Introduction

Antenatal corticosteroids are recommended for women at risk of preterm birth between 24 and 34 weeks’ gestation [1,2] and have proven benefit for reducing neonatal morbidity and mortality and potentially reducing neurodevelopmental delay in childhood [3].

However, there are concerns that in utero exposure to corticosteroids could have long-term adverse effects [4]. The developmental origins of health and disease (DoHaD) hypothesis proposes that events in early life may influence long-term health [5], and one key proposed mechanism is exposure to excess corticosteroids during critical periods of development resulting in persisting changes in hypothalamic–pituitary–adrenal axis function [6,7]. In animal studies across a range of species, antenatal exposure to corticosteroids has resulted in altered cardiovascular function including elevated blood pressure (BP) and sympathetic nerve activity, changes in hepatic metabolism, glucose homeostasis, and insulin resistance [7–14]. Human observational data have variably reported either higher or unchanged BP, although most studies assessed outcomes in adolescence or early adulthood [15–17]. A small number of observational studies of those born at very low birthweight have reported no association between antenatal corticosteroid exposure and glycated haemoglobin, plasma low-density lipoprotein (LDL) cholesterol, plasma triglycerides, or body mass index (BMI) [18,19], but may be confounded by the indication for treatment or health care disparities.

A 2020 Cochrane systematic review identified only 2 randomised trials of antenatal corticosteroids that have assessed offspring outcomes in early adulthood and noted the need for further follow-up studies to investigate effects in adulthood [3]. One study assessed 81 survivors at 20 years and found lower systolic BP in corticosteroid exposed participants but no effect on diastolic BP, anthropometry, or medical history [20]. The second assessed 534 30-year-old offspring of participants in the Auckland Steroid Trial (AST), the first and one of the largest randomised controlled trials of antenatal corticosteroids for women at risk of preterm birth, undertaken December 1969 to February 1974 [21,22]. Cardiovascular risk factors were not different between groups, including BP and lipid profile, but plasma insulin at 30 min after a 75 gram oral glucose tolerance test was higher in the betamethasone-exposed group, potentially suggesting mild insulin resistance [23]. However, the prevalence of cardiovascular risk factors and events is low at this age, and follow-up at older ages is required to assess clinically relevant outcomes.

In addition, although antenatal corticosteroids reduce neonatal respiratory distress syndrome (RDS), animal studies have reported that they interrupt lung development, leading to concerns that this could increase risk of emphysema in later life [8]. Previous follow-up of the AST indicated no differences in lung function tests between treatment groups at 30 years of age, but the prevalence of chronic obstructive airways disease is also low at this age [24].

We therefore assessed the offspring of participants in the AST at 50 years of age to investigate the long-term effects of antenatal exposure to corticosteroids on cardiovascular, metabolic, and respiratory outcomes.

Methods

Results

In the AST, 1,218 infants were born to 1,115 women and 987 survived to 28 days (Fig 1). Between January 2020 and May 2022, 424 adult survivors were recruited to this follow-up study (46% of those presumed alive), of whom 405 (96%) both completed a questionnaire and consented to data linkage, 9 (2%) only completed a questionnaire and 10 (2%) only consented to data linkage.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Fig 1. Trial flow diagram for the Auckland Steroid Trial 50-year follow-up.

*Number of participants assessed for eligibility not available in original trial 1969–1974 records. †Included participants successfully traced but a response was not obtained. MACE, major adverse cardiovascular event. ‡Includes participants assessed at 50-year follow-up and participants deceased after 28 days of age for whom administrative data was available. Denominator is participants alive at 28 days (493 in betamethasone and 494 in placebo group).

https://doi.org/10.1371/journal.pmed.1004378.g001

Those eligible who did and did not participate had similar baseline characteristics, though participants were more likely to be female (50.0% versus 40.8%) and were less likely to be born at term (29.0% versus 40.2%) (Table 1). Those who died prior to 50-year follow-up had a lower gestational age at trial entry and at birth and were more likely to have had RDS and a low Apgar score. Baseline characteristics of participants whose mothers were randomised to betamethasone were similar to those randomised to placebo, except the betamethasone group had a lower proportion of females (45.9% versus 54.9%) (Table 2) [32].

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 1. Baseline characteristics of those eligible who did and did not participate.

https://doi.org/10.1371/journal.pmed.1004378.t001

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 2. Baseline and adult characteristics of participants whose mothers were randomised to betamethasone and placebo.

https://doi.org/10.1371/journal.pmed.1004378.t002

The co-primary composite outcome of cardiovascular risk factors occurred in 159/229 (69.4%) of the betamethasone group and 131/195 (67.2%) of the placebo group (GLM aRR 1.02, 95% CI [0.89, 1.18]; p = 0.735). The co-primary outcome of age at first MACE was (median, 5th, 95th centile) 41.8 years (20.5, 48.5) in the betamethasone group and 44.0 years (24.2, 50.3) in the placebo group (Cox aHR 0.58, 95% CI [0.23, 1.49]; p = 0.261), although the proportion of participants with any event was low (1.4% betamethasone group; 2.4% placebo group) (Table 3).

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 3. Primary and secondary outcomes.

https://doi.org/10.1371/journal.pmed.1004378.t003

All of the components of the composite of cardiovascular risk factors outcome were similar between groups (Table 3). Age at first event for the components of the MACE outcome did not differ between treatment groups (Table 3).

The 6-step, unmatched win ratio was 1.18 (95% CI [0.98, 1.42]; p = 0.088), with a total of 110,274 wins (representing a better outcome) in the betamethasone group and 93,728 wins in the placebo group (Table 3). Each of the outcomes making up the 6 steps of the win ratio did not differ between groups (Table 3). The number of wins and losses at each step are available in Fig A in S2 Appendix.

Treatment groups did not differ in self-reported height; GLM aMD 1.3 centimetres (cm) (95% CI [−0.4, 3.1]; p = 0.121), weight (aMD 3.0 kilograms (kg), 95% CI [−1.3, 7.3]; p = 0.160), and BMI (aMD 0.8 kg/m², 95% CI [−0.7, 2.3]; p = 0.259), nor the proportion of overweight or obesity (aRR 1.05, 95% CI [0.92, 1.21]; p = 0.432) (Table 3).

All-cause mortality from randomisation to 50-year follow-up was 139/601 (23.1%) in the betamethasone group and 165/617 (26.7%) in the placebo group (GLM aRR 0.89, 95% CI [0.74, 1.08]; p = 0.236). Causes of death more than 28 days after birth were similar between groups (Table 4).

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 4. Causes of death after 28 days of age.

https://doi.org/10.1371/journal.pmed.1004378.t004

The composite outcome for ischemic heart disease and stroke did not differ between groups (Table 3). No participants met the definition for peripheral vascular disease.

The proportion with the composite of obstructive airways disease did not differ between the betamethasone group (77/229, 41.5%) and the placebo group (66/195, 38.5%) (GLM aRR 1.01, 95% CI [0.76, 1.35]; p = 0.930). The components of this composite also did not differ between groups (Table 3).

The prespecified subgroup analyses did not reveal any interactions between treatment effect and the dose of antenatal corticosteroid administered, multiple pregnancy, infant sex, tocolytic used or reason for risk of preterm birth, although the number of participants and outcomes in subgroups was very low in some cases and findings should be interpreted with caution (Table C in S2 Appendix). The win ratio did not differ markedly in sensitivity analyses excluding stillbirths or excluding deaths before 28 days (Table D in S2 Appendix). Other sensitivity analyses, including adjustment for gestation length, also did not markedly alter the findings for the primary and secondary outcomes (Table E in S2 Appendix). There was also no significant interaction between treatment effect and gestational age at delivery (post hoc analysis requested during peer review, Table F in S2 Appendix).

Discussion

We studied cardiovascular outcomes at 50 years in 424 offspring born to mothers who participated in the first, and one of the largest, randomised controlled trials of antenatal corticosteroids prior to preterm birth. We found no difference between treatment groups for the co-primary outcomes of composite of cardiovascular risk factors or age at first MACE, or for their components. The composite outcome of cardiovascular risk factors also included prediabetes and gestational diabetes mellitus, which are associated with cardiovascular disease [33,34]. We also found no difference in a win ratio, intended to provide a more global assessment of the impact of antenatal betamethasone, incorporating both early and late mortality, along with cardiovascular events, diabetes diagnosis, respiratory admissions, self-reported general health, and time in hospital. To our knowledge, these findings represent the longest follow-up of children with antenatal exposure to betamethasone and demonstrate that at 50 years, there is no evidence of an increase in cardiovascular risk factors or adverse cardiovascular events. Thus, the substantial neonatal benefits of antenatal corticosteroids for preterm birth do not appear to be outweighed by negative later consequences [1]. Moreover, antenatal corticosteroids administered prior to preterm birth reduce early life healthcare care costs [35], and our findings suggest that they are very likely to remain cost-effective through into adulthood.

Our results are consistent with the findings in the earlier, 30-year, follow-up of offspring of participants in this clinical trial, which showed no differences between groups in rates of hypertension, systolic or diastolic BP, diabetes mellitus, or fasting lipid concentrations [23]. It is also consistent with another study following up 81 participants of a randomised controlled trial that found participants exposed to antenatal betamethasone had a lower systolic BP at 20 years than those exposed to placebo, although laboratory testing for dyslipidaemia and diabetes mellitus was not undertaken [20]. A recent systematic review of cardiovascular function after antenatal corticosteroid exposure, based predominantly on observational data, also concluded that there was no association between antenatal corticosteroid exposure and offspring BP but the evidence was too limited to draw firm conclusions about other aspects of cardiovascular function [17]. Concerns regarding premature cardiovascular disease after antenatal exposure to corticosteroids have followed the evidence of increased cardiovascular risk factors in animal models and human evidence for a potential role of the hypothalamic–pituitary–adrenal axis in cardiovascular disease pathophysiology [8–11,36]. Previous studies investigating the cardiovascular effects of antenatal corticosteroids, both follow-up of clinical trials and observational studies, have focused on secondary endpoints such as risk factors rather than adverse cardiovascular events which are clinically of greater importance [8,17,37,38]. Our findings of no difference in the prevalence of risk factors or of cardiovascular events suggest that any effect on later cardiometabolic health of exposure to a single course of antenatal corticosteroids is unlikely to be clinically important, at least up to 50 years.

There have been concerns that in utero exposure to antenatal corticosteroids may interrupt lung branching and alveolarization, potentially increasing the risk of later obstructive airways disease [8]. Consistent with this, increasing airway obstruction has been reported between 8 and 18 years in extremely preterm or low birthweight survivors, 73% of whom were exposed to antenatal corticosteroids [39]. We did not identify any difference between groups for the composite outcome of obstructive airways disease, although most participants with this outcome had asthma rather than COPD, and there were few extremely preterm infants. This finding is consistent with the lack of a difference in lung function, as assessed by spirometry, between betamethasone and placebo groups at 30 years in an earlier follow-up of participants in the AST, and between 6- and 8-year-old children exposed to single or repeat courses of antenatal corticosteroids in a more recent trial [24,40]. Although COPD is still uncommon at age 50, our findings suggest that premature COPD seems unlikely to be of clinical concern after antenatal corticosteroids.

Due to difficulties in predicting preterm birth, not all infants receiving antenatal corticosteroids will be born preterm, and recent studies have raised concerns that those born at term, who do not ultimately benefit from corticosteroid exposure may be at a small increased risk of adverse long-term outcomes compared to term-born controls who were not exposed to antenatal corticosteroids [41]. However, these cohort studies are inevitably confounded by the indications for use of antenatal corticosteroids and healthcare disparities. In the AST, where the control group had similar indications for the use of antenatal corticosteroids as those in the betamethasone group, just under one third of participants were born at term, similar to the proportion seen in current clinical practice [42]. We also found no significant interaction between treatment effect and gestational age at birth. Thus, the present study provide reassurance that use of antenatal corticosteroids for threatened or indicated preterm birth provides net clinical benefit in the short- and long-term, even though the prediction of timing of early birth remains imperfect.

Strengths of this study include that it assesses outcomes from a randomised trial, greatly reducing the risk of bias due to confounding. Observational studies on the long-term effects of antenatal corticosteroids are particularly difficult to interpret because of the confounding effects of healthcare disparities and the indication for treatment with antenatal corticosteroid.

We combined self-reported questionnaire data with information from administrative datasets to improve identification of outcomes by reducing the impact of recall bias, as self-reported data alone is known to underestimate prevalence of noncommunicable diseases such as hypertension, hyperlipidaemia, and diabetes mellitus [43,44]. However, the use of administrative data has important limitations, including the risk of outcome misclassification through miscoding at data collection, lack of specificity in outcome definitions (for example, through classifying diagnoses according to treatments), and the influence of healthcare access on likelihood of appearing in an administrative dataset. Nevertheless, there is no reason to believe that these biases differed between the randomised groups, although they could contribute bias towards a null finding.

There were a number of limitations of this study. First, the follow-up rate was relatively low (46% of those presumed to be alive, primarily driven by difficulty in tracing participants decades after the last study contact), which increases the risk of attrition bias. However, most baseline characteristics were similar between those assessed and those lost to follow-up, and there were few baseline differences between randomised groups. Further, additional adjustments and sensitivity analyses to explore these differences did not alter the findings. Second, we did not undertake in person assessment of BP and blood testing, for logistic reasons due to geographical dispersal of the cohort over 50 years, so the outcomes of hypertension, hyperlipidaemia, and diabetes may be underestimated. However, there is no reason to think this underestimate differed between randomised groups. Third, the overall event rate for the MACE was lower than anticipated, so our study had limited power to detect small differences between groups. However, given the substantial neonatal benefits of exposure to antenatal corticosteroids, small differences between groups in the primary outcomes at 50 years are unlikely to be clinically important.

Finally, there was a higher proportion of women in the placebo group than the betamethasone group, consistent with the known increased mortality of male preterm neonates, especially in the absence of antenatal corticosteroid treatment. This difference would be likely to favour the placebo group given the lower risk of cardiovascular disease in women. Adjustment for sex did not alter results and there was no evidence in subgroup analyses that sex influences the effect of betamethasone on primary or secondary outcomes. Thus, the imbalance in sex is unlikely to have affected our findings.

We found no evidence that the prevalence of cardiovascular risk factors or age at MACE is altered up to 50 years after antenatal exposure to betamethasone. Clinicians can have confidence that the established benefits of antenatal corticosteroids for preterm birth in reducing neonatal morbidity and mortality and probable benefits for childhood neurodevelopment are not outweighed by an increase in adult cardiovascular disease.

Supporting information

Acknowledgments

We thank the mothers and their offspring who participated in the original trial and this follow-up study, without whom this work would not have been possible, and acknowledge the seminal contributions of the original trialists, the late Ross Howie and Mont Liggins, who generously made available the original data and documentation from the Auckland Steroid Trial. We also thank Trisha Meagher-Lundberg for study coordination and Coila Bevan for participant tracing.