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.