Materials and Methods
This systematic review and NMA was performed according to the PRISMA
statement10. This review was registered on the
PROSPERO database (CRD42020204486). The research question was “Which
interventions for preventing preterm birth improve the gestational age
at birth in women with twin gestation regarding cervical length?”.
We performed a Systematic Review of randomized clinical trials searching
for studies on PubMed, MEDLINE, Cochrane Library, EMBASE, Web of
Science, BVS, Scopus, and grey literature in May 2022. The search
strategy used a combination of specific terms using Boolean connectors
for each database with no exclusion criteria regarding period or
language. The basic search strategy was composed by the following:
“twin” OR “multiple gestation” OR “multiple
pregnancy” AND “progesterone” OR “cervical
cerclage” OR “pessary” OR “hydroxyprogesterone”. (Complete
search strategy is available in Appendix 1).
We included randomized controlled trials comparing intervention
treatment (progesterone, cerclage or pessary) with a control group or
another intervention to prevent spontaneous preterm delivery in women
with a twin pregnancy and a short cervix. Short cervical length was
defined as a cervical length lower than 40mm11.
The primary outcome was spontaneous preterm birth (sPTB) <34
weeks. Secondary outcome was PTB<34 weeks from any cause.
We included studies reporting on natural or 17-alpha hydroxyprogesterone
caproate with any administration route (oral, rectal, vaginal and
intramuscular), cervical cerclage (McDonald or Shirodkar) and cervical
pessary. We also included studies in which women received a combination
of these interventions. The comparison group could have received a
different treatment strategy, placebo or standard treatment. We excluded
studies if they reported on women with preterm labor or previously
threatened preterm labor, interventions for preterm premature rupture of
membranes and treatment for women with cervical dilatation. No language
restrictions were considered. If needed we contacted the authors to
obtain additional data not presented in the papers.
Studies´ references were
imported to the Endnote web reference manager, and duplicates were
excluded. Two authors (TV and ABP) evaluated titles and abstracts from
the selected papers. If there were conflicting decisions, a third author
(RCP) makes the final decision. Finally, two authors (TV and ABP)
independently accessed the full texts of potentially eligible articles,
retrieved and reviewed studies for eligibility. A third author evaluated
any conflicted decision. All excluded articles after full-text analysis
were described according to the reason why they were excluded. The
included articles were submitted to a quality assessment using RoB2
tool12 and we considered risk of bias if the study
presented two or more concerns in the components. We assessed integrity
using a screening checklist to assess data integrity of Randomized
Clinical Trials13.
Descriptive statistical analyses were performed using Stata 17.0 and
overall confidence in the results of NMA were assessed using the CINeMA
tool14.
We performed
random-effect NMA to synthesize evidence from the entire network by
integrating direct and indirect estimates for each intervention into a
single summary effect, using the statistical package ‘network’ in Stata,
version 17.0. League tables with summary relative effect sizes (Odds
Ratios) for each possible pair of interventions were presented. We used
the surface under the cumulative ranking curves (SUCRA) to rank all
interventions. We assessed global inconsistency by using a
design-by-treatment interaction model and local inconsistency through
the side-splitting approach.