MANUSCRIPT CITATION

Halbmeijer NM, Onland W, Cools F, Swarte R, van der Heide-Jalving M, Merkus MP, van Kaam AH. Effect of Systemic Hydrocortisone Initiated 7 to 14 Days after Birth in Ventilated Preterm Infants on Mortality and Neurodevelopment at 2 years’ Corrected Age. JAMA 2021; 324 (6):355-357. PMID 34313697.

REVIEWED BY

A/Prof Brett J Manley, Neonatologist, The Royal Women’s Hospital Melbourne

Dr Gillian W Foo, Neonatal Fellow, The Royal Women’s Hospital Melbourne

Prof Peter G Davis, Neonatologist, The Royal Women’s Hospital Melbourne

TYPE OF INVESTIGATION

Treatment

QUESTION

In preterm infants born <30 weeks’ gestation and/or with birth weight <1250 grams who were receiving mechanical ventilation between days 7-14 of age (P), does a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (I) vs. placebo (C) reduce death or neurodevelopmental impairment (NDI) (O) at 2 years’ corrected age (T)?

METHODS

• Design: Longer-term follow-up of infants enrolled in a multi-centre, randomised-controlled trial of hydrocortisone to reduce death or bronchopulmonary dysplasia (BPD) at 36 weeks’ post-menstrual age (PMA).
• Allocation: Random allocation in 1:1 ratio, using randomly permuted block sizes generated electronically
  – infants from multiple births were randomized independently unless parents/caregivers requested that siblings were allocated to same treatment group
• Blinding: Parents, caregivers and outcome assessors blind to allocation.
• Follow-up period: 2-years, corrected for prematurity
• Setting: 19 neonatal intensive care units in the Netherlands and Belgium
• Patients:
  • Inclusion criteria:
    a) Infants born <30 weeks and/or with birth weight <1250 grams
    and
    b) Ventilator-dependent between 7-14 days’ postnatal age
    and
    c) High-risk of developing BPD, defined as respiratory index (RI) of ≥3.5 for more than 12 hours per day for at least 48 hours. The trial protocol was amended after commencement and the RI threshold was lowered to 3.0 and then to 2.5, at 6 and 13 months after commencement of recruitment.
  • Exclusion criteria:
    a) Infants with chromosomal defects (eg. Trisomy 13, 18, 21) or major congenital malformations (e.g. congenital diaphragmatic hernia, Pierre-Robin sequence)
    b) Infants who had received corticosteroids to improve lung function in the first week of life
• Intervention: 22 day course of systemic hydrocortisone sodium succinate with total cumulative dose of 72.5mg/kg:
  5mg/kg/day in 4 doses per day for 7 days
  3.75mg/kg/day in 3 doses per day for 5 days
  2.5mg/kg/day in 2 doses per day for 5 days
  1.25mg/kg/day in 1 dose per day for 5 days
• Outcomes:
  • Primary outcome:
  •  At 2 years’ corrected age, a composite of death or NDI, with NDI defined as presence of 1 or more of the following: cognitive and/or motor composite score less than 85 on the Bayley Scales of Infant and Toddler Development Third Edition, Dutch version (BSID-III); cerebral palsy greater than level II in the Gross Motor Function Classification System (GMFCS); or hearing or visual impairment.
  • Secondary outcomes (from Statistical Analysis Plan, supplement 2):
  • Individual components of the composite primary outcome: survival to 2 years’ corrected age (time-to-event); BSID-III composite cognitive and composite motor scores; cerebral palsy and its severity using the GMFCS; hearing problems and severity; visual loss and severity; behaviour problems assessed by the Child Behaviour Checklist; number of hospital readmissions since first discharge to home; growth at 2 years’ corrected age (weight, length and head circumference); use of inhalation medication, number of antibiotics courses and number of steroid courses for asthmatic exacerbations during the last year; and use of (para)medical support during the 2 years follow up period.
• Analysis and Sample Size: No sample size calculation was undertaken for the 2-year outcome. The original randomised trial had a primary outcome of death or BPD at 36 weeks’ PMA. A target sample size of 200 infants in each treatment group was based on an estimated probability of death or BPD of 0.60 in the placebo group, a 15% absolute risk reduction with hydrocortisone treatment, 80% power and a 2-tailed Type 1 error of .05 and in anticipation of a 10% drop out rate. Crude absolute risk differences (RDs) and odds ratios (ORs) with 95% CIs were calculated for the 2-year outcome and its individual components for all infants as randomized. A logistic regression and generalized linear model were used to estimate, respectively, the OR and RD for the composite outcome adjusted for stratification factors (centre, gestational age). Potential confounding was examined using multivariable logistic regression models with the preselected risk factors of gestational age and small for gestational age for the composite outcome, supplemented with parental education and multilingual environment for the NDI component, and with baseline respiratory index (product of mean airway pressure and the fraction of inspired oxygen), sex, and multiple birth for the death component. Missing long-term outcome data were not imputed because there was sufficient information to classify this outcome in more than 95% of the participants. A 2-sided P < .05 was regarded as statistically significant. Analyses were conducted with SPSS version 26.0 (IBM Corp). The study protocol and statistical analysis plan are available online as supplements to the primary paper.
• Patient follow-up: % included in analysis
  • At 2 years’ corrected age, 356 of 371 infants (96%) were evaluated for the outcome death or NDI; 95 infants died, and neurodevelopment assessment was performed in 95% (262/276) of survivors.

MAIN RESULTS

The rates of the combined outcome, death or NDI at 2 years’ corrected age were similar in the hydrocortisone and placebo groups: 57% vs. 63%, OR 0.78 (95% CI 0.51-1.19), p=0.28.

There was weak evidence of an association between hydrocortisone therapy and a lower rate of death: 22% vs. 30%, OR 0.66 (95% CI 0.41-1.05), p = 0.08. The rate of NDI was similar between the groups: 44% vs 47%, OR 0.90 (95% CI 0.55-1.47), p =0.68.

The individual NDI domains were not significantly different between the groups (see Table 2). Adjustment for preselected risk factors did not change these findings. Other secondary outcomes included in the Statistical Analysis Plan were not presented, perhaps due to space limitations as this manuscript was published as a letter.

CONCLUSION

The authors concluded that administration of a 22-day course of systemic hydrocortisone to very preterm infants who were mechanically ventilated at 7-14 days of age, compared with placebo, did not improve the composite outcome of death or NDI at 2 years’ corrected age, and that the possible beneficial hydrocortisone effect on survival needs further investigation.

COMMENTARY

The safety and effectiveness of postnatal corticosteroids (PCS) to prevent or treat BPD remains an active area of research. After fluctuations in their popularity over the past 40 years, PCS remain widely used as treatments for extremely preterm infants with evolving BPD in neonatal intensive care units worldwide.

The Cochrane Library has two reviews of PCS, based on the timing of drug commencement: ‘early’ use (<8 days of age)(1)  and ‘late’ use (>7 days of age).(2) Dexamethasone and hydrocortisone have been the primary systemic PCS of interest. Dexamethasone has been studied more extensively than hydrocortisone as ‘early’ therapy (21/32 randomised trials on the Cochrane review were on Dexamethasone) and despite an important reduction in rates of death or BPD rate at 36 weeks’ PMA, the incidence of cerebral palsy is higher (RR 1.42, 95% CI 1.06-1.91)(2) in these infants who received Dexamethasone. The PREMILOC (3) trial in 2016 attempted to assess the effect of ‘early’ systemic hydrocortisone use in premature neonates treated within the first 10 days of life and despite the early cessation of the trial, demonstrated improved survival without BPD at 36 weeks’ PMA (OR 1.48, 95% CI 1.02-2.16, p= 0.04) with no increased risk for long-term neurodevelopmental impairment at 22 months’ corrected age.(4) From this study, it was postulated that hydrocortisone may be the early PCS of choice for the prevention of BPD.

The STOP-BPD trial is the first to address the ‘late’ use of hydrocortisone in infants at high risk of BPD. It reported no important difference in the primary composite outcome of death or BPD at 36 weeks’ PMA (70.7% hydrocortisone vs 73.7% in placebo, p=0.54), although there was a reduction in mortality at 36 weeks’ PMA (15.5% vs 23.7%, OR 0.59; 95% CI 0.35-0.995 p=0.048).  The authors acknowledged that the study was not powered to detect smaller differences in the primary outcome, also limiting the ability to detect important differences at 2 years. At the 2-year follow-up assessment, the composite outcome of death and NDI was not statistically significantly different (OR 0.79 95% CI 0.51-1.22 p=0.28). However, the reduced risk of death in the hydrocortisone group persisted. The risk of death was lower in the hydrocortisone group (39/181 vs 56/190) by 8%, a clinically important effect size, even if the result did not reach accepted levels of statistical significance. These results demonstrate that dichotomous composite endpoints in neonatal trials, where the components that are not equal in importance, can be fraught.(5)

We note the high rate of open-label hydrocortisone use within this trial. Table 2 in the primary study showed 108/190 (57%) infants in the placebo group eventually received ‘rescue’ hydrocortisone for their clinical status. This may have reduced the power of the trial to demonstrate beneficial or harmful effects of hydrocortisone, both in the short- (36 weeks’ PMA) and longer-term (2 years).

This study further fuels the discussion regarding the interaction between baseline BPD risk and the treatment effect of PCS on longer-term outcomes in extremely preterm infants.(6) Patient selection, timing and choice of systemic PCS remain topics of research. Current trials are underway of alternative methods of administering PCS to prevent BPD in the sickest preterm infants.(7)

REFERENCES

1. Doyle LW, Cheong JL, Ehrenkranz RA, Halliday HL. Early (<8 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database of Systemic Reviews 2017, Issue 10. Art. No. CD0001146 Accessed 20 Sept 2021
2. Doyle LW, Cheong JL, Ehrenkranz RA, Halliday HL. Late (>7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database of Systemic Reviews 2017, Issue 10. Art No. CD 0001145. Accessed 22 Sept 2021
3. Baud O, Maury L, Lebail F, Ramful D, El Moussawi F, Nicaise C, et. al; PREMILOC trial study group. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. Lancet. 2016; 387(10030):1827-36. Epub 2016 Feb 23.
4. BaudO, Trousson C, Biran V, Leroy E, Mohamed D, Alberti C, et.al; PREMILOC Trial group. Two-year neurodevelopmental outcomes of extremely preterm infants treated with early hydrocortisone: treatment effect according to gestational age at birth. Archives of Disease in Chilhood – Fetal and Neonatal Edition 2019;104:F30-F35.
5. Owen LS, Cheong JL, Davis PG. Bronchopulmonary dysplasia as a trial endpoint: time for re-evaluation? The Lancet Child & Adolescent Health 2019 Vol 3 (12): 842-844
6. Doyle LW, Halliday AL, Ehrenkranz RA, Davis PG, Sinclair JC. An update on the impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk of bronchopulmonary dysplasia. J Ped 2014; 165 :1258-60
7. Australian and New Zealand Clinical Trials Registry Sydney (NSW): NHMRC Clinical Trials Centre, University of Sydney (Australia); 2005 – Identifier ACTRN 12617000322336 A multi-centre, randomised controlled trial of surfactant plus budesonide to improve survival free of bronchopulmonary dysplasia in extremely preterm infants 2017. Available from https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372110