflammatory and immunosuppressive effects of steroids are

well known. A detailed discussion of these effects is beyond the scope of this review. Many reports of second¬ ary and opportunistic infections in children receiving steroid therapy have been published. Steroids are thought to depress the immune response in the following ways: (1) interfering with phagocytosis and intracellular digestion; (2) inhibiting migration of cells to areas of inflam-

mation; (3) reducing humoral antibody titers; and (4) suppressing cellmediated These

hypersensitivity.46 immunosuppressive effects are probably less severe in patients receiving alternate day therapy. MacGregor et al47 showed that delayed hypersensitivity responses to appro¬ priate antigens increased in seven patients when they were switched from a daily to an alternate day pred¬ nisone regimen. Dale et al13 showed that cutaneous inflammatory re¬ sponses were decreased in patients receiving daily steroids, but in pa¬ tients receiving alternate day thera¬ py, the inflammatory responses were normal on the "off" day. The monocytic inflammatory response was de¬ creased in patients on alternate day therapy on the "on" day.13 FETAL AND NEONATAL COMPLICATIONS

Recent interest in glucocorticoid prophylaxis for respiratory distress syndrome has stimulated further study of the toxic effects of steroids on the fetus and the neonate. This subject has recently been reviewed by Tauesch48 and will not be discussed here in detail. Tauesch concluded, however, that "no examples of fetal or maternal risk have been documented to date in human beings that would obviate the potential benefit of this form of (steroid) therapy." References 1. Adverse ophthalmic effects of corticosteroids. Med Lett Drug Ther 10:20-22, 1968. 2. Black RL, Oglesby RB, VonSallman L, et al: Posterior subcapsular cataracts induced by corticosteroids in patients with rheumatoid arthritis. JAMA 174:166-171, 1960. 3. Kobayashi Y, Akaishi K, Nishio T, et al: Posterior subcapsular cataracts in nephrotic children receiving steroid therapy. Am J Dis Child 128:671-673, 1974. 4. Fine RN, Offner G, Wilson WA, et al: Posterior subcapsular cataracts: Posttransplantation in children. Ann Surg 182:585-589, 1975. 5. Berkowitz JS, David DS, Sakai S, et al: Ocular complications in renal transplant recipi-

ents. Am J Med

55:492-495, 1973. 6. Ivey KJ, Dennssesten L: Pseudotumor cerebri associated with corticosteroid therapy in an adult. JAMA 208:1698-1700, 1969. 7. Walker AE, Adamkiewicz JJ: Pseudotumor cerebri associated with prolonged corticosteroid therapy: Report of four cases. JAMA 188:779-784, 1964. 8. Gordon RC, Kelsey WM: Pseudotumor cerebri in congenital adrenal hyperplasia. Am J Dis Child 113:727-729, 1967. 9. Weisberg LA, Chutorian AM: Pseudotumor cerebri of childhood. Am J Dis Child 131:1243\x=req-\ 1248, 1977. 10. Wintrobe MM: Clinical Hematology. Philadelphia, Lea & Febiger Publisher, 1974. 11. John TJ: Leukocytosis during steroid therapy. Am J Dis Child 111:68-70, 1966. 12. Floyd M, Muckle TJ, Kerr DN: Prednisone\x=req-\ induced leukocytosis in nephrotic syndrome. Lancet 1(607):1192-1193, 1969. 13. Dale DC, Fauci AS, Wolff SM: Alternate\x=req-\ day prednisone: Leukocyte kinetics and suscepti bility to infections. N Engl J Med 291:1154-1158, 1974. 14. Azarnoff DL: Steroid Therapy. Philadelphia, WB Saunders Co, 1975. 15. Conn HO, Blitzer BL: Nonassociation of adrenocorticosteroid therapy and peptic ulcer. N Engl J Med 294:473-479, 1976. 16. Baar HS, Wolff OH: Pancreatic necrosis in cortisone-treated children. Lancet 1:812-815, 1957. 17. Stumpf HH, Wilens SL, Somoza C: Pancreatic lesions and peripancreatic fat necrosis in cortisone-treated rabbits. Lab Invest 5:224\x=req-\ 235, 1956. 18. Oppenheimer EH, Boitnott JK: Pancreatitis in children following adrenal corticosteroid therapy. Bull Hopkins Hosp 107:297-306, 1960. 19. Riemenschneider TA, Wilson JF, Vernier RL: Glucocorticoid-induced pancreatitis in children. Pediatrics 41:428-437, 1968. 20. Fisher DE, Bickel WH: Corticosteroid\x=req-\ induced avascular necrosis. J Bone Joint Surg (Am) 53:859-872, 1971. 21. Hill RB Jr: Fatal fat embolism from steroid-induced fatty liver. N Engl J Med 265:318-320, 1961. 22. Afifi AK, Bergman RA, Harvey JC: Steroid myopathy. Johns Hopkins Med J 123:158\x=req-\ 173, 1968. 23. Byers RK, Bergman AB, Joseph MC: Steroid myopathy. Pediatrics 29:26-36, 1962. 24. Eberlein WR, Bongiovanni AM, Rodriquez CS: Diagnosis and treatment: The complications of steroid treatment. Pediatrics 40:279-282, 1967. 25. Cress RL, Blennerhassett J, MacDonald FR, et al: Aseptic necrosis following renal transplantation. J Bone Joint Surg (Am) 50:1577-1590, 1968. 26. Cole WG, Neal BW: Corticosteroids and avascular necrosis of the femoral head in childhood. Aust Paediat J 11:243-246, 1975. 27. Bennett WM, Strong D: Arthralgia after high dose steroids. Lancet 1:332, 1975. 28. Kobayashi O, Wada H, Utsumi J, et al: Urinary lithiasis in children treated with adrenocorticosteroid hormone. Acta Med Biol 15:91-105,

Downloaded From: http://archpedi.jamanetwork.com/ by a New York University User on 05/28/2015

1967. 29. Daeschner

CW, Singleton EB, Curtis JC: calculi and nephrocalcinosis in infants and children. J Pediatr 57:721-732, 1960. 30. Kerrebijn KF, Kroon JP: Effect on height of corticosteroid therapy in asthmatic children. Arch Dis Child 43:556-561, 1968. 31. Lam LN, Arneil GC: Long-term dwarfing effects of corticosteroid treatment for childhood nephrosis. Arch Dis Child 43:589-594, 1968. 32. Morris HG: Growth and skeletal maturation in asthmatic children: Effect of corticosteroid treatment. Pediatr Res 9:579-583, 1975. 33. Soyka LF: Treatment of the nephrotic syndrome in childhood: Use of an alternate-day predisone regimen. Am J Dis Child 113:693-701,

Urinary

tract

1967. 34. Root AW, Bongiovanni AM, Eberleen WR: Studies of the secretion and metabolic effects of human growth hormone in children with glucocorticoid-induced growth retardation. J Pediatr 75:826-832, 1969. 35. Sadeghi-Nejad A, Senior B: Adrenal function, growth and insulin in patients treated with corticoids on alternate days. Pediatrics 43:277\x=req-\ 283, 1969. 36. Elders MJ, Wingfield BS, McNatt ML, et al: Glucocorticoid therapy in children. Am J Dis Child 129:1393-1396, 1975. 37. Cope CL: Adrenal Steroids and Disease. Philadelphia, JP Lippincott Co, 1972. 38. Kobayashi A, Utsunomiya T, Horino M, et al: Nephrosis, steroids, pancreatitis and diabetic ketoacidosis. Am J Dis Child 125:726-729, 1973. 39. Ruiz JO, Simmons RL, Callender CO, et al: Steroid diabetes in renal transplant recipients:

Pathogenetic factors and prognosis. Surgery

73:759-765, 1973. 40. Pennisi AJ, Fiedler J, Lipsey A,

et al:

Hyperlipidemia in pediatric renal allograft recipients. J Pediatr 87:249-251, 1975. 41. Price JE, Rigler LG: Widening of the mediastinum resulting from fat accumulation. Radiology 96:497-500, 1970. 42. Graber AL, Ney RL, Nicholson WE, et al: Natural history of pituitary-adrenal recovery after long-term suppression with corticosteroids.

J Clin Endocrinol 25:11-16, 1965. 43. Aceto T, Beckhorn GD, Jorgensen JR, et al: Iatrogenic ACTH-cortisol insufficiency. Ped Clin North Am 13:543-557, 1966. 44. Morris HG, Jorgensen JR: Recovery of endogenous pituitary-adrenal function in corticosteroid-treated children. J Pediatr 79:480-488, 1971. 45. Ackerman GL, Nolan CM: Adrenocortical responsiveness after alternate-day corticosteroid therapy. N Engl J Med 278:405-409, 1968. 46. Zurier RB, Weissmann G: Anti-immunologic and anti-inflammatory effects of steroid therapy. Med Clin North Am 57:1295-1305, 1973. 47. MacGregor RR, Sheagren JN, Lipsett MB, et al: Alternate-day prednisone therapy: Evaluation of delayed hypersensitivity responses, control of disease and steroid side effects. N Engl J Med 280:1427-1431, 1969. 48. Tauesch HW: Glucocorticoid prophylaxis for respiratory distress syndrome: A review of potential toxicity. J Pediatr 87:617-623, 1975.