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\begin{document}

\title{Dexamethasone vs. betamethasone for preterm birth: a systematic review
and network meta-analysis}



\author[1]{Agustín Ciapponi}%
\author[1]{Karen Klein}%
\author[1]{Daniela Colaci}%
\author[2]{Fernando Althabe}%
\author[1]{J. M. Belizan}%
\author[3]{Allie  Deegan}%
\author[4]{Areti Veroniki}%
\author[5,6]{Iván   Flórez}%
\affil[1]{1.	Instituto de Efectividad Clínica y Sanitaria (IECS-CONICET)}%
\affil[2]{World Health Organization}%
\affil[3]{New York University College of Global Public Health}%
\affil[4]{University of Ioannina}%
\affil[5]{University of Antioquia}%
\affil[6]{McMaster University Faculty of Health Sciences}%


\vspace{-1em}



  
  \date{May 05, 2024}


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\selectlanguage{english}
\begin{abstract}
Objective To compare the effectiveness and safety of dexamethasone
versus betamethasone for preterm birth (registered in PROSPERO
CRD42017078006). Search strategy We searched in MEDLINE, EMBASE,
Cochrane Library, LILACS, Clinical Trials.gov, International Clinical
Trials Registry Platform, reference lists and contacted field experts.
Selection criteria, data collection and analysis Randomized controlled
trials comparing any corticosteroids against each other or against
placebo. Three researchers independently selected, extracted data and
assessed the risk of bias of the included studies by using EROS and
COVIDENCE software. We performed a pairwise meta-analysis and Bayesian
network meta-analysis. Main results We included 45 trials (11227 women,
11878 infants). There was no important difference between
corticosteroids in neonatal death (odds ratio{[}OR{]} 1.05; 95\%
confidence interval 0.62-1.84; moderate-certainty evidence{[}CE{]}),
neurodevelopmental disability (OR 1.03; 0.80-1.33; moderate-CE),
intraventricular haemorrhage (OR 1.04; 0.56-1.78); low-CE) and
birthweight (+5.29 gr; -49.79 to 58.97; high-CE). Compared with
betamethasone, dexamethasone may reduce chorioamnionitis (OR 0.70;
0.45-1.06; moderate-CE), foetal death (OR 0.81; 0.24-2.41; low-CE) while
may increase puerperal sepsis (OR 2.04; 0.72-6.06; low-CE) and
respiratory distress syndrome (OR 1.34; 0.96-2.11; moderate-CE),
however, the confidence interval indicates both beneficial and
detrimental effects. Conclusions We found no important difference on
neonatal death, neurodevelopmental disability, intraventricular
haemorrhage and birthweight between corticosteroids. Compared with
betamethasone, dexamethasone may reduce chorioamnionitis and foetal
death, but may increase endometritis/puerperal sepsis and respiratory
distress syndrome. Further research is warranted to improve the
certainty of evidence. Keywords preterm birth, antenatal
corticosteroids, dexamethasone, betamethasone, systematic review,
network meta-analysis%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Preterm birth (less than 37 weeks' gestation) accounts for around 11\%
of all live births worldwide, poses risks of adverse outcomes and can be
attributed 35\% of deaths among newborns.\textsuperscript{1-3} Preterm
birth represents a significant health burden worldwide, mainly in
Low-to-Middle-Income Countries (LMICs).

Respiratory distress Syndrome (RDS) is a serious complication of preterm
birth and the primary cause of early neonatal death, lifelong disability
and poor quality of life. RDS affects up to half of babies born before
28 weeks and a third of babies born before 32 weeks.\textsuperscript{4}
Antenatal corticosteroids for preterm birth prevent RDS and neonatal
mortality\textsuperscript{5}, however there still persist doubts about
the applicability in LMICs\textsuperscript{6} and there is no consensus
regarding the type of corticosteroid to use; nor the dose, frequency,
timing of use or the route of administration. Currently, either
betamethasone or dexamethasone are the recommended corticosteroid for
clinical practice. The World Health Organization (WHO)
guidelines\textsuperscript{7} states that there is no conclusive
evidence that would support a recommendation of one over the other. We
acknowledged that dexamethasone has an advantage over betamethasone in
terms of lower cost and wider availability, and it is currently listed
on the WHO Essential Medicine List and in WHO's Managing complications
in pregnancy and childbirth guide.\textsuperscript{8}

Two Cochrane systematic reviews have synthesized the effects of
corticosteroids. Brownfoot et al. 2013\textsuperscript{9} and Roberts et
al. 2017\textsuperscript{10}, which compared any corticosteroids for
preterm birth against each other, or against placebo, respectively.
Although Brownfoot et al.\textsuperscript{9} focused on direct
comparisons, authors also assessed indirect comparisons of
corticosteroids with placebo for some outcomes based on Roberts
2006\textsuperscript{11}. While the indirect estimates suggest no
significant differences between corticosteroids for puerperal sepsis, a
significant difference favoured betamethasone for
chorioamnionitis.\textsuperscript{11}

Direct comparisons in Brownfoot 2013\textsuperscript{9} showed that
dexamethasone may have some benefits compared to betamethasone such as
less intraventricular haemorrhage. Roberts 2017\textsuperscript{10}
suggested that dexamethasone may also be associated with a higher rate
of chorioamnionitis. New additional published
trials\textsuperscript{12-14}, that almost doubled the previous number
of participants involved in direct comparisons, warranted a network
meta-analysis (NMA), to urgently define this hot topic. Our aim was to
assess the comparative clinical effectiveness and safety of
dexamethasone versus betamethasone for women at risk of preterm birth.

\textbf{METHODS}

We reported the study according to the PRISMA extension statement for
NMA.\textsuperscript{15} The study protocol, registered in PROSPERO
(CRD42017078006), contains method details.

\textbf{Search strategy}

We conducted a literature search~strategy without language
restriction.~We updated the exhaustive searches of the previous Cochrane
reviews\textsuperscript{9,10}from the oldest search date reported in
Brownfoot~2013\textsuperscript{9}(February 13, 2013)~until October 2019,
in~PubMed MEDLINE, EMBASE,~LILACS,~ Cochrane Library, Clinical
Trials.gov and the International Clinical Trials Registry Platform
(ICTRP) for ongoing trials~search.~The MeSH search terms included
premature~birth, betamethasone, dexamethasone and glucocorticoids (Full
search strategy in \textbf{Appendix S1} ). We~also~searched~references
of included studies and~contacted~experts for additional evidence.

\textbf{Study selection and data collection}

We included published or unpublished randomized controlled trials (RCT)
or quasi-RCT~that included~women at risk of preterm birth (before 37
weeks),~and~comparing any corticosteroids against each other or against
placebo regardless the~dose or schedule.

The primary outcomes for the mother (however defined by study authors)
were chorioamnionitis and endometritis/puerperal sepsis, for the
foetus/neonate were neonatal death and RDS and for the child
neurodevelopmental disability at two years follow-up (blindness,
deafness, moderate/severe cerebral palsy, or development
delay/intellectual impairment\textsuperscript{16}.

The secondary outcomes were: maternal death; perinatal death; foetal
death; chronic lung disease; intraventricular haemorrhage; mean
birthweight; and low birth weight.

Three authors (KK, DC, AC) independently screened~titles and abstracts
and reviewed the full-texts of the potentially eligible studies by using
EROS\textsuperscript{17} and COVIDENCE\textsuperscript{18} software, and
independently extracted data into a pre-piloted data extraction form
including~the RoB of using the Cochrane tool\textsuperscript{6}.~~We
classified a summary RoB for each study as high risk if at least one
domain~is classified~as high risk and the others as low/moderate risk.

\textbf{Data synthesis and statistical analysis}

We conducted the statistical analyses in accordance with Cochrane
guidelines.\textsuperscript{19}

We estimated odds ratio (OR) for dichotomous outcomes and mean
difference (MD) for continuous outcomes, along with their 95\%
confidence intervals (CI) trough pairwise meta-analysis for direct
comparisons. Heterogeneity was quantified with the
I\textsuperscript{2}statistic\textsuperscript{20} (30-60\% was
considered 'moderate' heterogeneity). We used a random-effects model and
tested subgroup differences (P\textless{} 0.05 or I\selectlanguage{ngerman}² \textgreater{}
30\%).

We performed a Bayesian random-effects NMA to estimate treatment effects
and 95\% credible intervals (CrI), if the between-study homogeneity,
transitivity and coherence assumption across treatment comparisons were
judged to be justifiable.\textsuperscript{21,22,23,24}We explored the
network geometry and connectivity using network diagrams.

We assessed the statistical heterogeneity of the entire network by the
heterogeneity variance (\selectlanguage{greek}τ\selectlanguage{english}\textsuperscript{2}) considering the empirical
distribution.\textsuperscript{25}

Our~prespecified~subgroup analyses~included gestational age at trial
entry (24-28~, 29-34~, 35-37 weeks);~intact vs ruptured membranes~and
country~income level:~LMIC vs HIC\textsuperscript{26}. We
performed~sensitivity analysis by low-moderate~overall quality of the
studies and by using masked treatments.~ We performed network
meta-regression based on gestational age~at~entry, GNI per capita and
the year of publication.

We assessed small-study effects and publication
bias,\textsuperscript{27} We estimated SUCRA values with their
CrIs\textsuperscript{28,29}in a rank-heat plot.\textsuperscript{30}NMA
were conducted in OpenBugs (version 3.2.3)\textsuperscript{31} and
pairwise meta-analysis in RevMan 5.3.\textsuperscript{32}.

We assessed the confidence in the estimates by outcome using the GRADE
approach and specific criteria for intransitivity (based on potential
effect modifiers) and incoherence (based on the statistical
consistency).\textsuperscript{33,34}Two authors (AC, IDF) independently
graded the certainty of the evidence (CE), and differences were resolved
by consensus.

Additionally, we conducted a focus group to reflect patients'
perspectives in the discussion (\textbf{Appendix S3} ).

\textbf{RESULTS}

We identified 765 records after removing duplicates, and we finally
included 45 RCTs\textsuperscript{12-14, 35-76} involving 11,227 women
and 11,878 infants (\textbf{Figure 1} ). Thirteen RCTs compared
dexamethasone vs. betamethasone (2,903 women and 3,170 infants) and 32
compared corticosteroids vs. placebo/no treatment (8,324 women and 8,708
infants). In addition to the 12
trials\textsuperscript{28,29,31,32,39,44,47,48,54,56,59,62}included by
Brownfoot 2013\textsuperscript{9} and the
30\textsuperscript{21-27,30,33-38,40-43,45,46,49-53,55,57,58,60,61}included
by Roberts 2017\textsuperscript{10}, we included three additional
ones\textsuperscript{12-14} (1,896 women and 2,059 infants) and we
identified four ongoing trials\textsuperscript{6,77-79}.

\textbf{Characteristics of included, excluded and ongoing studies}

The included trials had heterogeneous characteristics and intervention
schemes. The most common doses used were 24 mg of dexamethasone and
betamethasone (\textbf{Appendix S2} : \textbf{Table S2.1} ,\textbf{S2.2}
). The studies were published between 1972 and 2019. Sixteen studies
were conducted in the USA, four in Iran, and two studies each were
conducted in United Kingdom, the Netherlands, Finland, France, Israel
and Brazil. Most studies were conducted in HICs (37), five in upper MICs
and only three in lower MICs (median GNI per capita was 20,170 USD). The
sample size varied from 18 to 2,831 women (median 118 women). Membranes
were intact, ruptured and mixed (both intact and ruptured) in 7, 12 and
26 studies, respectively. Regarding the recruitment gestational age, 30
RCTs set 23-28 weeks as the lower limit and 33 studies set 34-37 weeks
as the upper limit (median gestational age 30.44 weeks).

\textbf{Table S2.3} describes the ongoing studies'
characteristics,\textsuperscript{6,77-79}and \textbf{Table S2.4} the
reason of excluded studies initially included by
full-text\textsuperscript{80-82}).

\textbf{Risk of bias assessment of included studies}

Global RoB was considered low in 21 studies (47\%), 58\% for random
sequence generation, 38\% for allocation concealment, 49\% for blinding
of participants and personnel, 33\% for blinding of outcome assessment,
56\% for incomplete outcome data, 69\% for selective reporting and 36\%
for other bias (\textbf{Appendix S4: Risk of bias figures and tables} ).

\textbf{NMA results: dexamethasone vs. betamethasone}

The geometry of the treatment networkis presented in \textbf{Figure 2} ,
and the direct, indirect and NMA (mixed) effect estimations for the main
eight outcomes of the comparison dexamethasone vs. betamethasone are
presented in \textbf{Figure 3} and \textbf{Table 1} of Summary of
finding. We also present in the \textbf{Appendix S5} the direct
comparison forest-plots, in \textbf{Appendix S6} the summary of finding
tables of each corticosteroid vs. control, in \textbf{Appendix S7} the
pairwise meta-analysis forest-plots by type of corticosteroid against
placebo and in \textbf{Appendix S8} the NMA outputs and SUCRA values.

\textbf{-Chorioamnionitis} (6,698 patients, 15 studies)

Compared with placebo/no treatment (control), dexamethasone probably
increases chorioamnionitis but in one side of the confidence interval
could also reduce it: OR 1.46 (95\%CI 0.81-2.66). On the contrary
betamethasone reduces chorioamnionitis: OR 0.63 (95\%CI 0.41-0.95). The
test for subgroup differences by corticosteroid type showed this
disparity (P= 0.010, I\selectlanguage{ngerman}² 84.2\%).

Compared with betamethasone, dexamethasone probably reduces
chorioamnionitis but in one side of the CrI is slightly
detrimental:\textbf{OR 0.70} (95\%CrI 0.45-1.06), \textbf{moderate-CE} .
We found serious incoherence between direct and indirect evidence (Ratio
of OR {[}ROR{]} 3.18 {[}95\%CI 1.26-8.02{]}).

\textbf{-Endometritis/puerperal sepsis} (4,030 patients, 10 studies)

Dexamethasone may increase endometritis/puerperal sepsis and
betamethasone probably have little or no effect against control: OR 1.93
(95\%CI 0.8534.41) and 0.94 (95\%CI 0.47-1.87), respectively (Test for
subgroup differences suggest disparities; P: 0.16, I² 49.8\%).

There was no report of direct evidence regarding this outcome. Indirect
evidence suggest that compared with betamethasone, dexamethasone may
increase endometritis/puerperal sepsis, but in one side of the CrI is
protective: \textbf{OR 2.04} (95\%CrI 0.72-6.06), \textbf{low-CE} .

\textbf{-Neonatal Death} (8697 patients, 23 studies)

Both dexamethasone and betamethasone reduce neonatal death against
control: OR 0.60 (95\%CI 0.37-0.94) and OR 0.57 (95\%CI 0.39-0.80),
respectively (Test for subgroup differences shows no disparity; P: 0.81,
I² 0\%). We found no incoherence; ROR 1.15 (95\%CI 0.44-2.96), therefore
we considered the NMA evidence the most reliable estimation. Compared
with betamethasone, dexamethasone probably has no effect on neonatal
death, but the CrI is compatible with beneficial or detrimental
effect:\textbf{OR 1.05} (95\%CrI 0.62-1.84), \textbf{moderate-CE} .

\textbf{-Foetal death} (3857 patients, 13 studies)

Dexamethasone may reduce foetal death and betamethasone probably have
little or no effect against control: OR 0.86 (95\%CI 0.32-2.16) and 1.05
(95\%CI 0.58-2.15), respectively (Test for subgroup differences shows no
disparity; P: 0.70, I² 0\%). There was no report of direct evidence
regarding this outcome. Indirect evidence suggest that compared with
betamethasone, dexamethasone may reduce foetal death, but the CrI limits
is compatible with large beneficial or detrimental effect: \textbf{OR
0.81} (95\%CrI 0.24-2.41), \textbf{low-CE} .

\textbf{-Respiratory distress Syndrome} (9784 patients, 30 studies)

Both dexamethasone and betamethasone may reduce neonatal death against
control: OR 0.64 (95\%CI 0.47-0.90) and 0.47 (95\%CI 0.35-0.60),
respectively (Test for subgroup differences suggest disparities; P:
0.11, I² 54.7\%).

We found no serious incoherence; ROR 1.14 (95\%CI 0.71-2.75), therefore
we considered the NMA evidence the most reliable estimation. Compared
with betamethasone, dexamethasone probably increases RDS but the CrI is
compatible with a small protective effect: \textbf{OR 1.38} (95\%CrI
0.96-2.11), \textbf{moderate-CE} .

\textbf{-} \textbf{Neurodevelopmental disability} (2628 patients, 3
studies)

We did not find direct evidence for betamethasone vs. placebo.
Dexamethasone may reduce neurodevelopmental disability against control:
OR 0.39 (95\%CI 0.01-8.08).

Compared with betamethasone, dexamethasone probably has no effect on
neurodevelopmental disability, but the CrI is compatible with large
beneficial or detrimental effect: OR 1.14 (95\%CrI 0.24-13.86). Two of
the included studies had rare events. The frequentist analysis suggested
more precise and reliable estimation an \textbf{OR 1.03} (95\%CI
0.80-1.33), \textbf{moderate-CE} .

\textbf{-Intraventricular haemorrhage (IVH)} (7449 patients, 17 studies)

Both dexamethasone and betamethasone reduce IVH: OR 0.473 (95\%CI
0.281-0.738) and 0.381 (95\%CI 0.191-0.668), respectively (Test for
subgroup differences shows no disparity; P: 0.88, I² 0\%).

We found no serious incoherence; ROR 1.54 (95\%CI 0.57-4.16). The NMA
evidence suggested that compared with betamethasone, dexamethasone may
reduce IVH but the CrI is compatible with beneficial or detrimental
effect: OR 0.812 (95\%CrI 0.420-1.427), low-CE. However, we found mild
heterogeneity (I\textsuperscript{2} 31\%) and important subgroup
differences by corticosteroid type (I² 63.5\%).

Considering the very high risk of attrition bias (43\% of non-analysed
infants), the unique marked effect favouring dexamethasone of the study
Elimian 2007\textsuperscript{46} and the incoherence that this study had
generated, we performed a post-hoc sensitivity analysis excluding it.
Both the heterogeneity and subgroup differences changed to an I² of 0\%.
The new estimation, still\textbf{low-CE} , \textbf{OR 1.04} (95\%CrI
0.56-1.78) was more consistent with the indirect evidence (ROR 1.14
(95\%CI 0.51-2.57) and therefore we considered it as the most reliable
estimation (forest-plots in \textbf{Appendix S5} ).

\textbf{-Mean birthweight} (8645 patients, 23 studies)

Both dexamethasone and betamethasone have no effect on birthweight
against control: MD -17.04gr (95\%CI -75.48; 41.41) and -9.74 gr.
(95\%CI -43.11; 23.63), respectively (Test for subgroup differences
shows no disparity; P: 0.80, I² 0\%). We found no serious incoherence;
ROR 1.15 (95\%CI 0.44-2.96) and both direct and indirect evidence were
considered as high certainty evidence, therefore we considered the NMA
evidence the most reliable estimation. Dexamethasone has no effect mean
birthweight:\textbf{mean difference +} 5.29\textbf{gr} (95\%CrI -49.79,
58.97) \textbf{high-CE} .

\textbf{-Other outcomes}

We did not find direct evidence about low birthweight. May be no
difference between betamethasone vs. control on maternal death: OR 0.98
(95\%CI 0.06-15.90). Dexamethasone and betamethasone probably reduce
perinatal death: OR 0.62 (95\%CI 0.33-1.18) and 0.66 (95\%CI 0.48-0.91),
respectively (Test for subgroup differences shows no disparity; P: 0.86,
I² 0\%). Dexamethasone may increase chronic lung disease and
betamethasone may reduce this outcome, but the 95\%CI is also be
compatible with large beneficial or detrimental effect: OR 1.30 (95\%CI
0.57-2.96) and 0.75 (95\%CI 0.22-2.62), respectively (Test for subgroup
differences shows no disparity; P: 0.47, I² 0\%).

We did not find direct evidence regarding maternal death, perinatal
death, and we found scarce evidence about low birth weight and chronic
lung disease and they were assessed only by pairwise meta-analysis.
Compared with betamethasone, dexamethasone may reduce these outcomes,
however the 95\%CI is compatible with large beneficial or detrimental
effect: OR 0.75 (95\%CI 0.33-1.71, low-CE) and OR 0.92 (95\%CI
0.62-1.37) respectively (forest-plots in \textbf{Appendix S5} ).

Meta-regression did not find statistically significant differences. The
subgroup and sensitivity analysis did not reveal important changes
regarding the main analysis. All the 95\%CI were compatible with
beneficial or detrimental effects (\textbf{Appendix S9} ).

\textbf{DISCUSSION}

\textbf{Main Findings}

Both corticosteroids have proven effective for women at risk of preterm
birth on most neonatal and child relevant outcomes compared with placebo
or no treatment.

We found that compared with betamethasone, dexamethasone may reduce the
rates of chorioamnionitis around 30\% and foetal death 20\%, but may
increase puerperal sepsis 100\% and respiratory distress syndrome 40\%.
Probably, there are no difference in neonatal death and
neurodevelopmental disability and may have no difference in IVH and in
birthweight. Except for neurodevelopmental disability, and birthweight
these effects were imprecise.

\textbf{Strengths and limitations}

Among the strengths of our work we can mention that we followed the
Cochrane guidelines Cochrane\textsuperscript{19}, the PRISMA-NMA
extension\textsuperscript{15}for reporting and we registered the study
protocol in advance. Our work is the most updated and complete
systematic review assessing clinical effectiveness and safety of
corticosteroids. Our exhaustive search strategy, included clinical
trials registries and~contacted~experts for additional relevant
evidence.~Although we did not hand-search conference proceedings it is
unlikely that our search strategy missed RCTs not included in biomedical
databases nor the trials registers.

This NMA added two small trials\textsuperscript{13,14}and one of large
good quality trial that compared directly dexamethasone with
betamethasone\textsuperscript{12} to the body of evidence. It provided
new indirect estimations and increased the precision of the estimations,
still low for most outcomes, by combining direct and indirect evidence.
The prespecified meta-regression, subgroup and sensitivity analyses
reinforced the robustness of our results.

We assessed the certainty of the evidence by the GRADE-NMA
approach\textsuperscript{33,34}, the validity of the transitivity
assumption by comparing the distribution of potential effect modifiers
across comparisons and the coherence assumption by the
design-by-treatment interaction model and loop-specific
approaches.\textsuperscript{22,24}

The results of the NMA were mostly coherent, except for
chorioamnionitis, may be due to differences between populations included
in indirect and direct evidence, and differences in RoB. The indirect
evidence came mostly from mothers with ruptured
membranes\textsuperscript{36,37,41,47,49,51,52,55-57,60,65,67,69,72}while
the direct evidence from a mix of mothers with intact and ruptured
membranes\textsuperscript{12}. However, meta-regression, subgroup and
sensitivity analyses did not explain this incoherence. Therefore, for
chorioamnionitis, following the GRADE approach\textsuperscript{33}, we
considered the direct evidence the most reliable estimation of 23 fewer
cases (43 fewer or 5 more) per 1000 women treated with dexamethasone.

We included studies conducted in a range of 50 years and healthcare
advances, specifically in neonatology, could be an extra-source of
heterogeneity that could partially explain the contradictory direction
of effect for some outcomes, but the effect modifiers or RoB did not
provide a solid explanation of the effects. The contradictory beneficial
or detrimental effect of different outcomes warranted our decision to
explore the patients' perspectives about our findings comparing
corticosteroids trough a focus group (\textbf{Appendix 3).} Briefly,
women failed to make a decision about which corticosteroids they would
choose because the trade-off between risk and benefits were very complex
for them. They agreed that it would be a decision that they would share
or delegate to a professional with whom they established a bond of
trust.

The evidence shows limitations, regarding its generalizability to
lower-resource countries, since only
three\textsuperscript{14,42,47}(7\%) out of the included RCTs were from
lower-MICs and none from LICs. Trials have been largely conducted in
tertiary hospitals and recruited highly selected
populations.\textsuperscript{83} Concerns about safety and efficacy in
low-resource settings were supported by the adverse findings in neonatal
deaths and maternal infection of ACT, a community-based, cluster-RCT
conducted in six LMICs.\textsuperscript{84} However we did not find
important differences by income country classification and by GNI per
capita. Hopefully, the ongoing ACTION study could answer this
question.\textsuperscript{6}

\textbf{Interpretation}

Antenatal corticosteroids for preterm birth have shown to reduce
neonatal morbidity and mortality\textsuperscript{10} are
cost-effective\textsuperscript{85}, and are routinely recommended
worldwide.\textsuperscript{7,86,87}The Cochrane
review,\textsuperscript{10}and our review are aligned with these studies
and recommendations.

The other Cochrane review,\textsuperscript{9} comparing both
corticosteroids, did not include recent evidence. The new trial
ASTEROID\textsuperscript{12}, almost doubled the number of included
women under direct comparisons, provided information for our main
outcomes, improved the precision for neurosensory disability estimates,
and unlike that it was believed it found that dexamethasone may have a
beneficial effect on chorioamnionitis.

The potential beneficial effect of dexamethasone on IVH suggested by
very low-CE, was reduced with the inclusion of the ASTEROID
trial\textsuperscript{12} and completely disappeared when excluding
Elimian 2007.\textsuperscript{46} This post-hoc sensitivity analysis,
based on the very high risk of attrition bias of this study, provided
more consistent results with the indirect evidence. Additionally, a
meta-analyses found an increased risk of neurodevelopmental impairment
in children with periventricular/intraventricular
haemorrhage\textsuperscript{88}, mainly driven by cerebral
palsy\textsuperscript{89}. Since we did not find a differential effect
of dexamethasone on neurosensory disability it would be unlikely a
favourable effect on IVH. Additionally, even if a reduction in IVH was
true, it is more important the observed absence of differences on
long-term disability for the quality of life of
survivors.\textsuperscript{90}

Roberts 2006\textsuperscript{11} assessed indirect estimations favouring
betamethasone for chorioamnionitis. This was consistent with our
indirect estimation but opposite to the ASTEROID
trial\textsuperscript{12} findings that were considered the most
reliable estimation for this outcome.

Our NMA improved the precision and certainty of most previous
estimations. We identified a another NMA that evaluated antenatal
maternal administration dexamethasone, betamethasone and ambroxol to
prevent RDS.\textsuperscript{91} Compared with placebo, all
interventions reduced RDS and neonatal death, but no significant
difference in the incidence of bronchopulmonary dysplasia. They also
suggest that ambroxol seems to be the most effective treatment for
reducing the incidence of RDS and neonatal death based on its SUCRA
values. This conclusion was not consistent with a Cochrane
review\textsuperscript{92} or the relevant preterm birth management
guidelines.\textsuperscript{7,86}

A wise choice should consider all factors besides evidence, including
local availability, costs and cost-utility.\textsuperscript{93,94}A full
course of betamethasone costs around US\$35 while dexamethasone \$1 (3\%
of the cost of betamethasone).\textsuperscript{94} The
cost-effectiveness of the administration of betamethasone based in
individual trials is controversial, and it should be based in the best
estimation of effectiveness.\textsuperscript{95,96}Mainly LMICs still
have significant challenges to provide safe and effective antenatal
corticosteroid use, including ensuring accurate gestational age
determination, establishing clear treatment guidelines, strengthening
provider capacity, incorporating corticosteroid in national essential
medicines lists, and monitoring use and outcomes.\textsuperscript{97}

\textbf{CONCLUSION}

This comprehensive NMA confirmed that corticosteroids were mostly
effective for neonatal and child relevant outcomes compared with placebo
or no treatment. There was no important difference between
corticosteroids on neonatal death, neurodevelopmental disability, IVH
and birthweight. Low to moderate-CE suggest that dexamethasone may
reduce chorioamnionitis, and foetal death but may increase puerperal
sepsis and RDS. However, the 95\%CI indicates both beneficial and
detrimental effects for these outcomes. The opposing direction of these
outcomes does not allow to derive recommendations about what
corticosteroid should be used and large well designed RCTs are warranted
to improve the certainty of evidence. Ideally, they should represent low
resource settings and also evaluate the best schemes of administration.
Individual participant data meta-analysis could help to answer these
questions. In the meantime, monitoring short-term and long-term health
outcomes, including neurodevelopmental disability will be important.

Since there is no robust evidence on which corticosteroid should be
prescribed, decisions should be based on availability, costs,
opportunity, and facilities. Shared decision-making would help patients
to take their choices when facing this scenario.

\textbf{Disclosure of interests}

All authors have completed the ICMJE uniform disclosure form at
www.icmje.org/coi\_disclosure.pdf and declare: no support from any
organisation for the submitted work; no financial relationships with any
organisations that might have an

interest in the submitted work in the previous three years; no other
relationships or activities that could appear to have influenced the
submitted work.

\textbf{Contribution to authorship}

JB, FA and AC conceived the study; AC, FA, JB, IDF, AAV designed the
study;

KK, DC, AD and AC collected and abstracted the data; IDF, AAV undertook
the statistical

analysis; AC, FA, JB, IDF, AAV, KK, AD, DC drafted the manuscript; all
authors had full access to all the data, including statistical reports
and tables; all authors analysed and interpreted the data; all authors
critically revised the manuscript for important intellectual content; AC
is the guarantor.

\textbf{Details of ethics approval}

Not applicable.

\textbf{Funding and competing interest.}

This study received no external funding.

\textbf{Acknowledgments}

We acknowledge Daniel Comandé for his support as librarian and Ioannis
Gallos and Argyro Papadopoulou for their exhaustive revision of the
manuscript.

We also acknowledge the Lic. María Belizán and Lic. Natali Ini for
coordinating and analysing the focus group that explored the women's
perspectives of our findings.

\textbf{Supporting Information}

Additional supporting information may be found online in the Supporting
Information section at the end of the article.

\textbf{Appendix S1} : Search Strategy

\textbf{Appendix S2} : Characteristics of included, ongoing and excluded
studies

\textbf{Table S2.1} Main characteristics of population and setting of
included studies\textbf{Table S2.2} Characteristics of included
studies\textbf{Table S2.3} Characteristics of ongoing
studies\textbf{Table S2.4} Characteristics excluded studies

\textbf{Appendix S3} : Focus group: patients' perspectives

\textbf{Appendix S4} : Risk of bias figures and tables

\textbf{Figure S4.1:} Risk of bias graph by risk of bias item (\% across
all included studies)\textbf{Figure S4.2:} Risk of bias summary by risk
of bias item for each included study

\textbf{Table S4.1} Support for judgement of included studies by risk of
bias item

\textbf{Appendix S5} : Pairwise meta-analysis results for direct
comparison dexamethasone vs. betamethasone forest-plots

\textbf{Appendix S6} : Summary of finding tables of corticosteroid vs.
placebo/no treatment

\textbf{Table S6.1} Summary of finding table: dexamethasone vs.
control\textbf{Table S6.2} Summary of finding table: betamethasone vs.
control

\textbf{Appendix S7} : Pairwise meta-analysis results for direct
comparison corticosteroids vs. placebo/no treatment forest-plots by type
of corticosteroid

\textbf{Appendix S8} : Network meta-analysis outputs

\textbf{Appendix S9} : Meta-regression, subgroup and sensitivity
analysis

\textbf{Appendix S10} : PRISMA NMA Checklist

\textbf{Table/Figure Caption List}

\textbf{Table 1.} Summary of finding table: dexamethasone vs.
betamethasone

\textbf{Figure 1.} Study flowchart

\textbf{Figure 2.} Network composition by outcome

\textbf{Figure 3.} Network and direct forest plot for dexamethasone vs.
betamethasone

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