Cardiovascular outcomes 50 years after antenatal exposure to betamethasone: Follow-up of a randomised double-blind, placebo-controlled trial

PLoS Med. 2024 Apr 1;21(4):e1004378. doi: 10.1371/journal.pmed.1004378. eCollection 2024 Apr.


Background: Antenatal corticosteroids for women at risk of preterm birth reduce neonatal morbidity and mortality, but there is limited evidence regarding their effects on long-term health. This study assessed cardiovascular outcomes at 50 years after antenatal exposure to corticosteroids.

Methods and findings: We assessed the adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) (1969 to 1974). The first 717 mothers received 2 intramuscular injections of 12 mg betamethasone or placebo 24 h apart and the subsequent 398 received 2 injections of 24 mg betamethasone or equivalent volume of placebo. Follow-up included a health questionnaire and consent to access administrative data sources. The co-primary outcomes were the prevalence of cardiovascular risk factors (any of hypertension, hyperlipidaemia, diabetes mellitus, gestational diabetes mellitus, or prediabetes) and age at first major adverse cardiovascular event (MACE) (cardiovascular death, myocardial infarction, coronary revascularisation, stroke, admission for peripheral vascular disease, and admission for heart failure). Analyses were adjusted for gestational age at entry, sex, and clustering. Of 1,218 infants born to 1,115 mothers, we followed up 424 (46% of survivors; 212 [50%] female) at mean (standard deviation) age 49.3 (1.0) years. There were no differences between those exposed to betamethasone or placebo for cardiovascular risk factors (159/229 [69.4%] versus 131/195 [67.2%]; adjusted relative risk 1.02, 95% confidence interval [CI] [0.89, 1.18;]; p = 0.735) or age at first MACE (adjusted hazard ratio 0.58, 95% CI [0.23, 1.49]; p = 0.261). There were also no differences in the components of these composite outcomes or in any of the other secondary outcomes. Key limitations were follow-up rate and lack of in-person assessments.

Conclusions: There is no evidence that antenatal corticosteroids increase the prevalence of cardiovascular risk factors or incidence of cardiovascular events up to 50 years of age. Established benefits of antenatal corticosteroids are not outweighed by an increase in adult cardiovascular disease.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adrenal Cortex Hormones
  • Adult
  • Betamethasone / adverse effects
  • Female
  • Follow-Up Studies
  • Humans
  • Infant
  • Infant, Newborn
  • Lung
  • Male
  • Middle Aged
  • Pregnancy
  • Premature Birth* / drug therapy
  • Premature Birth* / epidemiology
  • Premature Birth* / prevention & control
  • Respiratory Distress Syndrome, Newborn* / drug therapy
  • Respiratory Distress Syndrome, Newborn* / prevention & control


  • Betamethasone
  • Adrenal Cortex Hormones

Grants and funding

This work was supported in part by: The Aotearoa Foundation (AW, Grant #9909494 awarded to JH). The Auckland Medical Research Foundation (AW, Grant number #1421003). Cure Kids New Zealand (SD is the Cure Kids Chair of Child Health Research). The Health Research Council of New Zealand (CC, GG, CM, BM, JH, Grant #19/690 awarded to JH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.