The proportions of term or late preterm births after exposure to early antenatal corticosteroids, and outcomes: systematic review and meta-analysis of 1.6 million infants

Abstract

Objective To systematically review the proportions of infants with early exposure to antenatal corticosteroids but born at term or late preterm, and short term and long term outcomes. Design Systematic review and meta-analyses. Data sources Eight databases searched from 1 January 2000 to 1 February 2023, reflecting recent perinatal care, and references of screened articles. Eligibility criteria for selecting studies Randomised controlled trials and population based cohort studies with data on infants with early exposure to antenatal corticosteroids (<34 weeks) but born at term (≥37 weeks), late preterm (34-36 weeks), or term/late preterm combined. Data extraction and synthesis Two reviewers independently screened titles, abstracts, and full text articles and assessed risk of bias (Cochrane risk of bias tool for randomised controlled trials and Newcastle-Ottawa scale for population based studies). Reviewers extracted data on populations, exposure to antenatal corticosteroids, and outcomes. The authors analysed randomised and cohort data separately, using random effects meta-analyses. Main outcome measures The primary outcome was the proportion of infants with early exposure to antenatal corticosteroids but born at term. Secondary outcomes included the proportions of infants born late preterm or term/late preterm combined after early exposure to antenatal corticosteroids and short term and long term outcomes versus non-exposure for the three gestational time points (term, late preterm, term/late preterm combined). Results Of 14 799 records, the reviewers screened 8815 non-duplicate titles and abstracts and assessed 713 full text articles. Seven randomised controlled trials and 10 population based cohort studies (1.6 million infants total) were included. In randomised controlled trials and population based data, ∼40% of infants with early exposure to antenatal corticosteroids were born at term (low or very low certainty). Among children born at term, early exposure to antenatal corticosteroids versus no exposure was associated with increased risks of admission to neonatal intensive care (adjusted odds ratio 1.49, 95% confidence interval 1.19 to 1.86, one study, 5330 infants, very low certainty; unadjusted relative risk 1.69, 95% confidence interval 1.51 to 1.89, three studies, 1 176 022 infants, I 2 =58%, τ 2 =0.01, low certainty), intubation (unadjusted relative risk 2.59, 1.39 to 4.81, absolute effect 7 more per 1000, 95% confidence interval from 2 more to 16 more, one study, 8076 infants, very low certainty, one study, 8076 infants, very low certainty), reduced head circumference (adjusted mean difference −0.21, 95% confidence interval −0.29 to −0.13, one study, 183 325 infants, low certainty), and any long term neurodevelopmental or behavioural disorder in population based studies (eg, any neurodevelopmental or behavioural disorder in children born at term, adjusted hazard ratio 1.47, 95% confidence interval 1.36 to 1.60, one study, 641 487 children, low certainty). Conclusions About 40% of infants exposed to early antenatal corticosteroids were born at term, with associated adverse short term and long term outcomes (low or very low certainty), highlighting the need for caution when considering antenatal corticosteroids. Systematic review registration PROSPERO CRD42022360079.

The influence of prenatal dexamethasone administration before scheduled full-term cesarean delivery on short-term adverse neonatal outcomes: a retrospective single-center cohort study

“…Notably, full-term and late preterm infants are inherently exposed to elevated levels of endogenous steroids and may additionally receive prenatal corticosteroids ( 30 ). A recent meta-analysis involving 1.6 million infants found that early prenatal exposure to corticosteroids, when compared to no direction, was associated with an increased risk of neonatal intensive care unit admissions among full-term infants (OR: 1.49, 95% CI: 1.19–1.86) ( 23 ). This highlights the pressing need for informed, evidence-based use of corticosteroids to minimize the potential for over-treatment and subsequent neonatal mortality.…”

Late Preterm Corticosteroids Exposure and Neurodevelopmental Outcomes

“…What is still at issue is the direct translation of randomized trial evidence into clinical practice. Can a subgroup analysis of 160 children who had been born at term in an RCT follow-up study cancel out the concerns raised by observational data on almost 700 000 infants? The dissemination of the ALPS trial results rapidly influenced practice and professional guidelines and led to a 4-fold increase in the rate of antenatal corticosteroids administration for late preterm deliveries in the US by 2018. Concomitantly, the number of term-born neonates exposed to antenatal corticosteroids more than doubled .…”

“…The available randomized outcome data on late preterm antenatal corticosteroids cannot be further stratified by gestational age at delivery due to missing information, and the questionable stratification based on a postrandomization event (delivery date) is an additional confounding factor. Several observational studies have found an association between antenatal corticosteroids and worse neurodevelopmental and cognitive outcomes, especially in children who had been born late preterm and term, findings echoed in a recent meta-analysis . Although the level of reliability of evidence derived from observational studies is limited due to the increased potential for confounding, the number of such reports, their consistency, their different geographic provenance, and the quality of reporting make their complete dismissal impossible.…”

In Reply:

“…This very high rate of preterm delivery underlines either the severity of the condition indicating inclusion in the trial or the aggressiveness of its management. In France, unlike in the United States and the ALPS trial, expectant management until 37 weeks of gestation is recommended for both prelabor rupture of membranes 5 and nonsevere preeclampsia 6 ; gestational hypertension is not even an indication for antenatal corticosteroids. Therefore, not only are further randomized trials evaluating antenatal corticosteroid efficacy for preventing respiratory morbidity associated with late preterm birth needed in lowerand middle-income countries, as suggested by the authors, but also in higher-income countries, particularly in Europe, where clinical management of the conditions indicating antenatal corticosteroids differs dramatically from that in the ALPS trial.…”

“…The effect of antenatal steroids on twin pregnancy is complex and needs more evidence. 6 Another concern is that the study protocol published in the Clinical Trials Registry of India (CTRI/2019/09/021321) by the authors shows twin pregnancy as an exclusion. Was there a deviation from the published protocol (publication bias), and did they include twins as part of the study, which affects the external validity?…”