The effect of postnatal corticosteroids on growth parameters in infants with bronchopulmonary dysplasia

Introduction

Prematurely born infants with pulmonary insufficiency often require invasive mechanical ventilation. Although invasive respiratory support can be vital for adequate gas exchange to occur, prolonged mechanical ventilation duration can cause lung damage and inflammation, providing an additional risk to the development of bronchopulmonary dysplasia (BPD). Infants with BPD can be at risk of postnatal growth failure due to their high metabolic demands, hyperoxic state and increased energy expenditure secondary to pulmonary pathology. Recent advances in neonatal care and specific targeting of nutritional therapies, with parenteral nutrition and high enteral energy intake, have, however, resulted in improved postnatal growth and indeed we have recently described such an effect in infants with BPD [1].

Growth impairment, however, could be adversely affected by corticosteroids which are often prescribed to infants with evolving/established BPD with the aim of improving their respiratory status and facilitating successful extubation especially in those ventilated for prolonged periods. Reduced weight gain velocity in preterm infants has been linked to the catabolic effects of dexamethasone, however, such effects have been described as transient and reversible [2]. Indeed, corticosteroid administration has recently been reported to have had no adverse effects on postnatal weight gain from birth to discharge in a cohort of preterm infants born at less than 32 weeks of gestation, with better postnatal weight gain exhibited in infants receiving corticosteroids who did not go on to develop oxygen requirement at 36 weeks postmenstrual age [3].

Our aim was to determine in a whole population study, the effect of systemically administered corticosteroids on growth in infants with BPD and to determine if any effect was greater in infants who received multiple rather than a single course of postnatal corticosteroids.

Materials and methods

Analysis of a whole population was undertaken using a dataset from a previous study (REC: 19/WM/0172). The population included all infants born at less than 28 completed weeks of gestation who were admitted to neonatal units in England over a five-year period. Analysis was undertaken of those with a diagnosis of BPD and who survived to discharge. BPD was defined as the need for any respiratory support or oxygen requirement at 36 weeks postmenstrual age. Postnatal corticosteroid treatment was classified as administration of dexamethasone or hydrocortisone for more than five consecutive days during NICU admission, as this was longer than the course of treatment usually prescribed to prevent post extubation stridor and the shortest course to reduce side-effects in infants treated for chronic lung disease of prematurity. One course of postnatal steroids was defined as being administered for at least five days [4]. Weight and head circumference measurements at birth, 36 weeks PMA and discharge were standardised using z-scores using the UK-World Health Organisation (WHO) preterm reference chart. The difference (delta) in weight and head circumference z-scores from birth to discharge were calculated as was the weight z-score difference (delta) from birth to 36 weeks PMA.

Results

Within the BPD cohort of 6,104 infants, 28.3% received postnatal corticosteroids. The median (IQR) postmenstrual age of the first course of postnatal corticosteroid administration was 29.0 (27.3–31.2) weeks. Infants who received corticosteroids were less mature (median GA 25.0 vs. 26.3 weeks) and of lower birthweight (median 0.70 vs. 0.84 kg) than BPD infants who did receive postnatal corticosteroids. The postnatal corticosteroid group were mechanically ventilated for longer (37 vs. 12 days), received a greater duration of intravenous parenteral nutrition (24 vs. 17 days) and were less often receiving any form of breastmilk at discharge (35.5 vs. 41.8%). Infants who received corticosteroids had a longer neonatal stay (PMA discharge 43.1 vs. 38.6 weeks) and were more likely to be discharged home on supplemental oxygen (57.9 vs. 48.9%; p<0.001).

Infants who received corticosteroids had increased weight loss from birth to 36 weeks PMA [median (IQR) delta weight z-score 0.83 (−1.45 to −0.25)] compared to infants not receiving such treatment [−0.65 (−1.22 to −0.11), p<0.001], however after correcting for confounding factors this was no longer significant (p=0.217). At discharge, there was no significant difference in postnatal weight gain between those receiving corticosteroids [delta weight z-score −1.01 (−1.83 to −0.28)] compared to the infants who did not receive postnatal corticosteroids [−1.03 (−1.72 to −0.37), p=61]. Furthermore, there was no difference in delta head circumference z-score from birth to discharge between the two groups (p=0.33). Infants receiving more than one course of corticosteroids had similar postnatal weight gain and head circumference growth from birth to discharge to infants receiving only one course (p=0.62 and p=0.13 respectively).

Discussion

Extremely preterm infants with BPD who received corticosteroids did not have impairment in growth at NICU discharge and those receiving more than one course of corticosteroids had similar postnatal weight gain to those infants receiving only one course. A previous multicentre cohort study of preterm infants less than 32 weeks reported similar overall effects of systemic postnatal steroids on weight gain velocity and head circumference growth, as well as changes in weight and head circumference z-score from birth to discharge, yet did not report the effect of single vs. multiple courses [3]. In further agreement with our findings are studies reporting that poor weight gain is limited only to the period of corticosteroid treatment, with similar growth exhibited at term [5].

The BPD infants who were treated with corticosteroids had a longer duration of stay on the neonatal intensive care unit which may explain their similar or better postnatal growth at discharge to those not receiving corticosteroids. Such infants received longer courses of intravenous parenteral nutrition and greater use of high caloric preterm formula, indeed our BPD infants who received postnatal corticosteroids were less likely to be receiving any form of breastmilk. Enhanced parenteral nutrition has been shown to promote accelerated weight gain in preterm infants. It must, however, be acknowledged that increased weight gain postnatally does not necessarily translate to better nutritional status and improved quality of growth [6], with dexamethasone having been shown to affect the composition of weight gain at two and four weeks post commencing treatment, with less protein and more fat accretion. Indeed, hypertriglyceridemia within the first five days following corticosteroid administration has been demonstrated in infants of less than 29 weeks of gestation [7].

Poor head circumference growth in preterm infants during the neonatal period has been associated with motor and cognitive delay at 36 months follow up. Postnatal corticosteroid therapy within our study had no significant effect on head circumference growth from birth to discharge. There exists however conflicting evidence with regards to the effect of postnatal steroids on head growth. One study reported initial slowing of head growth during dexamethasone treatment, yet the infants included were only studied for four weeks and not longitudinally after discontinuing treatment [8]. On the contrary however, and in keeping with our findings, postnatal corticosteroids administered to infants with BPD were not found to be associated with reduced head growth when followed up at one year of age, suggesting a period of ‘catch up’ growth does occur [9]. Moreover, previous studies have demonstrated no adverse effects of delayed dexamethasone treatment on short term neurodevelopmental outcomes [OR 1.34 95% CI (0.46–3.98)], yet cumulative dosages were associated with risk of greater neurodevelopmental impairment [10]. The data we analysed demonstrated infants with BPD exhibited no significant difference in head circumference growth from birth to discharge when receiving single or multiple courses of corticosteroids.

The comparison of one course to multiple courses of corticosteroid treatment within our study demonstrated no significant differences on weight gain or head circumference growth during NICU admission. A previous study reported a reduction in growth during corticosteroid treatment when higher doses were used over a longer period, however, upon suspension of treatment there was recovery of adversely affected growth suggestive of a transitory effect on somatic growth [11].

Our study has strengths and some limitations. This was a large multicentre study including all neonatal units within England. Due to the retrospective nature of the study, we were not able to differentiate between the effects of dexamethasone and hydrocortisone or comment on the effect of specific dosage regimes, however, it is known wide variation in practice exists between neonatal networks [12] and by using a whole population cohort we have encompassed the effect of all regimens.

In conclusion, postnatal corticosteroid administration did not significantly affect weight gain or head circumference growth from birth to discharge in preterm infants with bronchopulmonary dysplasia, nor was there significant differences in the effects of multiple or single courses.