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\begin{document}

\title{The Effect of Antenatal Corticosteroid Use on Offspring Cardiovascular
Function: A Systematic Review}



\author[1]{Adalina Sacco}%
\author[2]{Emily Cornish (CPD ASSOCIATE)}%
\author[3]{Neil Marlow}%
\author[1]{Anna David}%
\author[4]{Dino Giussani}%
\affil[1]{University College London Hospitals NHS Foundation Trust}%
\affil[2]{UCL Institute for Women's Health}%
\affil[3]{University College London Institute for Women's Health}%
\affil[4]{University of Cambridge}%


\vspace{-1em}



  
  \date{May 21, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background Antenatal corticosteroids (ACS) are recommended in threatened
preterm labour to improve short term neonatal outcome. Preclinical
animal studies suggest detrimental effects of ACS exposure on offspring
cardiac development; their effects in humans are unknown. Objectives To
systematically review the human clinical literature to determine the
effects of ACS on offspring cardiovascular function. Main results
Twenty-six studies including 1921 patients were included, of which most
were cohort studies of mixed quality. The type of ACS exposure,
gestational age at exposure, dose and number of administrations varied
widely. Offspring cardiovascular outcomes were assessed from one day to
36 years postnatally. The most commonly assessed parameter was arterial
blood pressure (18 studies), followed by echocardiography (8 studies),
heart rate (5 studies), electrocardiogram (ECG, 3 studies) and cardiac
magnetic resonance imaging (MRI, 1 study). There were no clinically
significant effects of ACS exposure on offspring blood pressure.
However, there were insufficient studies assessing cardiac structure and
function using echocardiography or cardiac MRI to be able to determine
an effect. Conclusions Administration of ACS is not associated with
long-term effects on blood pressure in exposed human offspring. The
effects on cardiac structure and other measures of cardiac function were
unclear due to the small number of studies, study heterogeneity and
mixed quality. Given the emerging preclinical evidence of harm following
ACS exposure, there is a need for further research to assess central
cardiac function in human offspring exposed to ACS. Keywords: Antenatal
corticosteroids, ACS, cardiovascular, offspring, blood pressure%
\end{abstract}%



\sloppy


\textbf{The Effect of Antenatal Corticosteroid Use on Offspring
Cardiovascular Function: A Systematic Review}

\textbf{Short title: Antenatal Corticosteroids Cardiovascular Effects}

Manuscript word count: 2583

Table count: 3

Figure count: 3

Supplementary information: 0

Adalina Sacco MD MRCOG\textsuperscript{1,2*}, Emily Cornish BA
BMBCh\textsuperscript{1}, Neil Marlow DM FMedSci\textsuperscript{1},
Anna L David PhD FRCOG\textsuperscript{1,2}, Dino A. Giussani PhD ScD
FRCOG\textsuperscript{3-6}

\textsuperscript{1} Elizabeth Garrett Anderson Institute for Women's
Health, University College London, London, UK

\textsuperscript{2} Fetal Medicine Unit, University College London
Hospitals, London, UK

\textsuperscript{3}Department of Physiology, Development and
Neuroscience, University of Cambridge, Cambridge, UK

\textsuperscript{4}Centre for Trophoblast Research, University of
Cambridge, UK

\textsuperscript{5}Cambridge BHF Centre for Research Excellence,
University of Cambridge, UK

\textsuperscript{6}Cambridge Strategic Research Initiative in
Reproduction, University of Cambridge, UK

\textsuperscript{*}a.sacco@ucl.ac.uk

Fetal Medicine Unit, 1\textsuperscript{st} Floor, Elizabeth Garrett
Anderson Wing, 25 Grafton Way, London WC1E 6DB. Tel: 02034476163

\emph{Abstract}

\emph{Background}

Antenatal corticosteroids (ACS) are recommended in threatened preterm
labour to improve short term neonatal outcome. Preclinical animal
studies suggest detrimental effects of ACS exposure on offspring cardiac
development; their effects in humans are unknown.

\emph{Objectives}

To systematically review the human clinical literature to determine the
effects of ACS on offspring cardiovascular function.

\emph{Search strategy and selection criteria}

A systematic review was performed according to PRISMA guidelines in
MEDLINE, EMBASE and Cochrane databases. Offspring who had been exposed
to ACS during fetal life in comparison to those not receiving steroids,
those receiving a placebo or population data were included. Studies not
performed in humans or which did not assess cardiovascular function were
excluded.

\emph{Data collection and analysis}

Two authors independently screened studies, extracted data and assessed
quality of studies. Results were combined descriptively and analysed
using a standardised Excel form.

\emph{Main results}

Twenty-six studies including 1921 patients were included, of which most
were cohort studies of mixed quality. The type of ACS exposure,
gestational age at exposure, dose and number of administrations varied
widely. Offspring cardiovascular outcomes were assessed from one day to
36 years postnatally. The most commonly assessed parameter was arterial
blood pressure (18 studies), followed by echocardiography (8 studies),
heart rate (5 studies), electrocardiogram (ECG, 3 studies) and cardiac
magnetic resonance imaging (MRI, 1 study). There were no clinically
significant effects of ACS exposure on offspring blood pressure.
However, there were insufficient studies assessing cardiac structure and
function using echocardiography or cardiac MRI to be able to determine
an effect.

\emph{Conclusions}

Administration of ACS is not associated with long-term effects on blood
pressure in exposed human offspring. The effects on cardiac structure
and other measures of cardiac function were unclear due to the small
number of studies, study heterogeneity and mixed quality. Given the
emerging preclinical evidence of harm following ACS exposure, there is a
need for further research to assess central cardiac function in human
offspring exposed to ACS.

\emph{Funding}

ALD is supported by the National Institute for Health Research
University College London Hospitals Biomedical Research Centre.

\emph{Keywords:}

Antenatal corticosteroids, ACS, cardiovascular, offspring, blood
pressure

\emph{Tweetable abstract:}

Exposure to antenatal corticosteroids does not have long-term effects on
blood pressure.

\textbf{Introduction}

Over the last 40 years, the administration of antenatal corticosteroids
(ACS) has become routine practice in mothers with threatened preterm
labour between 24 and 34 weeks of gestation\textsuperscript{1}. In this
circumstance, they are proven to reduce short-term neonatal morbidity -
especially that caused by respiratory distress syndrome,
intraventricular haemorrhage, necrotising enterocolitis and sepsis - and
mortality\textsuperscript{2} \textsuperscript{3}. Prophylactic treatment
with ACS is designed to mimic the maturational effects of the normal
endogenous, prepartum increase in fetal plasma cortisol concentration
that occurs close to term in humans and other
species\textsuperscript{4}. Glucocorticoids are known to switch tissue
accretion to differentiation. Therefore, ACS accelerate maturation of
many fetal organs and systems, enhancing the preterm baby's successful
transition to neonatal life\textsuperscript{4} \textsuperscript{5}.

Despite clear life-saving benefits of ACS, there is increasing awareness
of possible adverse off-target effects\textsuperscript{56}
\textsuperscript{7}. A systematic review in humans showed improved major
neurodevelopmental outcomes (e.g. lower rates of cerebral palsy) in
children exposed to ACS\textsuperscript{8}, but a large amount of animal
data have suggested an association between ACS administration and a
range of neuro-anatomical and neuro-behavioural changes
\textsuperscript{7} \textsuperscript{9} \textsuperscript{10}. The
developing cardiovascular system is also affected by glucocorticoid
signalling. Preclinical animal studies have suggested that ACS may have
long-term adverse effects on the heart and the
circulation\textsuperscript{5} \textsuperscript{6} \textsuperscript{711}
but much less is known about cardiovascular consequences of ACS exposure
in humans. Therefore, the aim of this study was to systematically review
the human clinical literature to determine the effects of ACS on
offspring cardiovascular function.

\textbf{Methods}

\emph{Protocol and Registration}

This systematic review was conducted in accordance with the Preferred
Reporting Items for Systematic reviews and Meta-analyses (PRISMA)
guidance\textsuperscript{12}. The protocol was registered with the
International Prospective Register of Systematic Reviews
(PROSPERO-CRD42020178521).

\emph{Eligibility criteria}

Eligible studies were those in which cardiovascular function had been
assessed in humans who had been exposed to ACS during fetal life in
comparison to those not receiving steroids, those receiving a placebo or
population data. Studies not performed in humans or which did not assess
cardiovascular function were excluded. Randomised trials and
observational studies (cohort and case-control) were included, as were
case series with n[?]3. There is no accepted numerical definition of a
case series\textsuperscript{13}. We used an empirical cut-off of at
least three cases however, because of the risk of publication bias with
individual case reports. Systematic and narrative reviews were excluded
after checking reference lists for primary studies. Publications from
1990 to January 2021 were considered eligible and no language
restrictions were applied.

\emph{Search strategy}

A systematic review was conducted in MEDLINE, EMBASE and Cochrane
databases using a combination of Medical Subject Headings (MeSH) and
free text as follows:

antenatal corticosteroid OR antenatal glucocorticoid OR antenatal
steroid OR prenatal steroid OR dexamethasone OR betamethasone

AND

cardiovascular OR heart OR echocardiography OR blood pressure

Subsequently, a grey literature (first 100 hits in Google Scholar and
Pubmed) search was performed, and reference lists of relevant review
articles were manually checked. Forward citation searching was also
performed, whereby key papers identified were located in Web of Science
to identify other work where they may have subsequently been cited;
references of these papers were also checked. Covidence software
(Veritas Health Innovation Ltd, Melbourne, Australia) was used to
eliminate duplicate articles and manage study screening.

\emph{Study selection}

Two authors (A.S. and E.C.) independently screened all studies by title
and abstract and subsequently assessed full-text articles. Disagreements
were resolved by consensus.

\emph{Data extraction}

Two authors (A.S. and E.C.) independently extracted data from all
studies and entered them into a standardised Excel (Microsoft,
Washington, USA) form. Data which did not match were discussed, and the
study was reviewed to reach a consensus.

\emph{Quality assessment of studies}

Two authors (A.S. and E.C.) assessed study quality and risk of bias
independently using a standardised Excel form. Randomised trials were
analysed using the Cochrane Collaboration's tool\textsuperscript{14} for
assessing risk of bias. Case-control and cohort studies were analysed
using the Newcastle-Ottawa scale\textsuperscript{15} for assessing the
quality of non-randomised studies. An adaptation of the Murad
tool\textsuperscript{16} was used for case series.

\emph{Statistics}

Results were combined descriptively and analysed using a standardised
Excel form. Due to the anticipated rarity of studies and heterogeneity
of parameters investigated, meta-analysis was not planned.\emph{}

\textbf{Results}

\emph{Study selection}

The electronic literature search identified 3938 studies (Figure 1);
search of the grey literature and reference lists identified a further
19 studies. Following import of the literature search results, 1337
studies were immediately removed as duplicates. Screening by title and
abstract of 2620 studies was performed and 2529 studies were excluded as
irrelevant. The full texts of 69 remaining articles were reviewed and 43
studies were excluded as shown in Figure 1. Eventually 26 studies were
included in this systematic review.

\emph{Study characteristics}

Characteristics of included studies are shown in Table 1. The majority
of studies were cohort studies (19/26, 73.1\%); the remainder were
randomised controlled trials (5/26, 19.2\%), case control studies (1/26,
3.8\%) and case series (1/26, 3.8\%). A total of 1921 patients were
described in the included studies.

\emph{Quality assessment}

Quality assessment of included studies is given in Figure 2. The
majority of studies were cohort studies of mixed quality. Case
representativeness, demonstration that cardiac problems were not present
before the intervention, and both duration and completeness of follow up
were all areas of low quality. For randomised trials, there was an
unclear risk of bias for most parameters.

\emph{Antenatal corticosteroid exposure}

The gestational age of maternal ACS administration was not stated in
11/26 studies (42.3\%). The remaining 15 studies reported maternal
administration of ACS between 22-36 weeks of gestation. ACS exposure in
terms of preparation of drug used, dose and number of doses varied
widely between studies (Table 2).

\emph{Age at delivery and testing}

The gestational age at delivery was given as a range in most studies.
Combining all studies gave a range of gestational age at delivery of
23-41 weeks for patients described. The age at which cardiovascular
testing was undertaken ranged from 1 day old to 36 years (Figure 3).

\emph{Types of cardiovascular test}

Figure 3 shows the types of cardiovascular test undertaken according to
age of participants at follow-up. Blood pressure (either peripheral or
central) was assessed in eighteen studies, echocardiography in eight
studies, heart rate in five studies, electrocardiogram (ECG) in three
studies and cardiac magnetic resonance imaging (MRI) in one study.
Several studies assessed more than one outcome measure and/or determined
outcome measures at more than one time point.

\emph{Blood pressure (BP)}

Peripheral blood pressure in offspring exposed to ACS was assessed in
eighteen studies \textsuperscript{17} \textsuperscript{1819}
\textsuperscript{20} \textsuperscript{2122} \textsuperscript{23}
\textsuperscript{2425} \textsuperscript{26} \textsuperscript{2728}
\textsuperscript{29} \textsuperscript{3031} \textsuperscript{32}
\textsuperscript{3334}. Three of the eighteen studies also assessed
central blood pressure \textsuperscript{29} \textsuperscript{3132}. The
findings of these studies are shown in Table 3. Twelve studies found no
difference in blood pressure (peripheral or central, systolic or
diastolic) between offspring exposed to ACS and controls. Six studies
showed an increase in mean arterial pressure (MAP) in offspring exposed
to ACS compared to controls \textsuperscript{1719} \textsuperscript{22}
\textsuperscript{2830} \textsuperscript{31}. These studies were all
performed in the early neonatal period, and they reported that an
increase in the MAP of the infant which the authors either reported was
either clinically beneficial (reducing the need for vasopressor BP
support) or the authors reported was clinically irrelevant (a small
change which did not persist).

\emph{Echocardiography}

Offspring echocardiography following ACS exposure was assessed in eight
studies. Five of these studies assessed only the presence or absence of
patent ductus arteriosus (PDA) - three found no difference in offspring
exposed to ACS compared to controls \textsuperscript{3530}
\textsuperscript{31}, and two found that the incidence of PDA was
reduced in infants who had been exposed to ACS at specific time points
or in subgroup analyses \textsuperscript{3637}. The remaining three
studies assessed cardiac structure and function using a wide range of
echocardiographic parameters. Two of these studies found no difference
between offspring exposed to ACS and controls \textsuperscript{18}
\textsuperscript{24}. One showed transient hypertrophic cardiomyopathy
in neonates exposed to multiple ACS doses when comparing
echocardiographic parameters to population norms \textsuperscript{38}.

\emph{Heart rate}

Five studies determined changes in offspring heart rate following ACS
exposure. Three of these studies showed no difference in heart rate
between ACS exposure and controls \textsuperscript{1824}
\textsuperscript{39}. Two studies found an increase in heart rate in ACS
exposed infants - one found that in the first 72 hours after birth,
unexposed infants had lower mean peak heart rate than those were exposed
to ACS, which the authors describe as clinically irrelevant
\textsuperscript{19}. The other study showed that infants exposed to ACS
had a higher heart rate response to a stress test (heel prick) than
those who had not been exposed ACS \textsuperscript{40}.

\emph{ECG}

ECG was assessed in three studies. Two studies showed no difference in
ECG parameters (respiratory sinus arrhythmia and heart rate variability)
between offspring exposed to ACS and those who were not
exposed\textsuperscript{41} \textsuperscript{39}. One study showed in
subgroup analysis that non-black offspring exposed to ACS had lower
heart rate variability than those not exposed \textsuperscript{42}. This
effect was greater in non-black females compared to non-black males, and
no difference was found in black offspring.

\emph{Cardiac MRI}

One study assessed cardiac MRI \textsuperscript{29}. This showed an
increase in aortic arch stiffness (decreased aortic arch distensibility
and increased aortic arch pulse wave velocity) in offspring exposed to
ACS compared to controls. Exposure to ACS was associated with a
localised increase in aortic arch stiffness, similar in magnitude to
term-born individuals a decade older\textsuperscript{29}.

\emph{}

\textbf{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
PDA\textsuperscript{30 31 35 36 37}, while the other three studies
explored central cardiac function \textsuperscript{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
norms\textsuperscript{38}. 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
ACS\textsuperscript{18}. 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
ACS\textsuperscript{24}. 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
ACS\textsuperscript{29}. This study reported that \emph{in
utero}exposure 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
newborns\textsuperscript{43}. 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
recommended\textsuperscript{44}. 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 \textsuperscript{5} \textsuperscript{6} \textsuperscript{745}
\textsuperscript{46} \textsuperscript{4748} \textsuperscript{49}
\textsuperscript{5051} \textsuperscript{52} \textsuperscript{5354}
\textsuperscript{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
hypertrophy\textsuperscript{5} \textsuperscript{6} \textsuperscript{745}
\textsuperscript{46} \textsuperscript{4748} \textsuperscript{49}
\textsuperscript{5051} \textsuperscript{52} \textsuperscript{5354}
\textsuperscript{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.

\textbf{Conclusion}

This systematic review found that administration of ACS is not
associated with long-term effects on blood pressure in exposed human
offspring. The effects on cardiac structure and other measures of
cardiac function were unclear due to study heterogeneity mixed quality.
Given the widespread use of ACS and the emerging preclinical evidence
that ACS exposure compromises cardiac development, ascertaining their
potential direct long-term effects on cardiovascular structure and
function in exposed children should be a clinical priority going
forward. We would therefore recommend further clinical research on the
effects of ACS specifically on cardiac function in children both born
preterm and at term.



\textbf{Acknowledgments, Sources of Funding, \& Disclosures}

\emph{Contribution}

AS, DG, AD and NM conceived and planned the study. AS and EC performed
searches, screening, data extraction and quality analysis. All authors
contributed to writing and editing the manuscript.

\emph{Sources of Funding}

ALD is supported by the National Institute for Health Research
University College London Hospitals Biomedical Research Centre.

\emph{Disclosures}

None

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