Hypertrophic Cardiomyopathy in Preterm Infants Treated With Methylprednisolone for Bronchopulmonary Dysplasia

Abstract

To the Editor.Glucocorticoids, and in particular dexamethasone, have been used extensively in the prophylaxis and treatment of bronchopulmonary dysplasia in preterm infants. In fact, extensive studies have proven that dexamethasone, given early (<96 hours of life)1 or moderately early (7–14 days of life),2 is effective in reducing the combined frequency of bronchopulmonary dysplasia and mortality. Unfortunately, such effect is associated with numerous adverse effects such as hyperglycemia, hypertension, hypertrophic cardiomyopathy, psychomotor development delay, and cerebral palsy. In particular, the relative risk for the development of hypertrophic cardiomyopathy is 4.39 (95% confidence interval: 1.40–13.37) in infants who received early dexamethasone treatment1 and 14.3 (95% confidence interval: 1.20–67.69) in infants who received moderately early dexamethasone treatment.2Therefore, the American Academy of Pediatrics advised against the treatment with dexamethasone of infants with birth weights <1500 g (very low birth weight [VLBW]), recommended to limit its use to exceptional clinical circumstances and carefully designed randomized, controlled trials, and suggested the opportunity of following clinical trials investigating the use of alternative antiinflammatory corticosteroids.3 Accordingly, we started to treat VLBW preterm infants on maximal ventilatory and oxygen support (median arterial/alveolar oxygen ratio: 0.09; range: 0.07–0.11) with a 12-day tapering course of methylprednisolone given intravenously every 6 hours (0.6, 0.4, 0.2, 0.1 mg/kg per dose for 3 days each).4 From January 1, 2003, to June 30, 2005, we treated with methylprednisolone 10 preterm infants (median gestational age: 24 weeks [range: 23–26 weeks]; median birth weight: 620 g [range: 430–730 g]) affected by respiratory distress syndrome and mechanically ventilated at the median postnatal age of 16.5 days (range: 9–44 days). These patients did not present adverse effects from steroid treatment other than hyperglycemia (1 case) and hypertrophic cardiomyopathy. In fact, echocardiographic study showed in 4 patients (40%) a thickening of the intraventricular septum (reference value: 1.8–4.5 mm) that ranged between 5 and 7 mm (median value: 6 mm) and was associated in 2 cases with a mild thickening of the posterior left ventricular free wall, without an impairment of left ventricular outflow. No pharmacologic therapy was necessary for these patients. However, methylprednisolone was discontinued immediately (median treatment duration: 8.5 days; range 7–10 days), and the pathologic echocardiographic findings disappeared after a median period of 26 days (range: 22–32 days). Among the methylprednisolone-treated infants, 6 (60%) survived, including 3 infants who developed hypertrophic cardiomyopathy.We compared the occurrence of hypertrophic cardiomyopathy with that found in preterm VLBW infants affected by respiratory distress syndrome who did not receive steroid treatment (n = 20) or who were treated with dexamethasone. These infants were randomly selected between those who were born immediately before of after infants treated with methylprednisolone. We found that hypertrophic cardiomyopathy was strongly more frequent in methylprednisolone-treated versus untreated infants (40% vs 0%; P < .0001, calculated by using Fisher's Exact Test) but was similar in methylprednisolone- versus dexamethasone-treated infants (40% vs 20%; P < .3149).Methylprednisolone may represent a possible alternative to dexamethasone in preventing or treating bronchopulmonary dysplasia. However, we found a strong association between the treatment with methylprednisolone and the development of hypertrophic cardiomyopathy in VLBW preterm infants at risk for bronchopulmonary dysplasia.The mechanisms of cardiac hypertrophy resulting from corticosteroid therapy remain unclear, as do those of neurodevelopment injury associated with dexamethasone treatment. Moreover, actual knowledge does not permit evaluating the eventual pathophysiological correlation between cardiac and brain damage. Thus, it cannot be excluded that, similar to dexamethasone, methylprednisolone can exert detrimental adverse effects on both the heart and central nervous system in preterm infants.For these reasons we suggest that, in planning future clinical trials to investigate the use of corticosteroids in preterm infants, those making the choice of drug take into account all of its reported adverse effects. From this point of view, methylprednisolone and dexamethasone similarly induce the occurrence of hypertrophic cardiomyopathy in preterm infants with respiratory distress syndrome.