Strengths and limitations
Among the strengths of our work we can mention that we followed the
Cochrane guidelines
Cochrane19, the
PRISMA-NMA extension15for 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
trials13,14and one of large good quality trial that compared directly dexamethasone
with betamethasone12 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
approach33,34,
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.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
membranes36,37,41,47,49,51,52,55-57,60,65,67,69,72while the direct evidence from a mix of mothers with intact and ruptured
membranes12. However,
meta-regression, subgroup and sensitivity analyses did not explain this
incoherence. Therefore, for
chorioamnionitis, following the GRADE
approach33, 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 (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
three14,42,47(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.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.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.6