Journal Club Papers
Associations Between Maternal Antenatal Corticosteroid Treatment and Psychological Developmental and Neurosensory Disorders in Children. Räikkönen et al. JAMA Network Open, August 2022.
The long-term outcomes for children exposed to steroids antenatally remain uncertain. The findings of past studies are conflicting, but a number point towards adverse effects on developmental outcomes.
This study comes from the same team that brought us the 2020 JAMA paper that found a higher risk of any mental or behavioural disorder among steroid-exposed children born at term, and among treatment-discordant sibling pairs, compared with non-exposed children (JCOTR Edition 6; (doi:10.1001/jama.2020.3937).
This new study aimed to examine whether antenatal corticosteroid treatment is associated with psychological developmental and neurosensory disorders in children born either term, or preterm. It was a population-based study that used retrospective, linked registry data from Finland.
670 097 singleton children were included (median follow-up 5.8 years, IQR 3.1-8.7 years)
2.2% (n=14,868) were exposed to steroids during pregnancy. Of these, 45.3% (6730) were born at term, and 54.7% (8138) were born preterm. Data were not available on timing, or number of treatments.
1) Total cohort: compared to those not exposed, steroid exposure during pregnancy was significantly associated with:
- developmental disorders of speech and language (adjusted hazard ratios (aHR), 1.38 [95% CI, 1.27-1.50]; P < .001), scholastic skills (aHR, 1.32 [95% CI, 1.13-1.54]; P = .004), and motor function (aHR, 1.32 [95% CI, 1.18-1.49]; P < .001)
- global developmental disorder (aHR, 1.35 [95% CI, 1.17-1.56]; P < .001)
- other/unspecified disorder of psychological development (aHR, 1.88 [95% CI, 1.58-2.25]; P < .001)
- vision or hearing loss (aHR, 1.22 [95% CI, 1.04-1.43]; P = .02)
2) Term-born cohort only: treatment exposure during pregnancy was significantly associated with higher aHRs for:
- specific developmental disorders of speech and language (aHR, 1.47 [95% CI, 1.31-1.66]; P < .001), scholastic skills (aHR, 1.28 [95% CI, 1.01-1.63]; P = .04), and motor function (aHR, 1.38 [95% CI, 1.12-1.70]; P < .001)
- global developmental disorder (aHR, 1.42 [95% CI, 1.16-1.75]; P < .001)
- other/unspecified disorder of psychological development (aHR, 1.92 [95% CI, 1.51-2.43]; P < .001)
- epilepsy (aHR, 1.57 [95% CI, 1.22-2.01]; P < .001)
- cerebral palsy (aHR, 2.18 [95% CI, 1.47-3.23]; P < .001).
3) Sibling cohort: Among the 4,128 sibling pairs born at term who were discordant for steroid treatment (241,621 total pairs; 1.7%), treatment exposure was associated with a higher risk of any psychological developmental and neurosensory disorder (absolute difference, 1.2% [95% CI, 0.03%-2.4%]; P < .001; aHR, 1.22 [95% CI, 1.04-1.42]; P = .01).
4) Preterm cohort: Reassuringly, steroid exposure were not associated with either significant benefit, or risk. Hence, steroids should continue to be offered to those at high risk of imminent preterm birth.
This study adds to cautionary evidence accumulating on the potential risks of antenatal steroid exposure. It seems those exposed to corticosteroids in utero, but then birth at term incur an increased risk of psychological development and neurosensory disorders when they reach childhood.
Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial. Schmitz et al. Lancet. 18 Aug 2022.
Review contributed by Jess Atkinson.
Concerns about adverse growth and neurodevelopmental dose-related side effects of antenatal steroids have given rise to the concept that the current dose used clinically may be too high. And it may be possible that a lower dose could still provide short-term neonatal benefits, but lessen the risk of longer-term childhood problems. This study sought to investigate whether a half dose of betamethasone is non-inferior to the full dose for preventing respiratory distress syndrome (RDS).
This was a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial across 37 level three referral perinatal centres in France.
- Women were eligible for inclusion if they were pregnant with a singleton fetus at risk of preterm delivery and had already received a first injection of antenatal betamethasone before 32 weeks’ gestation (ie first dose of celestone, 11.4 grams).
- Between January 2017 – October 2019, 3,244 women were randomly assigned to receive either a half dose (saline placebo) or second full dose of betamethasone (5.4mg/mL betamethasone acetate plus 6.0mg/mL betamethasone sodium phosphate) 24 hours after their first dose. Randomisation was stratified by gestational age (<28 weeks or ≥28 weeks).
- The primary outcome was the need for exogenous intratracheal surfactant within 48 hours after birth.
Primary outcome: Exogenous intratracheal surfactant was required in 20.0% of infants in the half-dose group and 17.5% of infants in the full-dose group (risk difference 2.4% [95% CI 0.3-5.2]); non-inferiority was not shown (take note of the double negative!).
- The findings were similar in intention-to-treat and per-protocol analysis groups.
- There were no differences in secondary outcomes between the groups including rates of neonatal death, any respiratory distress syndrome; grade 3-4 intraventricular haemorrhage, stage ≥2 necrotising enterocolitis, severe retinopathy of prematurity, or bronchopulmonary dysplasia.
The interpretation is that a half-dose betamethasone regimen was associated with a 2.4% absolute increase in the need for exogenous intratracheal surfactant within the first 48 hours of life. There was also a trend towards more severe RDS (needing mechanical ventilation) with the half-dose regimen. However, it was not associated with a higher incidence of neonatal mortality or major prematurity-related complications, although it likely lacked the power needed to study these outcomes (ie. needed to be a bigger study).
This study does not support a single dose of betamethasone for preterm infants at risk of preterm birth.
The authors also highlight the importance of weighing these results against potential childhood outcomes. they point towards their planned follow-up analysis at five years of age.
It will be interesting to see whether the dose reduction has any impact on childhood outcomes because most of these findings were short-term neonatal outcomes. The risk/benefit equation could shift if childhood developmental outcomes are better in the single dose arm (which could be the case, given the findings of the first paper in this JCOTR edition).
Incidence of neonatal sepsis after universal antenatal culture-based screening of group B streptococcus and intrapartum antibiotics: A multicentre retrospective cohort study. Chan et al. BJOG. 10 Aug 2022.
Review contributed by Jess Atkinson.
This retrospective study cohort included 460,552 women attending routine antenatal services across 8 public hospitals and 31 Maternal and Child Health Centres in Hong Kong between 2009-2020. Universal GBS screening was implemented in Hong Kong from 1 January 2012; risk-based screening was used prior to this.
Universal GBS screening and intrapartum antibiotic prophylaxis (IAP) has been shown to reduce the incidence of early-onset GBS disease (day 0 – 7 of life). Researchers hypothesised that the introduction of universal screening and intrapartum antibiotic prophylaxis might lead to the delayed presentation of late-onset GBS disease (day 8 – 120 of life) and a relative increase in E. coli infections due to alterations in the maternal vaginal microbial environment.
- All women who attended for pregnancy care between 2009-2020 were eligible for inclusion.
- Women with a miscarriage or termination of pregnancy prior to 24 weeks were excluded.
- Outcomes were compared between women who attended for pregnancy care from 2009 –Dec 2011 (risk screening period) with women who attended for pregnancy care from Jan 2012 – Dec 2020.
- A standard antibiotic regimen was used: bolus dose of 5 million units IV penicillin G, followed by 2.5 million units 4 hourly until delivery (or erythromycin, clindamycin or vancomycin if penicillin-allergic)
- Primary outcomes included GBS colonisation rate and early- and late-onset neonatal sepsis (including sepsis caused by GBS or E. coli).
An interrupted time-series model – examining data before and after an interruption, or change in practice – was used to examine the effect of universal culture-based screening on each outcome between the study cohorts.
Key findings: After implementation of universal GBS screening and intrapartum antibiotic prophylaxis, the incidence of early-onset neonatal sepsis decreased significantly (3.25 [95% CI 2.95-3.57] vs 2.26 [95% CI 0.67-1.31] per 1000 live births, p<0.05).
- In total, 318,740 women had culture-based GBS screening; 63,767 screened positive (20.0%).
- The incidence of early-onset GBS disease decreased from 1.03 per 1000 live births (95% CI 0.87-1.22) in 2009-11 to 0.26 per 1000 live births (95% CI 0.64-0.92) in 2012-2020 (p<0.05).
- The incidence of early-onset GBS disease was higher than E. coli pre-2012 but was persistently lower post-2012.
- The incidence of early-onset neonatal sepsis caused by E. coli did not change throughout the study period.
The incidence of early onset neonatal sepsis decreased in association with universal GBS screening, due to the decreased incidence of early-onset GBS disease. There was no associated increase in sepsis caused by other organisms, such as E. coli, or in late-onset neonatal sepsis.
After implementation of universal GBS screening and intrapartum antibiotic prophylaxis, the incidence of late-onset neonatal sepsis also decreased (5.16 [95% CI 4.78-5.56] vs 3.94 [95% CI 3.73-4.16] per 1000 live births, p<0.05). The authors suggest that the decreased incidence of late-onset GBS disease may be due to a heightened awareness of GBS disease, increased sanitation, and improved paediatric care.