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Systematic review of the long-term effects of postnatal corticosteroids

  • Allan C. Jenkinson , Ourania Kaltsogianni , Theodore Dassios and Anne Greenough ORCID logo EMAIL logo
Published/Copyright: August 23, 2023
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Journal of Perinatal Medicine
From the journal Journal of Perinatal Medicine Volume 51 Issue 9

Abstract

Background

Dexamethasone administration can reduce bronchopulmonary dysplasia, our objective was to identify long term adverse effects.

Content

A systematic review was performed to determine the childhood and adolescent cardiopulmonary and cognitive effects of dexamethasone systemically administered to preterm infants during neonatal intensive care. Relevant studies were identified by searching two electronic health databases and the grey literature. Spirometry assessments were used as respiratory outcomes, blood pressure and echocardiography assessments as cardiovascular outcomes and cognitive and motor function as cognitive outcomes. From 1,479 articles initially identified, 18 studies (overall 1,609 patients) were included (respiratory n=8, cardiovascular n=2, cognitive n=10); all were observational cohort studies. Dexamethasone exposure was associated with worse pulmonary outcomes in children and adolescents (more abnormal FVC and FEV1:FVC z scores). Dexamethasone exposure was associated in one study with lower IQ scores compared to preterm controls (mean 78.2 [SD 15.0] vs. 84.4 [12.6], [p=0.008]) and in two others was associated with lower total and performance IQ when compared to term controls (p<0.001).

Summary and outlook

Postnatal dexamethasone exposure has a negative influence on pulmonary and cognitive outcomes in childhood and adolescence. Medications with a better benefit to risk profile need to be identified.

Keywords: cardiac function; cognitive function; dexamethasone; lung function

Introduction

Bronchopulmonary dysplasia (BPD) is an important complication of preterm birth as it is associated with significant morbidity and mortality [1]. Systemic administration of dexamethasone can improve extubation success and reduce BPD [2] but does have adverse effects [3]. Follow up at two years corrected age demonstrated that dexamethasone given systemically postnatally increased respiratory morbidity [4], neuro-developmental impairment [5] and was associated with hypertrophic cardiomyopathy [6]. It is important, however, to determine if there are long term adverse effects of postnatal dexamethasone on respiratory, cognitive and cardiovascular function in older children and adolescents to give a more accurate risk benefit ratio. We, therefore, have performed a systematic review to examine the long-term health effects of administering dexamethasone during neonatal intensive care.

Methods

Literature search

Using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendations, we performed a systematic search of the following databases: Medline and EMBASE. The search strategies for Medline and EMBASE are included in the Supplementary (Appendix 1). A search of grey literature (first 100 hits in Google scholar and PubMed) and reference lists of relevant review articles were manually checked. The literature search was conducted on articles published between January 2000 and February 2023.

Article inclusion and exclusion criteria

Two authors independently screened all studies identifying duplicates, screening titles and abstracts and completing full text reviews. A third reviewer adjudicated over reviewer disagreements.

Articles were deemed eligible if they included details of respiratory, cardiac or cognitive assessment of children and/or adolescents (aged between 3 and 19 years) exposed to dexamethasone during neonatal intensive care and included both preterm dexamethasone exposed infants and control groups. The controls differed according to the study design. In some studies Preterm a prematurely born infants (a gestational age of less than 37 weeks) were included as the comparator group in other studies term born infants were used as the controls (a gestational age of greater than 37 weeks). Only articles in the English language were included.

The following types of articles were excluded after reviewing titles and abstracts: duplicates, letters, editorials, commentaries, reviews and meeting abstracts. Preclinical studies, pharmacodynamics and pharmacokinetics articles were also excluded.

Analysis

For the meta-analysis of respiratory reported outcomes, the included articles were required to report data on FVC z score, FEV1 z score, FEV1 % predicted and FEV1:FVC z score using spirometry. Data were treated as continuous variables and for each parameter a random-effects analysis was performed in Review Manager (RevMan, version 4.5).

Results

The electronic literature search identified 1,473 studies; 586 studies were immediately removed as duplicates. Screening by title, then abstract excluded a further 843 studies. The full text of the remaining 44 articles was then assessed with three additional articles found in the search of grey literature (Google Scholar) and reference lists. The PRISMA diagram detailing the screening process can be found in the Supplementary (Appendix 2).

Eighteen studies were included in the systematic review (Table 1). Nine studies reported outcomes at follow-up from randomised controlled trials (RCT) of dexamethasone; five of the studies were placebo controlled double blind RCTs. All 18 studies were observational cohort studies (Table 1). The total number of patients in the original studies was 3,539 and the total number in the follow up studies was 1,609. In most of the studies the reported populations had a gestational age of less than 32 weeks and/or a birthweight of less than 1500 g. The studies by Karemaker et al. [7], and Romagnoli et al. [8, 9] did not specify a gestational age or birthweight for inclusion, but their reported median/mean gestational age and birthweight were below the above limits (Table 1). In three studies there were significant differences in the demographics of the exposed and unexposed groups (Table 1). Most studies reported the dexamethasone regimen used (17 of 18); the dose, frequency and length of treatment varied (Table 1).

Table 1:

Summary of studies and participant demographics.

Author Age at follow up Type of study Original study participants Follow up study participants BW (dex exposed) BW (control) GA (dex exposed) GA (control) Dexamethasone dose regime
Romagnoli et al. [8] 3–4 Follow up of RCTb 50 30 850 (183) 948 (239) 27.5 (1.4) 27.1 (1.4) 0.5 mg/kg/day for the first six days, 0.25 mg/kg/day for the next six days, and 0.125 mg/kg/day for the last two days (total dose 4.75 mg/kg)
Romagnoli et al. [9] 3–4 Follow up of RCTb 50 45 940 (590–1,250) 940 (610–1,250) 28.2 (25–31) 28.4 (25–30) 0.5 mg/kg/d for the first 3 days, 0.25 mg/kg/d the next 3 days, and 0.125 mg/kg/d on the seventh day)
Mieskonen et al. [14] 8–10 Follow up of RCTc 23 16 905 (700–1,460) 830 (600–980) 25.9 (25.3–29) 25.8 (24.1–28.1) 0.5 mg/kg per day, divided into two doses, for one week
Jones et al. [25] 13–17 Follow up of RCTb 287 150 1,041 ± 340 998 ± 284 22–36 24–34 0.6 mg/kg/day for 1 week
Jones et al. [16] 13–17 Follow up of RCTb 287 150 1,041 ± 340 998 ± 284 22–36 24–34 0.6 mg/kg/day for 1 week
Gross et al. [26] 14–15 Follow up of RCTc 36 22 Dex42 851 (776–926)

Dex18 810 (620–100)		 948 (721–1,175) Dex42 26 (25–27)

Dex18 26 (24–28)		 27 (24–29) 0.5 mg/kg/day, with taper
Yeh et al. [13] 5–11 Follow up of RCTc 262 146 1,398 ± 340 1,371 ± 343 29.8 ± 2.3 29.4 ± 2.5 0.25 mg/kg D1-7; 0.12 mg/kg 8–14, 0.05 mg/kg 15-21
Wilson et al. [15] 4–9 Observational cohort 570 60 Dex (early) 1,032 (252)

Dex (late) 1,107 (368)		 Dex (early) 27.6 (1.6)

Dex (late) 27.5 (2.2)		 0.05 mg/kg/day 3/7, then 0.25 mg/kg 3/7, then 0.10 mg/kg/day 3/7, and finally 0.05 mg/kg for 3/7 [Total 12/7]
O’Shea et al. [27] 4–11 Follow up of RCTc N/A 84 758 (530–1,050) 784 (515–1,267) 25 (23–28) 26 (24–29) 0.25 mg/kg BD for 3/7, then 0.15 mg/kg BD for 3/7, then a 10 % reduction in the dose every 3/7 until the dose of 0.1 mg/kg on day 34.

After 3 days on this dose, 0.1 mg/kg qod was given until 42 days after entry.
Nixon et al. [28] 8–11 Follow up of RCTc 118 68 743 (523–1,172) 789 (557–1,293) 25 (23–28) 26 (23.6–29.9) 0.5 mg/kg/day that was tapered over 42 days
Karemaker et al. [7] 7–9 Observational cohort 208 139 Dex 972 ± 237 1,095 ± 193 Dex 27.8 ± 1.9 28.6 ± 1.0 0.5 mg/kg/day tapering off to 0.1/kg/day over 21/7 period
Smith et al. [29] 9–11 Observational cohort N/A 102 999 999 999 999 N/A
Crotty et al. [10] 5–7 Observational cohort N/A 228 720.4 (132.06)a 830.9 (103.9)a [ELBW]

3,500 (423.43)a [term]		 25.2 (1.58)a 27.4 (2.39) [ELBW]a

39.2 (0.97) [term]a		 0.1 mg/kg BD eight doses, then 0.05 mg/kg BD six doses
Wolbeek et al. [30] 14–17 Observational cohort 208 101 Dex 1,004 (249) 1,083 (239) Dex 27.73 (1.69)a 28.42 (1.35) 0.5 mg/kg/day tapering off to 0.1/kg/day over 21/7 period
Hitzert et al. [11] 8–11 Observational cohort 77 53 920 (480–1,570) N/A 27.1 (24–32) N/A 0.5 mg/kg/d for 3/7 then A) 10 day taper OR B) 42 day taper
Harris et al. [17] 11–14 Observational cohort 797 179 810 (±175)a 939 (±205)a 25.6 ± 1.3a 26.7 ± 1.2a 0.25 mg BD for 3/7, then 0.15 mg BD for 3/7, then 0.05 mg BD for 3/7
Kraft et al. [12] 6–13 Observational cohort 56 27 830 (750–960) N/A 26.7 (25.5–27.2) N/A 0.25 mg/kg/d for 3/7 then A) 6 day taper (1.125 mg/kg) OR B) 14 day taper (2.075 mg/kg)
Harris et al. [18] 16–19 Observational cohort 797 159 782 (173.1)a 943 (217)a 25.9 (1.3) 27.3 (1.3) 0.25 mg BD for 3/7, then 0.15 mg BD for 3/7, then 0.05 mg BD for 3/7

  1. BW, birthweight; GA, gestational age; Dex, dexamethasone; ELBW, extremely low birth weight; N/A, missing data; astatistically significant difference reported between groups. Data are presented as median (IQR) or mean (± standard deviation) (%) or mean difference (95 % CI). bUnblinded RCT, cplacebo controlled double blind RCT.

Respiratory assessment

Spirometry was performed in eight studies; in seven FEV1, FVC, FEV1:FVC, FEF25-75 were assessed, but in one study only PEFR was measured. Significantly inferior lung function in those exposed to dexamethasone was reported in half the studies (Table 2). A total of five articles were eligible for meta-analysis (Figure 1A–D).

Table 2:

Summary of respiratory outcomes.

Author Respiratory measurement Dexamethasone exposed Control RR or difference
Mieskonen et al. [14] FVC, % predicted 1.74 (0.38) 1.42 (0.36)a; 2.01 (0.46)b p<0.05a
FEV1, % predicted 81.8 (17.1) 77.5 (16.4)a; 102 (7.6)b p<0.01b
FEF50 % predicated 62.3 (25) 58.4 (23)a; 102 (15)b p<0.01b
∆FEV1 post bronchodilator 9.9 (4.9) 9.4 (8)a; 1.3 (4.0)b p<0.001b
Jones et al. [16] FVC, z score −0.32 (1.10) −0.41 (1.15)b Difference: 0.09 (0.32–0.50) NS
FEV1 z score −0.74 (1.17) −1.02 (1.2)b Difference: 0.28 (−0.14 to 0.07) NS
FEV1/FVC ratio 0.79 (0.76–0.83) 0.78 (0.71–0.85)b Difference: 0.02 (−0.02 to 0.04) NS
PEF, z score −0.58 (1.2) −0.79 (1.17)b Difference: 0.21 (−0.21 to 0.63) NS
FEF25–75 % % of predicted value 4.7 (4.0) 6.6 (4.8)b Difference: 6.0 (−2 to 0.04) NS
FVC>2 SD below mean RR: 0.95 (0.27–3.35) NS
FEV1>2 SD below mean RR: 0.77 (0.32–1.86) NS
Gross et al. [26] FVC, % predicted 106 (97–114)d; 83 (71–94)e 96 (79–114)c p<0.01
FEV1, % predicted 90 (78–102)d; 71 (54–87)e 73 (45–101)c p<0.05
FEF25–75 %, % predicated 81 (59–104)d; 66 (35–99)e 53 (12–94)c NS
RV % predicted 133 (103–164)d; 132 (97 vs. 167)e 176 (67–284)c NS
Nixon et al. [28] FVC % predicted 94 89a NS
FEV1 % predicted 86 76a NS
FEV1/FVC % predicted 81 80a NS
FEF25–75 %, % predicted 68 61a NS
∆FEV1 post bronchodilator 3 7a NS
Smith et al. [29] FVC, z score 93.9 (13.1) 98.5 (12.3)b Difference: −4.6 (−9.6 to 0.4) 0.07
FEV1 z score 81.5 (11.4) 88.3 (12.6)b Difference: −6.7 (−11.5 to −1.9) 0.01
FEV1/FVC ratio 80.6 (8.9) 83.3 (7.6)b Difference: −2.6 (−5.9 to 0.6) 0.11
PEF z score 84.9 (16) 92.9 (16.9)b Difference: −8.0 (−14.6 to −1.5) 0.02
FEF25–75 %, z score 64.6 (19.7) 78 (23.5)b Difference: −13.4 (−22.0 to −4.7) 0.003
Harris et al. [17] FVC, z score −0.24 (0.96) −0.73 (1.11)b Difference: −0.46 (0.74 to −0.18) p=0.001
FEV1 z score −0.55 (1.03) −1.44 (1.03)b Difference: −0.86 (−1.2 to 0.53) p<0.001
FEV1/FVC ratio −1.17 (1.69) −2.32 (2.11)b Difference: −0.86 (−1.20 to 0.53) p<0.001
PEF, % predicted 86 (14) 77 (13)b Difference: −8.34 (−113.06 to −3.62) p=0.001
FEF25–75 %, z score −1.24 (1.07) −1.98 (1.05)b Difference: −0.07 (−1.06 to −0.35) p<0.001
FRCpleth z score −0.11 (1.25) 0.39 (1.39)b Difference: 0.49 (0.004–0.94) p=0.031
RV z score 0.26 (1.09) 1.29 (1.67)b Difference: 0.99 (0.53–1.45); p<0.001
Harris et al. [18] FVC, z score −0.15 (1.36) −0.46 (1.28)b Difference: −0.01 (−0.62 to 0.06) 0.984
FEV1 z score −0.72 (1.28) −1.74 (1.14)b Difference: −0.65 (−1.19 to −0.10) 0.023
FEV1/FVC ratio −0.89 (1.1) −1.83 (1.25)b Difference: −0.08a 0.003
PEF z score −1.08 (1.00) −0.22 (1.05)b Difference: −0.75 (−1.13 to −0.38) 0.003
FEF25–75 %, z score −1.12 (1.16) −2.3 (1.22)b Difference: −0.08a 0.003
FRCpleth z score 0.39 (1.28) 1.24 (1.39)b Difference: 0.78a 0.011
RVpleth z score 1.75 (1.57) 0.81 (1.18)b Difference: 0.90 (0.32–1.48) 0.003

  1. FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; PEF, peak expiratory flow; FEFn%, forced expiratory flow at n% of the vital capacity; RV, residual volume; FRC, functional residual capacity; PEFR, peak expiratory flow rate; Data are presented as median (IQR) or mean (± standard deviation) (%) or mean difference (95 % CI). aPlacebo control group; bpreterm control group; cterm control group; ∆, change in %; d42 day tapering course; e18 day tapering course.

Figure 1: Meta-analysis of respiratory outcomes. (A) Standard mean difference in FVC z score between dexamethasone exposed and unexposed. (B) Standard mean difference in FEV1 z score between dexamethasone exposed and unexposed. (C) Standard mean difference in FEV1 % predicted between dexamethasone exposed and unexposed. (D) Standard mean difference in FEV1:FVC z score between dexamethasone exposed and unexposed. FVC, forced vital capacity; FEV1, forced expiratory volume in 1 min.
Figure 1:

Meta-analysis of respiratory outcomes. (A) Standard mean difference in FVC z score between dexamethasone exposed and unexposed. (B) Standard mean difference in FEV1 z score between dexamethasone exposed and unexposed. (C) Standard mean difference in FEV1 % predicted between dexamethasone exposed and unexposed. (D) Standard mean difference in FEV1:FVC z score between dexamethasone exposed and unexposed. FVC, forced vital capacity; FEV1, forced expiratory volume in 1 min.

Cognitive outcomes

Cognitive outcomes were assessed in 10 studies, with the Weschler Intelligence Scale for Children used in six (Table 3). Other assessments used were the Differential Ability Scales [10], the British Ability Scales and the Stanford-Binet Scale of Intelligence (third version) [8, 9]. When compared to term populations, children exposed postnatally to dexamethasone had a significantly lower IQ in two studies (Table 3) [11, 12]. When compared to a matched preterm population, Yeh et al. [13] found that dexamethasone exposed children had significantly lower verbal and performance IQ scores and scores for perceptual organization, freedom from distractibility, processing speed, immediate visual memory and visual-motor integration than dexamethasone unexposed infants. Compared with preterm peers, Crotty et al. found motor skills were poorer, but the total IQs were similar [10].

Table 3:

Summary of cognitive outcomes.

Author Assessment tools Dex exposed Dex unexposed
Romagnoli et al. [8] Scale of Intelligence Stanford-Binet IQ score 84.2 (12.4) 83 (15.6) NS
Romagnoli et al. [9] Scale of Intelligence Stanford-Binet IQ score 85.8 (13.9) 85.6 (16.3) NS
Gross et al. [26] Wechsler Intelligence Scale for Children, third edition (WISC-III) Full scale IQ 85 (77–93)b; 69 (51–86)c 73 (45–101) NS
Verbal IQ 89 (77–101)b; 74 (56–92)c 78 (48–108) NS
Performance IQ 83 (76–91)b; 68 (53–84)c 70 (40–100) NS
Yeh et al. [13] Wechsler Intelligence Scale for Children, third edition (WISC-III) Full scale IQ 78.2 (15.0) 84.4 (12.6) p=0.008
Verbal IQ 84.1 (13.2) 88.4 (11.8) p=0.04
Performance IQ 76.5 (14.6) 84.5 (12.7) p=0.001
Movement ABC-2, age-band 3 Total score 19.2 (12.4) 11.6 (10.3) p<0.001
Beery-Buktenica test of visual-motor integration Motor co-ordination 6.7 (2.3) 8.2 (2.5) p<0.001
Visual perception 6.5 (2.4) 7.9 (2.1) p=0.02
Visual-motor co-ordination 7.1 (2.4) 7.9 (1.8) p=0.02
Wilson et al. [15] British ability scales, second edition 86 (16)d; 90 (19)e NS
Strength and difficulties questionnaire 10 (5)d; 11 (6)e NS
Child Behaviour Checklist for children 4–18 years of age 45 (10)d; 41 (10)e NS
O’Shea et al. [27] Wechsler Intelligence Scale for Children, third edition (WISC-III) Full scale IQ 90 (48–115)a 85 (63–111)a NS
Verbal IQ 94 (56–118)a 90 (62–125)a NS
Performance IQ 86 (47–110)a 86 (66–106)a NS
Kaufman survey of early academic and language skills and the Vineland Adaptive Behavioural Scales (VABS) Verbal 95 (50–118)a 85 (52–115)a NS
Nonverbal 84 (47–109)a 79 (43–102)a NS
General cognitive 88 (52–103)a 81 (45–105)a NS
Crotty et al. [10] Differential ability scales General conceptual ability 94.2 (17.67) 99.5 (15.79)
Verbal composite 96.4 (18.61) 98.9 (15.34)
Beery-Buktenica test of visual-motor integration 87.0 (13.77) 95.3 (12.81) p=0.009
Wolbeek et al. [30] Wechsler Intelligence Scale for Children, third edition (WISC-III) Full scale IQ 86 (16) 90 (15) NS
Movement ABC-2, age-band 3, Total score 4.38 (2.45) 5.69 (2.62) NS [p=0.08]
Hitzert et al. [11] Wechsler Intelligence Scale for Children, third edition (WISC-III) Full scale IQ 88 (14)f
Verbal IQ 91 (15) NS
Performance IQ 86 (17) NS
Motor function: Movement ABC-2, age-band 3 Total score N/Ag N/Ag
Kraft et al. [12] Wechsler Intelligence Scale for Children, third edition (WISC-III) Full scale IQ 87 (75–87)h 0.18 (−0.30 to 0.65) p<0.001h
Verbal IQ 95 (85–109) NS
Performance IQ 77 (70–95)h p<0.001h
Movement ABC-2, age-band 3 Total score 16.5 (12.5–19.5)h −1.16 (−1.51 to 0.82) p<0.05h

  1. Data are presented as median (IQR) or mean (± standard deviation) (%) or mean difference (95 % CI) or amedian (5th–95th centile). b42-day dexamethasone tapering dose; c18-day dexamethasone tapering dose; dearly dexamethasone; elate dexamethasone; fcompared to the norm population, more DXM-treated children had total, verbal and performance IQs below 85 (p<0.001, p=0.002, p<0.001, respectively), and more children had a performance IQ below 70 (p=0.001); gcompared to the norm population, DXM-treated children scored worse on all scales of the Movement-ABC; hdex group w/lower total and performance IQs than norm population (p<0.001) but not preterm group; full scale IQ mean z-score −0.29 to −1.12 in dex group compared to norm population; motor mean z-score − 1.81 in dex group vs. ‘norm population’.

Cardiovascular assessment

Only one study [14] performed echocardiography at follow up and found no significant differences in cardiac volumes or markers of pulmonary hypertension (tricuspid regurgitation and mean pulmonary artery peak flow velocity). Two studies reported blood pressure measurement results with no significant differences between groups [15, 16].

Discussion

Children and adolescents born preterm exposed to dexamethasone during neonatal intensive care had inferior lung function at follow up. In the two largest studies inferior lung function was found at 11–14 years [17] and 16–19 years [18]. At both time points, there was a dose dependent reduction in lung function, an effect which persisted after adjustment for neonatal factors. Importantly, there was a significant deterioration in FEF75 and FEV1 between the ages of 11–14 and 16–19 years, when an improvement in lung function would have been expected during puberty. Over 90 % of the children and adolescents in those populations were exposed to antenatal corticosteroids and postnatal surfactant, so the results are relevant to the current era of neonatal care. The generally accepted lung function threshold for developing symptoms in COPD is a FEV1:FVC ratio below 70 % of the predicted value [19] which corresponds to a z-score of −2.19. The dexamethasone exposed group in the cohort studied by Harris et al. had an FEV1/FVC ratio z-score of −1.83 at 16–19 years [18] which is above the threshold but very close to it suggesting an increased risk of early onset COPD. Indeed, with a standard deviation of 1.25 some of the cohort would be at high risk.

Ten studies compared cognitive performance in preterm infants with or without postnatal corticosteroid exposure. The largest study reporting cognitive outcomes found that preterm infants who had corticosteroid exposure had significantly lower full IQ, verbal IQ, performance IQ as well as motor skills, coordination and visual motor integration scores at 5–11 years of age [13]. Two further studies including term controls found the dexamethasone exposed preterm populations to have poorer cognitive performance. Whilst there has been neurodevelopmental outcome reporting in children and adolescents born extremely premature [20, 21], this is the first time that administration of corticosteroids during neonatal intensive care has been shown to contribute a negative impact on cognitive outcomes in children and adolescents born extremely prematurely.

These adverse effects have biological plausibility. In preclinical models, systemically administered postnatal corticosteroids have been shown to result in delayed alveolarization and emphysematous changes resulting in fewer air spaces [22]. Dexamethasone has also been shown to increase brain apoptosis and defective myelination in neonatal rats [23, 24].

An effect of systemically administered postnatal corticosteroid use is hypertrophic cardiomyopathy because of abnormal cardiomyocyte maturation [6]. While this effect is reported as transient, there is no available evidence on the long-term effects on cardiac structure or function following postnatal corticosteroid exposure. No significant differences in blood pressure results at follow-up were reported between those exposed or not exposed [15].

This review is the first to summarise the long-term effects of systemically administered postnatal corticosteroids and there was a large number of included participants. A limitation of this review is the heterogeneity of outcome reporting, as well as the variability in the dosing regimes (Table 1). As a result, a meta-analysis of cognitive outcomes was not possible. Many of the studies were cohort studies from previous RCTs and loss to follow up was common as was selection bias with only those alive and capable of performing the outcome measures included.

Conclusions

The long-term effects of postnatal corticosteroids in childhood and adolescence have infrequently been reported, but include impaired respiratory and cognitive outcomes. There has been a move towards using inhaled corticosteroids to avoid the side-effects of systemically administered corticosteroids. A promising approach is using surfactant as the vehicle to deliver intra-tracheal budesonide, importantly the corticosteroid dose is much smaller [31]. Safer and effective treatments to prevent and ameliorate BPD need to be urgently identified.

Corresponding author: Professor Anne Greenough, Neonatal Intensive Care Centre, King’s College Hospital NHS Foundation Trust, Denmark Hill, 4th Floor Golden Jubilee Wing, London, SE5 9RS, UK; and Department of Women and Children, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK, Phone: +44 0203 299 4563, E-mail:

  1. Research ethics: Not applicable.

  2. Informed consent: Not applicable.

  3. Author contributions: AG, TD and AJ designed the systematic review, AJ and OK independently screened all possible studies and AG adjudicated if there were disagreements. All authors were involved in the preparation of the manuscript. The authors accept responsibility for the entire content of this manuscript and approved its submission.

  4. Competing interests: The authors state no conflict of interest.

  5. Research funding: None declared.

  6. Data availability: Not applicable.

References

1. Siffel, C, Kistler, KD, Lewis, JFM, Sarda, SP. Global incidence of bronchopulmonary dysplasia among extremely preterm infants: a systematic literature review. J Matern Fetal Neonatal Med 2021;34:1721–31. https://doi.org/10.1080/14767058.2019.1646240.Search in Google Scholar PubMed

2. Doyle, LW, Cheong, JL, Hay, S, Manley, BJ, Halliday, HL. Late (>= 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane Database Syst Rev 2021;11:CD001145. https://doi.org/10.1002/14651858.CD001145.pub5.Search in Google Scholar PubMed PubMed Central

3. Halliday, HL. Update on postnatal steroids. Neonatology 2017;111:415–22. https://doi.org/10.1159/000458460.Search in Google Scholar PubMed

4. Marlow, N, Greenough, A, Peacock, JL, Marston, L, Limb, ES, Johnson, AH, et al.. Randomised trial of high frequency oscillatory ventilation or conventional ventilation in babies of gestational age 28 weeks or less: respiratory and neurological outcomes at 2 years. Arch Dis Child Fetal Neonatal Ed 2006;91:F320–6. https://doi.org/10.1136/adc.2005.079632.Search in Google Scholar PubMed PubMed Central

5. Barrington, KJ. The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr 2001;1:1. https://doi.org/10.1186/1471-2431-1-1.Search in Google Scholar PubMed PubMed Central

6. Seok, H, Oh, JH. Hypertrophic cardiomyopathy in infants from the perspective of cardiomyocyte maturation. Korean Circ J 2021;51:733–51. https://doi.org/10.4070/kcj.2021.0153.Search in Google Scholar PubMed PubMed Central

7. Karemaker, RK, Karemaker, JM, Kavelaars, A, Tersteeg-Kamperman, M, Baerts, W, Veen, S, et al.. Effects of neonatal dexamethasone treatment on the cardiovascular stress response of children at school age. Pediatrics 2008;122:978–87. https://doi.org/10.1542/peds.2007-3409.Search in Google Scholar PubMed

8. Romagnoli, C, Zecca, E, Luciano, R, Torrioli, G, Tortorolo, G. A three year follow up of preterm infants after moderately early treatment with dexamethasone. Arch Dis Child Fetal Neonatal Ed 2002;87:F55–8. https://doi.org/10.1136/fn.87.1.f55.Search in Google Scholar PubMed PubMed Central

9. Romagnoli, C, Zecca, E, Luciano, R, Torrioli, G, Tortorolo, G. Controlled trial of early dexamethasone treatment for the prevention of chronic lung disease in preterm infants: a 3-year follow-up. Pediatrics 2002;109:e85. https://doi.org/10.1542/peds.109.6.e85.Search in Google Scholar PubMed

10. Crotty, KC, Ahronovich, MD, Baron, IS, Baker, R, Erickson, K, Litman, FR. Neuropsychological and behavioral effects of postnatal dexamethasone in extremely low birth weight preterm children at early school age. J Perinatol 2012;32:139–46. https://doi.org/10.1038/jp.2011.62.Search in Google Scholar PubMed

11. Hitzert, MM, Koenraad, N, de Bok, M, Maathuis, C, Roze, E, Bos, AF. Functional outcome at school age of preterm-born children treated with high-dose dexamethasone. Early Hum Dev 2014;90:253–8. https://doi.org/10.1016/j.earlhumdev.2014.01.013.Search in Google Scholar PubMed

12. Kraft, KE, Verhage, SE, den Heijer, AE, Bos, AF. Functional outcome at school age of preterm-born children treated with low-dose dexamethasone in infancy. Early Hum Dev 2019;129:16–22. https://doi.org/10.1016/j.earlhumdev.2018.12.016.Search in Google Scholar PubMed

13. Yeh, TF, Lin, YJ, Yuh, J, Lin, HC, Huang, CC, Hsieh, WS, et al.. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004;350:1304–13. https://doi.org/10.1056/nejmoa032089.Search in Google Scholar PubMed

14. Mieskonen, S, Eronen, M, Malmberg, LP, Turpeinen, M, Kari, MA, Hallman, M. Controlled trial of dexamethasone in neonatal chronic lung disease: an 8-year follow-up of cardiopulmonary function and growth. Acta Paediatr 2003;92:896–904. https://doi.org/10.1111/j.1651-2227.2003.tb00621.x.Search in Google Scholar

15. Wilson, TT, Waters, L, Patterson, CC, McCusker, CG, Rooney, NM, Marlow, N, et al.. Neurodevelopmental and respiratory follow-up results at 7 years for children from the United Kingdom and Ireland enrolled in a randomized trial of early and late postnatal corticosteroid treatment, systemic and inhaled (the Open Study of Early Corticosteroid Treatment). Pediatrics 2006;117:2196–205. https://doi.org/10.1542/peds.2005-2194.Search in Google Scholar PubMed

16. Jones, RA. Randomized, controlled trial of dexamethasone in neonatal chronic lung disease: 13- to 17-year follow-up study: II. Respiratory status, growth, and blood pressure. Pediatrics 2005;116:379–84. https://doi.org/10.1542/peds.2004-1819.Search in Google Scholar PubMed

17. Harris, C, Crichton, S, Zivanovic, S, Lunt, A, Calvert, S, Marlow, N, et al.. Effect of dexamethasone exposure on the neonatal unit on the school age lung function of children born very prematurely. PLoS One 2018;13:e0200243. https://doi.org/10.1371/journal.pone.0200243.Search in Google Scholar PubMed PubMed Central

18. Harris, C, Bisquera, A, Zivanovic, S, Lunt, A, Calvert, S, Marlow, N, et al.. Postnatal dexamethasone exposure and lung function in adolescents born very prematurely. PLoS One 2020;15:e0237080. https://doi.org/10.1371/journal.pone.0237080.Search in Google Scholar PubMed PubMed Central

19. Aaron, SD, Tan, WC, Bourbeau, J, Sin, DD, Loves, RH, MacNeil, J, et al.. Diagnostic instability and reversals of chronic obstructive pulmonary disease diagnosis in individuals with mild to moderate airflow obstruction. Am J Respir Crit Care Med 2017;196:306–14. https://doi.org/10.1164/rccm.201612-2531oc.Search in Google Scholar

20. Hallin, AL, Hellström-Westas, L, Stjernqvist, K. Follow-up of adolescents born extremely preterm: cognitive function and health at 18 years of age. Acta Paediatr 2010;99:1401–6. https://doi.org/10.1111/j.1651-2227.2010.01850.x.Search in Google Scholar PubMed

21. Husby, A, Wohlfahrt, J, Melbye, M. Gestational age at birth and cognitive outcomes in adolescence: population based full sibling cohort study. BMJ 2023;380:e072779. https://doi.org/10.1136/bmj-2022-072779.Search in Google Scholar PubMed PubMed Central

22. Tschanz, SA, Damke, BM, Burri, PH. Influence of postnatally administered glucocorticoids on rat lung growth. Biol Neonate 1995;68:229–45. https://doi.org/10.1159/000244241.Search in Google Scholar PubMed

23. Kim, JW, Kim, YJ, Chang, YP. Administration of dexamethasone to neonatal rats induces hypomyelination and changes in the morphology of oligodendrocyte precursors. Comp Med 2013;63:48–54.Search in Google Scholar

24. Memi, F, Zecevic, N, Radonjić, N. Multiple roles of sonic hedgehog in the developing human cortex are suggested by its widespread distribution. Brain Struct Funct 2018;223:2361–75. https://doi.org/10.1007/s00429-018-1621-5.Search in Google Scholar PubMed PubMed Central

25. Jones, RA. Randomized, controlled trial of dexamethasone in neonatal chronic lung disease: 13- to 17-year follow-up study: I. Neurologic, psychological, and educational outcomes. Pediatrics 2005;116:370–8. https://doi.org/10.1542/peds.2004-1818.Search in Google Scholar PubMed

26. Gross, SJ, Anbar, RD, Mettelman, BB. Follow-up at 15 years of preterm infants from a controlled trial of moderately early dexamethasone for the prevention of chronic lung disease. Pediatrics 2005;115:681–7. https://doi.org/10.1542/peds.2004-0956.Search in Google Scholar PubMed

27. O’Shea, TM, Washburn, LK, Nixon, PA, Goldstein, DJ. Follow-up of a randomized, placebo-controlled trial of dexamethasone to decrease the duration of ventilator dependency in very low birth weight infants: neurodevelopmental outcomes at 4 to 11 years of age. Pediatrics 2007;120:594–602. https://doi.org/10.1542/peds.2007-0486.Search in Google Scholar PubMed

28. Nixon, PA, Washburn, LK, Schechter, MS, O’Shea, TM. Follow-up study of a randomized controlled trial of postnatal dexamethasone therapy in very low birth weight infants: effects on pulmonary outcomes at age 8 to 11 years. J Pediatr 2007;150:345–50. https://doi.org/10.1016/j.jpeds.2006.12.013.Search in Google Scholar PubMed PubMed Central

29. Smith, LJ, van Asperen, PP, McKay, KO, Selvadurai, H, Fitzgerald, DA. Post-natal corticosteroids are associated with reduced expiratory flows in children born very preterm. J Paediatr Child Health 2011;47:448–54. https://doi.org/10.1111/j.1440-1754.2010.01992.x.Search in Google Scholar PubMed

30. Wolbeek, MT, de Sonneville, LM, de Vries, WB, Kavelaars, A, Veen, S, Kornelisse, RF, et al.. Early life intervention with glucocorticoids has negative effects on motor development and neuropsychological function in 14–17 year-old adolescents. Psychoneuroendocrinology 2013;38:975–86. https://doi.org/10.1016/j.psyneuen.2012.10.001.Search in Google Scholar PubMed

31. Yi, Z, Tan, Y, Liu, Y, Jiang, L, Luo, L, Wang, L, et al.. A systematic review and meta-analysis of pulmonary surfactant combined with budesonide in the treatment of neonatal respiratory distress syndrome. Trans Pediar 2022;11:525–36. https://doi.org/10.21037/tp-22-8.Search in Google Scholar PubMed PubMed Central

Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/jpm-2023-0297).

Received: 2023-07-19
Accepted: 2023-08-06
Published Online: 2023-08-23
Published in Print: 2023-11-27

© 2023 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

  1. Frontmatter
  2. Obituary
  3. A tribute to Professor Moshe Mazor, M.D.
  4. Mini Review
  5. Systematic review of the long-term effects of postnatal corticosteroids
  6. Opinion Paper
  7. The proposal of the novel fetal shoulder dystocia graduation: a clinical-based opinion
  8. Corner of Academy
  9. Prenatal diagnosis of bilobate placenta: incidence, risk factors and impact on pregnancy outcomes
  10. Original Articles – Obstetrics
  11. High mobility group box 1 in women with unexplained recurrent pregnancy loss
  12. Velamentous cord insertion in monochorionic twin pregnancies: a step forward in screening for twin to twin transfusion syndrome and birthweight discordance?
  13. Advanced maternal age (AMA) and 75 g oGTT glucose levels are pedictors for insulin therapy in women with gestational diabetes (GDM)
  14. Perinatal, obstetric and parental risk factors for asthma in the offspring throughout childhood: a longitudinal cohort study
  15. Increased risk of severe COVID-19 in pregnancy in a multicenter propensity score-matched study
  16. Comparative clinical and placental pathologic characteristics in pregnancies with and without SARS-CoV-2 infection
  17. An analysis of factors affecting survival in prenatally diagnosed omphalocele
  18. The impact of abnormal maternal body mass index during pregnancy on perinatal outcomes: a registry-based study from Qatar
  19. Original Articles – Fetus
  20. Embryonic and fetal tiny pericardial fluid collections at less than 12 weeks of gestation
  21. Modeling fetal cortical development by quantile regression for gestational age and head circumference: a prospective cross sectional study
  22. The effect of 50 GR oral glucose tolerance test on fetal celiac artery and superior mesenteric artery Doppler parameters in healthy pregnancies
  23. Original Articles – Neonates
  24. Carboxyhaemoglobin levels in infants with hypoxic ischaemic encephalopathy
  25. Exploring professionals’ views regarding prenatal counselling in congenital diaphragmatic hernia
  26. Letter to the Editor
  27. Cutting of the strangulated double nuchal umbilical cord in a release of the severe shoulder dystocia: forensically justified or controversial procedure
  28. Retraction
  29. Retraction of: Pre-operative tranexemic acid vs. etamsylate in reducing blood loss during elective cesarean section: randomized controlled trial
  30. Retraction of: Lidocaine vs. tramadol vs. placebo wound infiltration for post-cesarean section pain relief: a randomized controlled trial
https://doi.org/10.1515/jpm-2023-0297
Keywords for this article
cardiac function; cognitive function; dexamethasone; lung function
Creative Commons
BY 4.0

Articles in the same Issue

  1. Frontmatter
  2. Obituary
  3. A tribute to Professor Moshe Mazor, M.D.
  4. Mini Review
  5. Systematic review of the long-term effects of postnatal corticosteroids
  6. Opinion Paper
  7. The proposal of the novel fetal shoulder dystocia graduation: a clinical-based opinion
  8. Corner of Academy
  9. Prenatal diagnosis of bilobate placenta: incidence, risk factors and impact on pregnancy outcomes
  10. Original Articles – Obstetrics
  11. High mobility group box 1 in women with unexplained recurrent pregnancy loss
  12. Velamentous cord insertion in monochorionic twin pregnancies: a step forward in screening for twin to twin transfusion syndrome and birthweight discordance?
  13. Advanced maternal age (AMA) and 75 g oGTT glucose levels are pedictors for insulin therapy in women with gestational diabetes (GDM)
  14. Perinatal, obstetric and parental risk factors for asthma in the offspring throughout childhood: a longitudinal cohort study
  15. Increased risk of severe COVID-19 in pregnancy in a multicenter propensity score-matched study
  16. Comparative clinical and placental pathologic characteristics in pregnancies with and without SARS-CoV-2 infection
  17. An analysis of factors affecting survival in prenatally diagnosed omphalocele
  18. The impact of abnormal maternal body mass index during pregnancy on perinatal outcomes: a registry-based study from Qatar
  19. Original Articles – Fetus
  20. Embryonic and fetal tiny pericardial fluid collections at less than 12 weeks of gestation
  21. Modeling fetal cortical development by quantile regression for gestational age and head circumference: a prospective cross sectional study
  22. The effect of 50 GR oral glucose tolerance test on fetal celiac artery and superior mesenteric artery Doppler parameters in healthy pregnancies
  23. Original Articles – Neonates
  24. Carboxyhaemoglobin levels in infants with hypoxic ischaemic encephalopathy
  25. Exploring professionals’ views regarding prenatal counselling in congenital diaphragmatic hernia
  26. Letter to the Editor
  27. Cutting of the strangulated double nuchal umbilical cord in a release of the severe shoulder dystocia: forensically justified or controversial procedure
  28. Retraction
  29. Retraction of: Pre-operative tranexemic acid vs. etamsylate in reducing blood loss during elective cesarean section: randomized controlled trial
  30. Retraction of: Lidocaine vs. tramadol vs. placebo wound infiltration for post-cesarean section pain relief: a randomized controlled trial
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