Introduction

Below is an example of significant left ventricular (LV) hypertrophy and moderate right ventricular (RV) hypertrophy following dexamethasone exposure in a premature infant. In this case, intra-cavitary acceleration is evident. Clinically, the infant demonstrated stable systemic blood pressure, heart rate, normal urine output, and adequate perfusion. No LV or RV outflow tract obstruction was detected on color Doppler, B-mode, or spectral Doppler. However, an intra-cavitary gradient of at least 10 mmHg is present within the LV. The LV outflow tract velocity-time integral (LVOT-VTI) is shortened, indicating a reduced ejection time. The E/A ratio for LV inflow is significantly less than 1.0, with a prominent A-wave, suggestive of impaired diastolic function. The LV hypertrophy is concentric. The patent foramen ovale (PFO) is small with left-to-right shunting, reflecting higher left atrial (LA) pressure relative to right atrial (RA) pressure.

This hypertrophy is typically transient and resolves as steroids are tapered off. Regular monitoring is recommended to ensure that the LV outflow tract does not become obstructed. In cases of hemodynamic compromise, stopping steroids should be considered (while providing physiological replacement if there is adrenal insufficiency). Conventional methods to restore systemic perfusion may include optimizing preload and controlling heart rate, either with beta-blockers (such as esmolol) or sedation to prevent tachycardia, which can reduce filling time. Additionally, agents like vasopressin, norepinephrine, or phenylephrine may be required to increase systemic vascular resistance (SVR) and help "stent" the outflow tract.

See case discussion on infant with diabetic mother fore more details. 

Discussion

Postnatal corticosteroids have been used for decades in the prevention and treatment of bronchopulmonary dysplasia (BPD). The incidence of BPD is inversely proportional to gestational age (GA) at birth and directly related to the use and duration of mechanical ventilation (1). BPD is classified into different levels of severity: mild, moderate, or severe (2). According to the Canadian Neonatal Network, the overall incidence of moderate to severe BPD in infants born at 28 weeks GA or less is between 30% and 60% (3). To facilitate extubation and reduce neonatal mortality and BPD (4), postnatal steroids are used in infants with significant lung disease who are on prolonged mechanical ventilation. This practice is supported by a recent meta-analysis of 21 randomized controlled trials, which showed that postnatal steroid use beyond the first week of life was associated with reduced mortality at 28 days, lower rates of extubation failure at 3, 7, and 28 days post-exposure, and a decrease in BPD at 36 weeks postmenstrual age (PMA), without significant differences in the composite outcome of death or cerebral palsy (5). Additionally, a meta-regression analysis demonstrated a decrease in the risk of death or cerebral palsy with postnatal steroid use in infants at high risk of BPD (>50% chance of developing BPD) (6). Moreover, severe BPD and prolonged mechanical ventilation are associated with poor long-term neurodevelopmental outcomes (5). Therefore, when the risk of death or BPD is high, the potential benefits of postnatal steroids may outweigh the risks, favoring their use to improve long-term outcomes. This approach is recommended by the Canadian Paediatric Society, which mentions: "For infants who remain ventilated after the first week post-birth with increasing oxygen requirements and worsening lung disease, the benefits of dexamethasone therapy appear to outweigh the potential adverse effects. In these circumstances, low-dose dexamethasone (with an initial dose of 0.15 mg/kg/day to 0.2 mg/ kg/day, tapered over a short course [7 to 10 days]) should be considered."

Many studies have reported short- and long-term adverse effects of steroids in newborns, including hyperglycemia, transient high systolic blood pressure, and cerebral palsy (when administered within the first week of postnatal life) (5, 7). Steroids may also impact cardiac structure and function. Hypertrophic cardiomyopathy and interventricular septum (IVS) hypertrophy have been frequently observed in very preterm infants treated with high cumulative doses of dexamethasone (5 to 8 mg/kg) (8-11). Insulin often given in the context of hyperglycemia is also an anabolic agent, which may further worsen the hypertrophy of the heart induced by steroids. Previous echocardiographic studies have reported significant increases in IVS and left ventricular posterior wall (LVPW) thickness (measured by M-mode), as well as a decrease in left ventricular end-diastolic dimension (LVEDD), in newborns exposed to postnatal steroids (8-10). In one study, two infants developed Doppler evidence of left ventricular outflow tract (LVOT) obstruction without clinical signs of decreased systemic perfusion (10). Zecca et al. (12) described the adverse cardiac effects of early dexamethasone treatment in preterm infants born at <1250 grams and <30 weeks GA, compared to controls. Dexamethasone was initiated on day 4 at 0.5 mg/kg and tapered over 7 days to a total cumulative dose of 2.375 mg/kg. Echocardiography was performed at multiple time points: a) before treatment, b) 3 and 7 days after initiation, c) 7 days after discontinuation, and d) at 28 days of life. Markers of LV hypertrophy were present, including increased thickness of the end-systolic IVS, end-diastolic IVS, end-systolic LVPW, and end-diastolic LVPW at 7 days after dexamethasone initiation and discontinuation. Four neonates (20%) treated with dexamethasone developed LV myocardial hypertrophy without LVOT obstruction, but Doppler revealed turbulent flow in the LVOT, with a mean Vmax of 1.87 m/sec (range: 1.73–1.92 m/sec). LV hypertrophy resolved within two to three weeks after steroid discontinuation. Thus, LV hypertrophy was found to be a common and reversible side effect with a cumulative dexamethasone dose of 2.375 mg/kg. In another study, Skelton et al. investigated 31 premature infants (23–34 weeks GA at birth) receiving 0.4–0.6 mg/kg/day of dexamethasone starting at a median age of 11 days (range 2–34 days) and tapered over 2 to 3 weeks (13). Of these, 29 infants (94%) developed concentric, uniform LV hypertrophy by the third day of treatment, with ventricular wall thickness increasing by 55% to 67% on average, and exceeding 100% in 3 infants. There was no significant LVOT obstruction. Follow-up was available for 15 (48%) patients, all of whom showed complete resolution of LV hypertrophy by day 27.

The available data suggest that myocardial hypertrophy is not exclusively related to the cumulative dose or duration of dexamethasone. In one case report, a significant increase in IVS thickness was observed after a single dose of dexamethasone (14). Additionally, the “Minidex” study reported IVS hypertrophy in 24- and 25-week infants with very low doses of dexamethasone (0.05 mg/kg/day) (15). In this series, two extremely preterm infants developed clinical signs of low cardiac output, including a new systolic ejection murmur and poor peripheral perfusion, upon echocardiographic assessment. One infant showed blood flow acceleration with a Doppler-derived gradient of 110 mmHg within the LV cavity, between the hypertrophied IVS and the anterior papillary muscle. The other infant exhibited myocardial hypertrophy with interventricular stenosis. Both required beta-blocker therapy (16).

Dexamethasone, a potent anti-inflammatory, can significantly reduce pulmonary inflammation (22), potentially reducing alveolar transudation and edema. urthermore, extremely preterm infants are at high risk for a persistent patent ductus arteriosus (PDA), a fetal connection between the aorta and pulmonary artery. PDA exposes the pulmonary vasculature to systemic pressure and volume, contributing to pulmonary edema and abnormal vascular remodeling. Dexamethasone may accelerate PDA closure (23, 24) and reduce pulmonary edema through this mechanism.

A recent review of our local practice in infants born at less than 29 weeks GA showed a median cumulative dexamethasone dose of 1.19 mg/kg (IQR: 0.89–2.12), starting in the third week of life. Thus, in practice, we use a cumulative dose much lower than the doses associated with LV hypertrophy. Nevertheless, anecdotal cases have shown significant effects on heart structure and function, including LV hypertrophy shortly after the first doses of dexamethasone, suggesting other factors may contribute to cardiovascular side effects in these infants. The majority of infants who develop LV hypertrophy will have their cardiac remodelling revert to normal following titration and cessation of the steroids.

Echocardiography