Repeat doses of antenatal betamethasone and risk factors for cardio-metabolic disease at early school age

MANUSCRIPT CITATION

Mckinlay CJ, Cutfield WS, Battin MR, et al. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT. Pediatrics. 2015;135(2):e405-15. PMID: 25601978

REVIEWED BY

Mikael Norman
MD, PhD, professor
Department of Neonatal Medicine, H1:02
Karolinska Institutet & University Hospital

TYPE OF INVESTIGATION

Treatment

QUESTION

Does exposure to repeated antenatal betamethasone courses– as compared to a single course – increase childhood risk factors (altered body composition, decreased insulin sensitivity, increased ambulatory blood pressure, and decreased renal function) for later cardiometabolic disease?

METHODS

  • Design: A long term secondary outcome follow-up study of a randomized trial
  • Allocation: Concealed
  • Blinding: All enrolled women, clinicians, and investigators were blinded to treatment allocation.
  • Follow-up period: 6-8 years.
  • Setting: The primary RCT involved 23 centers in Australia and New Zealand between 1998 and 2004 participating in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids (ACTORDS trial, ISRCTN 48656428).1
  • Patients: All surviving children residing in New Zealand and recruited to the NZ sites of the ACTORDS1 study, were invited to participate in the early school-age (6-8 years of corrected age) follow-up study (n=328). Children with severe intellectual disability who could not assent to testing were excluded.
  • Intervention: In ACTORDS, women with single, twin, or triplet pregnancy at <32 weeks’ gestation were eligible if they had received a course of antenatal glucocorticoids ≥7 days previously and were judged to have ongoing risk of preterm birth. Women were randomly assigned to a single intramuscular injection of betamethasone or saline placebo. The allocated treatment could be repeated each week a woman remained undelivered and was considered by her responsible clinician to be at risk for preterm birth in the next 7 days, up to 32 weeks’ gestation (New Zealand 290 women and 352 fetuses).
  • Outcomes: Body composition (measured by whole-body dual energy x-ray absorptiometry or DXA), insulin sensitivity (glucose and insulin values obtained during a 90-minute frequently sampled intravenous glucose test), ambulatory blood pressure and heart rate (measured over a 24-hours) and glomerular filtration rate (based on plasma creatinine concentrations).
  • Analysis and Sample Size: The authors estimated that if 276 children were followed up, the study would have 80% power to detect differences of 0.34 standard deviations in normally distributed outcomes (2-sided test, significance level 0.05).
  • Patient follow-up: Of the 328 surviving children from the ACTORDS trial presumed to be residing in New Zealand at 6 to 8 years’ corrected age, 258 (81% of eligible children) underwent ≥1 of the physiologic investigations.

Results:

Selected Characteristics of the Study Cohort Repeat Betamethasone (n=103-123)  Placebo

(n=103-135)

Birth weight, g

median (interquartile range)

1550 (1114–2100) 1580 (1150–2128)
Gestational age, weeks mean (SD) 31.7 (3.5) 31.6 (3.5)
Females, % 46 43
Age at assessment, yrs

mean (SD)

7.3 (0.9) 7.2 (1.0)
 

Main Results

Treatment effect*
Fat mass, kg (whole body) 3.7 (2.6–6.3) 3.7 (2.5–6.2) 0·96 (0.76 to 1.20)
Glucose, mmol/L 4.7 (0.4) 4.8 (0.4) -0.1 (–0.2 to 0.0)
Insulin, mIU/L 5.2 (3.6–7.5) 4.8 (3.4–6.3) 1.02 (0.86 to 1.22)
24-h BP, mm Hg, Systolic 107 (7) 108 (9) -1 (–4 to 1)
24-h BP, mm Hg, Diastolic 67 (5) 68 (6) -1 (–2 to 1)
Estimated glomerular filtration rate, mL/min/1.73 m2 106.8 (14.4) 104.9 (14.6) 1.1 (–3.4 to 5.6)

*Treatment effects were reported as the mean difference (MD) for normally distributed data or the ratio of geometric means (RGM) for positively skewed data, both with a 95% confidence interval (CI). If the 95% CI for RGM includes 1, there is no significant difference between groups.

CONCLUSIONS:

The authors conclude that exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not increase risk factors for cardiometabolic disease at early school age.

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COMMENTARY:

This study provides new evidence regarding some aspects of long-term safety with the use of repeated courses of antenatal corticosteroids. The original aim of the ACTORDS study was to evaluate short term outcomes and it had shown reduced neonatal morbidity after repeated courses of antenatal corticosteroids1 without an associated increase in neurologic disability at 2 years of corrected age.2 The remaining concerns about the intervention concerned longer term safety. In the context of cardiometabolic health, the associations between preterm birth and later hypertension,3 diabetes,4 stroke5 and even death from cardiovascular disease6– boosted by animal data – have generated worries about glucocorticoid exposure in fetal life, especially if repeated. The central worry is that this glucocorticoid exposure might be in the causal pathway towards cardiometabolic disease in adult life. Previously there had been some conflicting observational data.6-11 The long-term evaluation by McKinlay et al carries an important message, i.e., there was no adverse cardiovascular and metabolic outcomes in children exposed to repeat dose(s) of antenatal betamethasone.

Although reassuring, there are some, as always, remaining questions and limitations. First, extremely preterm infants were few in the ACTORDS-study. The average gestational age at study entry was >28 weeks. It cannot be excluded that extremely low gestational age at exposure may exert long-standing on glucose metabolism.6 Secondly, although 6-8 years follow-up most be considered as long-term from a neonatologist´s perspective, it may be too short for the outcomes addressed. Finally, the authors state that they will report other outcomes separately. These include neurologic function, lung function, general intellectual ability, specific cognitive skills, behavior, general health, and health-related quality of life. I look forward to that report. Meanwhile, another study found no significant differences in Bayley test results or anthropometric measurements in 2 to 3-year-old children who had been exposed to repeat as compared with single courses of antenatal corticosteroids.12 And yet another RCT on multiple courses of antenatal glucocorticosteroid therapy compared with a single course did not find any increase or decrease in the risk of death or disability at 5 years of age.13

So what should the attending obstetrician and neonatologist recommend? A systematic review of 10 randomized trials comparing single and repeat courses of antenatal glucocorticoids for neonatal morbidity favors repeat courses.14 And although repeated courses have been associated with lower birth weight and small reductions in head circumference,14 data on long term safety outcomes are so far generally reassuring.14 According to ACOG presemt guidelines,15 a single rescue course of antenatal corticosteroids may be considered if the antecedent treatment was given more than 2 weeks prior, the gestational age is less than 32 weeks, and the women are judged by the clinician to be likely to give birth within the next week. The ACTORDS follow-up study reviewed herein adds further support for such recommendation.

REFERENCES

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