Discussion
This systematic review identified 26 studies in humans assessing cardiovascular function following antenatal corticosteroid (ACS) exposure where appropriate controls such as no exposure, placebo or population norms were included. Overall, no significant differences in measures of cardiovascular function were demonstrated. In particular, the majority of these studies focused solely on assessment of arterial blood pressure, finding either no effect or, in the neonatal period specifically, finding an increase in the MAP of the infant was either clinically beneficial (reducing the need for vasopressor BP support) or clinically irrelevant.
Comparatively fewer studies however determined the effect on ACS exposure on cardiac function, using for example echocardiography or cardiac MRI. We found 8 human clinical studies in children that determined effects of ACS exposure on cardiac function by echocardiography. Of these, 5 focused on the presence or absence of PDA30 31 35 36 37, while the other three studies explored central cardiac function 17 23 37. One study described a case series of three newborn infants exposed to ACS who showed evidence of hypertrophic cardiomyopathy when echocardiographic parameters such as left ventricle end systolic/diastolic dimension, ventricular septum thickness in systole/diastole and posterior wall thickness in systole/diastole were compared to population norms38. These changes were no longer present at six month follow up. The second study assessed 29 children aged 6 to 10 years whose mothers had received ACS compared to a cohort born at the same gestational age who had not been exposed to ACS18. Echocardiogram parameters were not different between the two groups. The third study assessed 51 children aged 7 to 10 years whose mothers had received ACS compared to a cohort born at the same gestational age who had not been exposed to ACS24. Echocardiographic parameters assessing systolic function, diastolic function and wall thickness were again not different between the two groups. Another human clinical study involved cardiac MRI in young men and women whose mothers were treated with ACS29. This study reported that in uteroexposure to ACS was associated with long-term localised changes in aortic stiffness and function, measured in offspring approximately 25 years later. Combined, therefore, the available human clinical data show variable effects of ACS on cardiac and aortic structure and function, highlighting a significant knowledge gap in this specific area.
Maternal ACS are administered to women at risk of preterm birth so as to reduce the risk of serious illness and death in newborns43. It is estimated that ACS reduce perinatal death by a risk ratio (RR) of 0.85 (95% CI 0.77-0.93), reduce neonatal death (RR 0.78 (95% CI 0.70-0.87)) and respiratory distress syndrome (RR 0.71 (95% CI 0.65-0.78)), Importantly the evidence demonstrates improved outcomes in preterm infants (24–34 weeks) delivered between 1 and 7 days after the administration of a single course of ACS. Often women in threatened preterm labour however do not deliver within this short time frame following ACS administration, and more go on to deliver after 34 weeks of gestation, when ACS are not recommended44. The administration of ACS to mature the fetal lung remains contentious, especially as treatment doses and regimens are largely unoptimised. A focus on human clinical studies determining effects of ACS on offspring cardiac structure and function is important.
Accumulating evidence derived from experimental animal models suggests that synthetic glucocorticoids can have profound effects on the cardiovascular system of offspring, without necessarily inducing alterations in blood pressure. A focus on human clinical studies determining the effects of ACS on offspring cardiovascular structure and function is therefore important. Studies in ovine, rodent and avian model systems all demonstrate that exposure to antenatal glucocorticoids, such as dexamethasone or betamethasone, administered in clinically relevant doses, can affect cardiac morphology, metabolism and function 5 6 745 46 4748 49 5051 52 5354 55. Reported effects include a premature switch from tissue accretion to differentiation, increased oxidative stress, alterations in mitochondrial fatty acid oxidation and activation of cellular senescence in fetal cardiomyocytes. Long-term adverse effects of synthetic steroids on cardiac function in offspring reported in preclinical experimental studies include weakened systolic function, an impaired cardiac functional reserve and left ventricular hypertrophy5 6 745 46 4748 49 5051 52 5354 55. Therefore, data derived from preclinical animal models suggest potent effects of the synthetic glucocorticoids that are used in human clinical practice on cardiac function that are independent of changes in arterial blood pressure and independent of prematurity. The implication is that the widespread use of ACS may induce potential damaging long-term effects on cardiovascular function in offspring, that may only manifest in late adulthood, such as for example an increased risk of cardiac failure and myocardial infarction. This systematic review is unable to determine if there is such an effect in humans due to insufficiently available data.
A strength of our study is that it was conducted using validated systematic review methodologies and ensured that appropriate controls were included in all eligible studies. However, the eligible studies had wide variation in the type or dose regimen of ACS used, the gestational age at administration, the gestational age at delivery, the age at follow-up and the type of cardiovascular assessment performed. Gestational age at delivery is a particular confounder, ranging from 23 to 41 weeks in included studies. It is therefore difficult to isolate any potential adverse effects of ACS on cardiovascular outcomes in the offspring independent of prematurity.